HK40004506A - Compounds or pharmacetical salts thereof, as well as uses and pharmceutical compositions thereof - Google Patents

Description

Compound or pharmaceutically acceptable salt thereof, application and pharmaceutical composition thereof

RELATED APPLICATIONS

The application is divided applications of Chinese patent application named as 'sGC stimulant' with two priorities of U.S. prior application with application numbers of 201480027900.3, 2014 03 and 14, and 2013 03 and 15, and U.S. prior application with application numbers of US61/790,637, and 2013 12 and 11, and U.S. prior application with application numbers of US61/914,915.

Technical Field

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations containing the same, and their use, alone or in combination with one or more other agents, for the treatment and/or prevention of various diseases, where an increase in Nitric Oxide (NO) concentration or an increase in cyclic guanosine monophosphate (cGMP) concentration may be desirable.

Background

Soluble guanylate cyclase (sGC) is the major receptor for Nitric Oxide (NO) in vivo. sGC can be activated via NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts GTP to the second messenger cyclic gmp (cgmp). Increased levels of cGMP in turn modulate the activity of downstream effectors, including protein kinases, Phosphodiesterases (PDEs), and ion channels.

In vivo, NO is synthesized from arginine and oxygen by various Nitric Oxide Synthases (NOs) and by successive reductions of inorganic nitrate. Three distinct NOS isoforms have been identified: activating inducible NOS (iNOS or NOS II) found in macrophages; constitutive neuronal NOS (nNOS or NOS I), which is involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure.

Experimental and clinical evidence indicates that decreased bioavailability and/or response to endogenously produced NO contributes to the development of cardiovascular disease, endothelial disease, renal disease, and liver disease, as well as erectile dysfunction and other sexual dysfunction (e.g., female sexual dysfunction or vaginal atrophy). In particular, the NO signalling pathway is altered in cardiovascular diseases including, for example, systemic and pulmonary hypertension, heart failure, angina pectoris, stroke, thrombosis and other thromboembolic diseases, peripheral arterial disease, liver, lung or kidney fibrosis, and atherosclerosis.

sGC stimulators are also useful for the treatment of lipid-related conditions such as, for example, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis.

Pulmonary Hypertension (PH) is a disease characterized by a sustained elevation of blood pressure in the pulmonary vasculature (pulmonary arteries, pulmonary veins, and pulmonary capillaries), which leads to right heart hypertrophy, ultimately leading to right heart failure and death. In PH, the bioavailability of NO and other vasodilators such as prostacyclin is reduced, while the production of endogenous vasoconstrictors such as endothelin is increased, resulting in excessive pulmonary vasoconstriction. sGC stimulators have been used to treat PH as they promote smooth muscle relaxation, which causes vasodilation.

Treatment with NO-independent sGC stimulators also promoted smooth muscle relaxation of the corpus cavernosum of healthy rabbits, rats, and humans, causing penile erection, indicating that sGC stimulators can be used to treat erectile dysfunction.

NO-independent, heme-dependent sGC stimulators (such as those disclosed herein) have several important distinguishing features, including a critical dependence on the presence of a reduced prosthetic heme moiety for their activity, a strong synergistic enzymatic activation in combination with NO, and stimulation of synthetic cGMP by direct stimulation of sGC independent of NO. The benzylic indazole compound YC-1 was the first sGC stimulator identified. Since then, other sGC stimulators with improved efficacy and specificity for sGC were developed. These compounds have been shown to produce anti-aggregation, anti-proliferative and vasodilatory effects.

Since compounds that stimulate sGC in an NO-independent manner offer significant advantages over other current alternative therapies, there is a need to develop novel sGC stimulators. It is potentially useful for the prevention, management and treatment of conditions such as: pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis, pulmonary fibrosis, erectile dysfunction, female sexual arousal disorder, and vaginal atrophy, as well as other cardiovascular disorders; it is also potentially useful for the prevention, management and treatment of lipid-related disorders.

Summary of The Invention

The present invention relates to compounds according to formula I', or a pharmaceutically acceptable salt thereof:

wherein X¹Selected from N, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl, and CF;

X²independently selected from N or C;

W

i) is absent, wherein J^BDirectly to a carbon atom bearing two J groups, each J being independently selected from hydrogen or methyl, n is 1 and J^BIs C optionally substituted by up to 9 fluorine_1-7An alkyl chain; wherein optionally said C_1-7one-CH of an alkyl chain₂-units may be replaced by-O-or-S-;

ii) is ring B, which is phenyl or a 5 or 6 membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, O or S; wherein ring B is phenyl or a 5 or 6 membered heteroaryl ring; each J is hydrogen; n is an integer selected from 0 to 3; and each J^BIndependently selected from halogen, -CN, C_1-6Aliphatic radical, -OR^BOr C_3-8A cycloaliphatic group; wherein each of said C_1-6Aliphatic radical and each of said C_3-8Cycloaliphatic radical being optionally and independently substituted by up to 3R³Substitution; each R^BIndependently selected from hydrogen, C_1-6Aliphatic radicals or C_3-8A cycloaliphatic group; wherein is C_1-6Each of said R of the aliphatic radical^BAnd is C_3-8Each of said R of the cycloaliphatic ring^BOptionally and independently up to 3 instances of R^3aSubstitution;

each R³Independently selected from halogen, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl);

each R^3aIndependently selected from halogen, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl);

o is an integer selected from 1 to 3;

each J^DIndependently selected from J^AHalogen, -CN, -NO₂、-OR^D、-SR^D、-C(O)R^D、-C(O)OR^D、-OC(O)R^D、-C(O)N(R^D)₂、-N(R^D)₂、-N(R^d)C(O)R^D、-N(R^d)C(O)OR^D、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂、-SO₂R^D、-SO₂N(R^D)₂、-N(R^d)SO₂R^D、C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^D、C_3-8A cycloaliphatic ring, a 6-to 10-membered aryl ring, a 4-to 8-membered heterocyclic ring, or a 5-to 10-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-to 10-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^DEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8A cycloaliphatic ring, each said 6-to 10-membered aryl ring, each said 4-to 8-membered heterocyclic ring, and each said 5-to 10-membered heteroaryl ring are optionally and independently substituted with up to 5R^5dSubstituted, wherein at least one J^DIs not hydrogen;

J^Aselected from hydrogen, halogen, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a Wherein R is^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring; or wherein R is^aAnd R^bTaken together with the nitrogen atom to which they are both attached to form a 4-8 membered heterocyclic ring, or a 5 membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S; wherein the 4-8 membered heterocycle and the 5-membered heterocycle areEach aryl ring is optionally and independently substituted with up to 6 fluoro;

each R^DIndependently selected from hydrogen, C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^f、C_3-8A cycloaliphatic ring, a 4-to 10-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 10-membered heterocyclic ring and each said 5-to 6-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^fEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 10-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5aSubstitution; wherein when any R is^DIs C_1-6Aliphatic radical or- (C)_1-6Aliphatic radical) -R^fWhen one of the radicals is present, the C is formed_1-6One or two-CH of aliphatic chain₂-the units may optionally be replaced by groups independently selected from: -N (R)^d) -, -CO-or-O-; with the condition that when X is¹Is CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl or CF, X²Is C; and at least one J^Dis-N (R)^D)₂And to one of the ring D carbons ortho to the two nitrogen atoms of the pyrimidine ring D, an example being R^DIs not pyridine or pyrimidine;

each R^dIndependently selected from hydrogen, C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^f、C_3-8A cycloaliphatic ring, a 4-to 8-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^fEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 8-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5bSubstitution(ii) a Wherein when any R is^dIs C_1-6Aliphatic radical or- (C)_1-6Aliphatic radical) -R^fWhen one of the radicals is present, the C is formed_1-6One or two-CH of aliphatic chain₂-the units may optionally be replaced by groups independently selected from: -N (R)^d) -, -CO-or-O-;

each R^fIndependently selected from C_1-3Alkyl radical, C_3-8A cycloaliphatic ring, a 4-to 10-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 10-membered heterocyclic ring and each said 5-to 6-membered heteroaryl ring contains 1 to 4 heteroatoms independently selected from O, N or S; and wherein each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 10-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5cSubstitution;

when J is^Dis-C (O) N (R)^D)₂、-N(R^D)₂、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂or-SO₂N(R^D)₂When the two R are^DGroups and attachment to the two R^DThe nitrogen atoms of a group together may form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein except for the two R^DEach said 4-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 3 additional heteroatoms independently selected from N, O or S, other than the nitrogen atom to which group is attached; and wherein each said 4-to 8-membered heterocycle and each said 5-membered heteroaryl ring are optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)C(O)R^DWhen R is in the above-mentioned range^DGroup and attachment to the R^DCarbon atom of a group, and the group attached to said R^dNitrogen atom of a group and^dgroups may form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein except for said R^dEach of said 4-to 8-membered heterocyclic rings and each of said 5-membered heteroaryl rings optionally contain up to 2 additional heteroatoms independently selected from N, O or S, other than the nitrogen atom to which group is attached;and wherein each said 4-to 8-membered heterocycle and each said 5-membered heteroaryl ring are optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)C(O)OR^DWhen R is in the above-mentioned range^DGroup and attachment to the R^DThe oxygen atom of the group, and the-N (R)^d)C(O)OR^DThe carbon atom of the-C (O) -moiety of group, and the group attached to the R^dThe nitrogen atom of the group and the group R^dThe groups may form a 4 to 8 membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S and is optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)C(O)N(R^D)₂When said R is attached to said nitrogen atom^DOne of the radicals with the nitrogen atom and with the R attached thereto^dThe N atom and the R of a group^dThe groups may form a 4 to 8 membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S and is optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)SO₂R^DWhen R is in the above-mentioned range^DGroup and said R^DThe sulfur atom to which a group is attached, and the R^dThe nitrogen atom to which a group is attached and with the R^dThe groups can combine to form a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S and is optionally and independently substituted with up to 5R⁵Substitution;

each R⁵Independently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶、-OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-C(O)N(R⁶)SO₂R⁶、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂OH、-SO₂NHOH、-SO₂N(R⁶)₂、-SO₂N(R⁶)COOR⁶、-SO₂N(R⁶)C(O)R⁶、-N(R⁶)SO₂R⁶、-(C＝O)NHOR⁶、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring each contain up to 4 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶Part C_1-6Alkyl moiety, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

attached to J^DTwo instances of R of the same or different atoms⁵Optionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; a phenyl or 5 or 6 membered heteroaryl ring,obtaining a bicyclic system wherein the two rings of the bicyclic system are in spiro, fused or bridged relationship; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -CONH₂-OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5aAnd each R^5bIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) R^6a、-OR^6a、-SR^6a、-COR^6a、-OC(O)R^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-C(O)N(R^6a)SO₂R^6a、-N(R^6a)C(O)R^6a、-N(R^6a)C(O)OR^6a、-N(R^6a)C(O)N(R^6a)₂、-N(R^6a)₂、-SO₂R^6a、-SO₂OH、-SO₂NHOH、-SO₂N(R^6a)₂、-SO₂N(R^6a)COOR^6a、-SO₂N(R^6a)C(O)R^6a、-N(R^6a)SO₂R^6a、-(C＝O)NHOR^6a、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl, - (C)_1-6Alkyl) R^6aPart C_1-6Alkyl moiety, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic group contains a ring one and a ring two in a fused or bridged relationship, the ring one being a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the ring two being a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

are respectively attached to R^DOr R^dTwo instances of R of the same or different atoms^5aOr two cases of R^5bOptionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -C (O) NH₂、-NR(CO)O(C_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5cIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R^6b、-OR^6b、-SR^6b、-COR^6b、-OC(O)R^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-C(O)N(R^6b)SO₂R^6b、-N(R^6b)C(O)R^6b、-N(R^6b)C(O)OR^6b、-N(R^6b)C(O)N(R^6b)₂、-N(R^6b)₂、-SO₂R^6b、-SO₂OH、-SO₂NHOH、-SO₂N(R^6b)₂、-SO₂N(R^6b)COOR^6b、-SO₂N(R^6b)C(O)R^6b、-N(R^6b)SO₂R^6b、-(C＝O)NHOR^6b、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring and each said 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R^6bPart C_1-6Alkyl moiety, each of said C_3-8A cycloalkyl ring, each of said 4-to 7-membered heterocyclic rings, each of said 5-or 6-membered heteroaryl rings, each of said benzyl groups, and each of said phenyl groups are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic group contains in a fused or bridged relationship a first ring which is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and a second ring which is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

is attached to R^fTwo instances of R of the same or different atoms^5cOptionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -CONH₂、-NR(CO)O(C_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5dIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶、-OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂OH、-SO₂NHOH、-SO₂N(R⁶)COR⁶、-SO₂N(R⁶)₂、-N(R⁶)SO₂R⁶、C_7-12Aralkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl or an oxo group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl, - (C)_1-6Alkyl) -R⁶Part C_1-6Alkyl moiety, C_7-12Aralkyl radical, C_3-8Each of the cycloalkyl ring, 4-to 7-membered heterocycle, 5-or 6-membered heteroaryl ring, or phenyl is optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(haloalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

attached to J^DTwo instances of R of the same or different atoms^5dWith J attached thereto^DTogether said one or more atoms of (a) may optionally form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -C (O) NH₂-OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-C(O)N(C_1-6Alkyl radical)₂、-C(O)NH(C_1-6Alkyl), -C (O) N (C)_1-6Haloalkyl)₂、-C(O)NH(C_1-6Haloalkyl), C (O) N (C)_1-6Alkyl) (C_1-6Haloalkyl), -COO (C)_1-6Alkyl), -COO (C)_1-6Haloalkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S; wherein

Is linked to R⁵Or R^5dTwo examples of the same nitrogen atom of R⁶Are each independently of R⁵Or R^5dTogether said nitrogen atoms of (a) may form a 5-to 8-membered heterocyclic ring or a 5-membered heteroaryl groupA ring; wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

is linked to R^5aOr R^5bTwo examples of nitrogen atoms of R^6aTogether with the nitrogen atom may form a 5-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

is linked to R^5cTwo examples of nitrogen atoms of R^6bTogether with the nitrogen atom may form a 5-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

two J's attached to two adjacent ring D atoms^DGroups together with the two adjacent ring D atoms may form a 5-to 7-membered heterocyclic or 5-membered heteroaryl ring fused to ring D; wherein the 5-to 7-membered heterocyclic ring or the 5-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from N, O or S; and wherein said 5-to 7-membered heterocyclic ring or said 5-membered heteroaryl ring is optionally and independently substituted with up to 3 oxo or- (Y) -R⁹Substitution;

wherein Y is absent or C_1-6A linkage in the form of an alkyl chain optionally substituted with up to 6 fluorines; and wherein when Y is said C_1-6In the case of alkyl chains, up to 3 methylene units of the alkyl chain may be replaced by a group selected from: -O-, -C (O) -or-N ((Y) -R)⁹⁰) -, wherein

i) When Y is absent, each R⁹⁰Independently selected from hydrogen, -COR¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-(C＝O)NHOR¹⁰、C_3-6Cycloalkyl ring, 4-an 8-membered heterocyclic, phenyl ring or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution; and is

ii) when Y is present, each R⁹⁰Independently selected from hydrogen, halogen, -CN, -OR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution;

each R⁹Independently selected from hydrogen, halogen, -CN, -OR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution;

each R¹⁰Independently selected from hydrogen, C_1-6Alkyl, - (C)_1-6Alkyl) -R¹³Phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R¹³Part C_1-6Alkyl moiety, each of said phenyl groups, each of said benzyl groups, each of said C groups_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3R^11aSubstitution;

each R¹³Independently selected from phenyl, benzyl, C_3-6A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said phenyl groups, each of said benzyl groups, each of said C groups_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3R^11bSubstitution;

each R¹¹Independently selected from halogen, oxo, C_1-6Alkyl, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution;

each R^11aIndependently selected from halogen, oxo, C_1-6Alkyl, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution; and is

Each R^11bIndependently selected from halogen, C_1-6Alkyl, oxo, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution;

each R¹²Selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each 5-or 6-membered heteroaryl ring being optionally and independently up to 3Examples the following groups are substituted: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo.

R^CIs composed of

i) Ring C; or

ii) is selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R^N、-COR⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)C(O)R⁷、-N(R⁷)C(O)OR⁷、-N(R⁷)C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷、-SO₂N(R⁷)₂、-C(O)N(R⁷)SO₂R⁷、-SO₂N(R⁷)COOR⁷、-SO₂N(R⁷)C(O)R⁷or-N (R)⁷)SO₂R⁷(ii) a Wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R^NEach C of_1-6The alkyl moiety is optionally and independently substituted with up to 6 fluorines and up to 2 of the following groups: -CN, -OR⁸Oxo, -N (R)⁸)₂、-N(R⁸)C(O)R⁸、-N(R⁸)C(O)OR⁸、-N(R⁸)C(O)N(R⁸)₂、-SO₂R⁸、-SO₂N(R⁸)₂、-NHOR⁸、-SO₂N(R⁸)COOR⁸、-SO₂N(R⁸)C(O)R⁸、-N(R⁸)SO₂R⁸；

Wherein each R⁷Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, phenyl, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 independentlyA ring heteroatom selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R⁸Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^NIndependently selected from a phenyl ring, a monocyclic 5 or 6 membered heteroaryl ring, a monocyclic C_3-6A cycloaliphatic ring or a monocyclic 4-to 6-membered heterocycle, wherein said monocyclic 5-or 6-membered heteroaryl ring or said monocyclic 4-to 6-membered heterocycle contains 1 to 4 heteroatoms selected from N, O or S; wherein the monocyclic 5 or 6 membered heteroaryl ring is not a1, 3, 5-triazinyl ring; and wherein said phenyl, said monocyclic 5-to 6-membered heteroaryl ring, said monocyclic C_3-6A cycloaliphatic ring or said monocyclic 4-to 6-membered heterocycle is optionally and independently substituted with up to 6 fluorines and/or up to 3J^MSubstitution;

each J^MIndependently selected from-CN, C_1-6Aliphatic radical, -OR^M、-SR^M、-N(R^M)₂、C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring contains 1 or 2 heteroatoms independently selected from N, O or S; wherein each of said C_1-6Aliphatic radical, each of said C_3-8The cycloaliphatic ring and each of said 4-to 8-membered heterocyclic rings are optionally and independently substituted with up to 3R^7cSubstitution;

each R^MIndependently selected from hydrogen, C_1-6Aliphatic radical, C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein each said 4-to 8-membered heterocyclic ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein

Ring C is a phenyl ring, a monocyclic 5-or 6-membered heteroaryl ring, a bicyclic 8-to 10-membered heteroaryl ring, a monocyclic 3-to 10-membered cycloaliphatic ring, or a monocyclic 4-to 10-membered heterocyclic ring, wherein the monocyclic 5-or 6-membered heteroaryl ring, the bicyclic 8-to 10-membered heteroaryl ring, or the monocyclic 4-to 10-membered heterocyclic ring contains 1 to 4 heteroatoms selected from N, O or S; wherein the monocyclic 5 or 6 membered heteroaryl ring is not a1, 3, 5-triazinyl ring; and wherein said phenyl, monocyclic 5-to 6-membered heteroaryl ring, bicyclic 8-to 10-membered heteroaryl ring, monocyclic 3-to 10-membered cycloaliphatic ring, or monocyclic 4-to 10-membered heterocyclic ring is optionally and independently substituted by up to p and J^C' substitution, wherein p is 0 or an integer selected from 1 to 3;

each J^C' is independently selected from halogen, -CN, -NO₂、C_1-6Aliphatic radical, -OR^H、-SR^H、-N(R^H)₂、C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring contains 1 or 2 heteroatoms independently selected from N, O or S; wherein each of said C_1-6Aliphatic radical, each of said C_3-8The cycloaliphatic ring and each of said 4-to 8-membered heterocyclic rings are optionally and independently substituted with up to 3R^7dSubstitution; or

Or, two J's attached to two adjacent ring C atoms^C' A group taken together with the two adjacent ring C atoms forms a 5 to 7 membered heterocyclic ring which is a new ring fused to ring C; wherein the 5-to 7-membered heterocyclic ring contains 1 to 2 heteroatoms independently selected from N, O or S;

each R^HIndependently selected from hydrogen, C_1-6Aliphatic radical, C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein each said 4-to 8-membered heterocyclic ring contains 1 to 3 heteroatoms independently selected from O, N or S; or, to-N (R)^H)₂Two examples of the same nitrogen atom of R^Hand-N (R)^H)₂Taken together to form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

each R^7cIndependently selected from hydrogen, halogen, -CN, -NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-8Cycloalkyl ring, -OR^8b、-SR^8b、-N(R^8b)₂、-C(O)O(C_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl) or oxo; wherein each said cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^7dIndependently selected from hydrogen, halogen, -CN, -NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-8Cycloalkyl ring, -OR^8c、-SR^8c、-N(R^8c)₂Or an oxo group; wherein each said cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^8bIndependently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^8cIndependently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

with the proviso that the compound is not a compound depicted below:

wherein J^DIs ethylene or-N (Me)₂，J^AIs hydrogen or methyl, and J^BIs fluorine or C_1-2An alkoxy group.

The present invention also relates to a compound according to formula I or a pharmaceutically acceptable salt thereof:

；

wherein:

wherein X is selected from N, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl, and CF;

ring B is phenyl or a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms, or ring B is thiophene;

n is 0 or an integer selected from 1 to 3;

each J^BIndependently selected from halogen, -CN, C_1-6Aliphatic radical, -OR^BOr C_3-8A cycloaliphatic ring; wherein each of said C_1-6Aliphatic radical and each of said C_3-8The cycloaliphatic radical being optionally substituted with up to 3 halogens;

each R^BIndependently selected from hydrogen, C_1-6Aliphatic radicals or C_3-8Cycloaliphatic ring, in which is C_1-6Each of said R of the aliphatic radical^BAnd is C_3-8Each of said R of the cycloaliphatic ring^BOptionally substituted with up to 3 halogens;

J^Aselected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a Wherein R is^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring;

J^Dabsent or selected from halogen, -CN, -CF₃Methoxy, trifluoromethoxy, nitro, amino or methyl;

R¹and R²Taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein said 4-to 8-membered heterocyclic ring or 5-or 6-membered heteroaryl ring optionally contains up to 3 ring heteroatoms independently selected from N, O or S in addition to said nitrogen atom and is optionally substituted with up to 5R⁵Substitution; or

Or, R¹And R²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocycle, 5-or 6-membered heteroaryl or C_1-6alkyl-R^Y(ii) a Wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocyclic group, 5-or 6-membered heteroaryl group and said C_1-6alkyl-R^YC of (A)_1-6Each alkyl moiety is optionallyAnd independently is substituted by up to 5R^5aSubstitution; with the proviso that R¹And R²Are never simultaneously hydrogen, and with the proviso that when X is CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl or CF, R¹And R²Is not pyridine or pyrimidine; or

Or, J^DAnd R¹Or R²Can form a 5-6 membered heterocyclic ring containing up to two heteroatoms selected from O, N and S and optionally being oxo or- (Y) -R for up to 3 times⁹Substitution;

wherein Y is absent or C_1-6A linkage in the form of an alkyl chain optionally substituted with up to 6 fluorines;

each R⁹Independently selected from hydrogen, fluorine, -CN, -OR¹⁰、-SR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, or a 5-6 membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(iii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings and each of said 5-to 6-membered heteroaromatic rings are optionally substituted with up to 3R¹¹Substitution;

each R¹¹Independently selected from halogen, C_1-6Alkyl, -CN, -OR¹²、-SR¹²、-COR¹²、-OC(O)R¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-C(O)N(R¹²)SO₂R¹²、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂、-SO₂N(R¹²)COOR¹²、-SO₂N(R¹²)C(O)R¹²、-N(R¹²)SO₂R¹²and-N ═ OR¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 3 of the following groups: fluorine, -OH, -O (C)_1-4Alkyl), phenyl and-O (C)_1-4Fluoroalkyl groups);

wherein each R¹⁰Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo; and is

Wherein each R¹²Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo;

R^Yis selected from C_3-8A cycloalkyl ring, a 4-to 8-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaromatic ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-8(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl groups, and each of said 5-to 6-membered heteroaromatic rings are optionally substituted with up to 5R^5cSubstitution;

each R^5cIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6b、-SR^6b、-COR^6b、-OC(O)R^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-C(O)N(R^6b)SO₂R^6b、-N(R^6b)C(O)R^6b、-N(R^6b)C(O)OR^6b、-N(R^6b)C(O)N(R^6b)₂、-N(R^6b)₂、-SO₂R^6b、-SO₂N(R^6b)₂、-SO₂N(R^6b)COOR^6b、-SO₂N(R^6b)C(O)R^6b、-N(R^6b)SO₂R^6b、-(C＝O)NHOR^6b、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring and each said 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said C_3-8A cycloalkyl ring, each of said 4-to 7-membered heterocyclic rings, each of said 5-or 6-membered heteroaryl rings, each of said benzyl groups, and each of said phenyl groups are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic rings contain in a fused or bridged relationship a first ring which is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the second ring is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

Is attached to R^YTwo instances of R of the same or different ring atoms^5cTogether with the ring atom or atoms may form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR' (CO) CO (C)_1-4Alkyl), -OH or halogen, wherein R "is hydrogen or C_1-2An alkyl group;

each R^5aIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6a、-SR^6a、-COR^6a、-OC(O)R^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-C(O)N(R^6a)SO₂R^6a、-N(R^6a)C(O)R^6a、-N(R^6a)C(O)OR^6a、-N(R^6a)C(O)N(R^6a)₂、-N(R^6a)₂、-SO₂R^6a、-SO₂N(R^6a)₂、-SO₂N(R^6a)COOR^6a、-SO₂N(R^6a)C(O)R^6a、-N(R^6a)SO₂R^6a、-(C＝O)NHOR^6a、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH、-NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-C(O)N(C_1-6Alkyl radical)₂、-C(O)NH(C_1-6Alkyl), -C (O) N (C)_1-6Haloalkyl)₂、-C(O)NH(C_1-6Haloalkyl), C (O) N (C)_1-6Alkyl) (C_1-6Haloalkyl), -COO (C)_1-6Alkyl), -COO (C)_1-6Haloalkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S; or

When R is¹Or R²Is one of up to 5 cases R^5aSubstituted C_3-8A cycloalkyl ring, a 4-to 8-membered heterocycle, or a 5-or 6-membered heteroaryl, to said R¹Or R²Of the same or different ring atoms^5aOptionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocycle, phenyl, or a 5-or 6-membered heterocycle to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4-to 6-membered heterocycle or the 5-or 6-membered heteroaryl ring contains up to 2 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, phenyl or a 5-or 6-membered heterocyclic ring optionally substituted with up to 2 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, oxo, - (CO) CO (C)_1-4Alkyl), -NR' (CO) CO (C)_1-4Alkyl) or halogen, wherein R' is hydrogen or C_1-2An alkyl group;

each R⁵Independently selected from halogen, -CN, C_1-6Alkyl, -OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-C(O)N(R⁶)SO₂R⁶、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂N(R⁶)₂、-SO₂N(R⁶)COOR⁶、-SO₂N(R⁶)C(O)R⁶、-N(R⁶)SO₂R⁶、-(C＝O)NHOR⁶、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, or a 4-to 7-membered heterocyclic ring, 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

R when attached to the nitrogen atom¹And R²Form up to 5 cases of R⁵When said 4-to 8-membered heterocyclic ring or 5-or 6-membered heteroaryl ring is substituted, these radicals R attached to the same or different atoms of said ring⁵Optionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

p is an integer selected from 0, 1 or 2;

ring C is a monocyclic 5-membered heteroaryl ring containing up to 4 ring heteroatoms selected from N, O or S, wherein the monocyclic 5-membered heteroaryl ring is not a1, 3, 5-triazinyl ring;

each J^CIndependently selected from halogen or C_1-4An aliphatic group optionally and independently substituted with up to 3 of the following groups: c_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl), -OH or halogen.

The invention also relates to a pharmaceutical composition comprising a compound according to formula I or formula I' or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient or carrier. The invention also relates to a pharmaceutical preparation or dosage form comprising the pharmaceutical composition.

The invention also provides a method of treating or preventing a disease, health condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof, alone or in combination therapy, wherein the disease, health condition or disorder is a peripheral, pulmonary, hepatic, renal, cardiac or cerebrovascular/endothelial disorder or condition, a genitourinary-gynecological or sexual dysfunction or condition, a thromboembolic disease, a fibrotic disorder, a pulmonary or respiratory disorder, a renal or hepatic disorder, an ocular disorder, an auditory disorder, a CNS disorder, a circulatory disorder, a superficial or dermatological disorder, a metabolic disorder, atherosclerosis, wound healing, or a lipid-related disorder that benefits from sGC stimulation or increased concentrations of NO or cGMP.

Detailed Description

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to these embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. The present invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that can be used to practice the present invention. In the event that one or more of the incorporated references, patents, or similar materials (including but not limited to defined terms, usage of terms, described techniques, etc.) differ or contradict the present application, the present application controls.

Definitions and general terms

For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic Table of the elements and the Handbook of chemistry and Physics, 75 th edition, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999 and "Advanced Organic Chemistry by March", fifth edition, Smith, M.B. and March, J. eds John Wiley & Sons, New York:2001, which is incorporated herein by reference in its entirety.

As described herein, compounds of formula I may be optionally substituted with one or more substituents, such as generally described below or as exemplified by particular classes, subcategories, and species of the invention. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted. In general, the term "substituted" means that one or more hydrogen groups in a given structure are replaced with a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents at each position can be the same or different unless otherwise specified. As will be apparent to those of ordinary skill in the art, such as-H, halogen, -NO₂、-CN、-OH、-NH₂or-OCF₃The group is not a substitutable group.

As used herein, the phrase "up to" refers to zero or any integer equal to or less than the numerical value following the phrase. For example, "up to 3" refers to any of 0, 1,2, or 3. As used herein, the atomic numerical range includes any integer therein. For example, a group having 1-4 atoms can have 1,2,3, or 4 atoms. When any variable occurs more than one time at any position, its definition at each occurrence is independent of all other occurrences.

The choice of substituents and combinations encompassed by the present disclosure are only those that allow the formation of stable or chemically feasible compounds. Such selections and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation. As used herein, the term "stable" refers to a compound that does not substantially change when it is subjected to conditions that allow for generation, and in some embodiments, when it is recovered, purified, and used for one or more of the purposes disclosed herein. In some embodiments, a stabilizing compound is a compound that does not substantially change when held at a temperature of 25 ℃ or below for at least one week in the absence of moisture or other chemical reaction conditions. Chemically feasible compounds are compounds that can be prepared by one skilled in the art based on the disclosure herein, if necessary with the relevant knowledge in the art.

Compounds, such as the compounds of formula I disclosed herein or other compounds, may exist in free form (e.g., amorphous or crystalline or polymorphic). Under certain conditions, the compounds may also form a co-form (co-form). As used herein, the term co-form is synonymous with the term multicomponent crystalline form. When the protons of one component of the co-form are significantly transferred to the other component, the resulting co-form is referred to as a "salt". Salt formation is determined by the magnitude of the pKa difference between the partners forming the mixture. For the purposes of this disclosure, compounds include pharmaceutically acceptable salts, even if the term "pharmaceutically acceptable salt" is not expressly noted.

Unless only one isomer is explicitly depicted or named, the structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, flip-atropisomer, and cis-trans isomer) forms of the structure, such as R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond conformations, and cis and trans conformers. Thus, single stereochemical isomers and racemates of the compounds of the present invention as well as mixtures of enantiomers, diastereomers and cis-trans isomers (double bonds or conformations) are within the scope of the present disclosure. Unless otherwise indicated, all tautomeric forms of the disclosed compounds are within the scope of the invention. For example, the following substituents are depicted:

where R may be hydrogen, all compounds shown below will be included:

the present disclosure also encompasses isotopically labeled compounds, which are consistent with those described herein, except for the following facts: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element, as specified, and uses thereof, are contemplated as being within the scope of the compounds of the present invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of: hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. certain isotopically-labelled compounds of the invention (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are useful for their ease of preparation and detectability. In addition, with heavier isomers such as deuterium (i.e., deuterium)²H) The substitution may provide a certain degree of metabolic stabilitySome therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances). Positron emitting isotopes such as¹⁵O、¹³N、¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to study substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl, ethynyl, and the like. It is to be understood that the term "aliphatic chain" is used interchangeably with the terms "aliphatic" or "aliphatic group".

As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon group. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, and the like.

The term "alkenyl" refers to a group having at least one site of unsaturation, i.e., a carbon-carbon sp²A straight or branched chain monovalent hydrocarbon group of a double bond, wherein alkenyl includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Unless otherwise specified, alkenyl groups contain 2 to 20 carbon atoms (e.g., 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms). Examples include, but are not limited to, vinyl, allyl, and the like.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, alkynyl groups contain 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms, or 2-3 carbon atoms). Examples include, but are not limited to, ethynyl, propynyl, and the like.

The term "carbocyclic" refers to a ring system formed solely of carbon and hydrogen atoms. Unless otherwise specified, carbocycle is used as a synonym for "non-aromatic carbocycle" or "cycloaliphatic radical" throughout the present disclosure. In some instances, the term may be used in the phrase "aromatic carbocyclic ring" and in such instances it refers to an "aryl" as defined below.

The term "cycloaliphatic radical" (or "nonaromatic carbocyclic ring", "nonaromatic carbocyclic radical", "nonaromatic carbocyclic") refers to a cyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic radical may be monocyclic, bicyclic, tricyclic, fused, spiro, or bridged. In one embodiment, the term "cycloaliphatic radical" refers to a monocyclic C₃-C₁₂Hydrocarbons or bicyclic radicals C₇-C₁₂A hydrocarbon. In some embodiments, any individual ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropylCyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.

The term "cycloaliphatic radical" also includes polycyclic ring systems in which a non-aromatic carbocyclic ring may be "fused" to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, so long as the attachment group or point is on the non-aromatic carbocyclic ring.

As used herein, "cycloalkyl" refers to a ring system that is fully saturated and has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cyclic group can be monocyclic, bicyclic, tricyclic, fused, spiro, or bridged. In one embodiment, the term "cycloalkyl" refers to a monocyclic C₃-C₁₂Saturated hydrocarbons or bicyclic hydrocarbons C₇-C₁₂A saturated hydrocarbon. In some embodiments, any individual ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

As used herein, "heterocycle" (or "heterocyclyl" or "heterocyclic") refers to a ring system in which one or more ring members are independently selected from heteroatoms that are fully saturated or contain one or more units of unsaturation, but are not aromatic and have a single point of attachment to the rest of the molecule. Unless otherwise specified, heterocycle is used as a synonym for "non-aromatic heterocycle" throughout this disclosure. In some instances, the term may be used in the phrase "aromatic heterocycle" and in this instance it refers to "heteroaryl" as defined below. The term heterocycle also includes fused, spiro or bridged heterocyclic ring systems. Unless otherwise specified, the heterocycle may be monocyclic, bicyclic, or tricyclic. In some embodiments, the heterocyclic ring has 3-18 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, or nitrogen, and each ring in the system contains 3 to 7 ring members. In other embodiments, the heterocyclic ring may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms), or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms). Examples of bicyclic heterocyclic systems include, but are not limited to, adamantyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl.

As used herein, the term "heterocycle" also includes polycyclic ring systems in which a heterocycle is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, so long as the attachment group or point is on the heterocycle.

Examples of heterocycles include, but are not limited to, the following monocyclic rings: 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-pyrrolidinyl, 3-morpholinyl, 3-pyrrolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following two rings: 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiepin, benzodithiane, and 1, 3-dihydro-imidazol-2-one.

As used herein, the term "aryl" (as in "aryl ring" or "aryl group") as used in "aralkyl", "aralkoxy", "aryloxyalkyl", alone or as part of a larger moiety, refers to a carbocyclic ring system in which at least one ring in the system is aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, aryl groups can be monocyclic, bicyclic, or tricyclic, and contain 6-18 ring members. The term also includes polycyclic ring systems in which an aryl ring is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, so long as the attachment group or point is on the aryl ring. Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthalene, fluorenyl, and anthracenyl.

The term "aralkyl" refers to a group in which the aryl ring is substituted with an alkylene group, wherein the beginning of the alkylene group allows the aralkyl group to be bonded to another portion of the compound of formula I. Alkylene groups are divalent, straight-chain or branched saturated hydrocarbon groups. As used herein, the term "C_7-12Aralkyl "means an aralkyl group in which the total number of carbon atoms in the aryl ring combined with the alkylene group is from 7 to 12. Examples of "aralkyl" include, but are not limited to, aryl, heteroaryl, and heteroaryl_1-6Phenyl rings substituted by alkylene, e.g. benzyl and phenylethyl, and by C_1-2Alkylene substituted naphthyl.

The term "heteroaryl" (or "heteroaromatic" or "heteroaryl group" or "aromatic heterocycle") as used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy" refers to a ring system in which at least one ring in the system is aromatic and contains one or more heteroatoms, each ring in the system containing 3 to 7 ring members and having a single point of attachment to the rest of the molecule. Unless otherwise specified, heteroaryl ring systems can be monocyclic, bicyclic, or tricyclic, and have a total of 5 to 14 ring members. In one embodiment, all rings in the heteroaryl system are aromatic. Also included in this definition are heteroaryl groups in which a heteroaryl ring is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, so long as the attachment group or point is on the heteroaryl ring. As used herein, a bicyclic 6,5 heteroaromatic system is, for example, a 6 membered heteroaromatic ring fused to a second 5 membered ring with the attachment group or point on the 6 membered ring.

Heteroaryl rings include, but are not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, 2-pyrrolyl, 5-pyrrolyl, 2-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., Pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; and the following two rings: benzimidazolyl, benzofuranyl, benzothienyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl).

As used herein, "ring" (or "cyclic" or "cyclic moiety") encompasses monocyclic, bicyclic, and tricyclic systems that include cycloaliphatic, heterocyclic, aryl, or heteroaryl groups, each as defined above.

A "fused" bicyclic ring system comprises two rings which share two contiguous ring atoms.

A "bridged" bicyclic ring system comprises two rings which share three or four adjacent ring atoms. As used herein, the term "bridge" refers to an atom or chain of atoms connecting two different parts of a molecule. Two atoms (usually, but not always, two tertiary carbon atoms) connected by a bridge are referred to as a "bridgehead". In addition to the bridge, the two bridgeheads are connected by at least two separate atoms or atom chains. Examples of bridged bicyclic systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl, and 2, 6-dioxa-tricyclo [3.3.1.03,7] nonyl. There is only one ring atom (usually a quaternary carbon atom) in common between the two rings of a "spiro" bicyclic system.

The term "ring atom" refers to an atom such as C, N, O or S, which is part of the following ring: an aromatic, cycloaliphatic, heterocyclic or heteroaryl ring. A "substitutable ring atom" is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen may optionally be replaced by a suitable substituent. Thus, the term "substitutable ring atom" does not include a ring nitrogen or carbon atom that is common when two rings are fused. Additionally, "substitutable ring atom" does not include a ring carbon or nitrogen atom whose structure is depicted as having attached to it one or more moieties other than hydrogen and no hydrogen is available for substitution.

"heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon atoms, including any oxidized form of nitrogen, sulfur, phosphorus or silicon, quaternized form of any basic nitrogen, or replaceable nitrogen of a heterocyclic or heteroaryl ring, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl).

In some embodiments, two independently occurring variables may be taken together with one or more atoms to which each variable is bonded to form a 5-8 membered heterocyclyl, aryl or heteroaryl ring, or a 3-8 membered cycloaliphatic ring. Exemplary rings formed when two independently occurring substituents are taken together with the atom or atoms to which each variable is bonded include, but are not limited to: a) two independently occurring substituents are bonded to the same atom and taken together with the atom to form a ring, wherein the two occurring substituents taken together with the atom to which they are bonded form a heterocyclyl, heteroaryl, cycloaliphatic, or aryl ring, wherein the groups are attached to the remainder of the molecule by a single point of attachment; and b) two independently occurring substituents are bonded to different atoms and taken together with the two atoms to form a heterocyclyl, heteroaryl, cycloaliphatic, or aryl ring, wherein the ring formed has two points of attachment to the rest of the molecule. For example, when phenyl is substituted with two occurrences of-OR ° as in formula D1:

these two occurrences of-OR ° taken together with the carbon atom to which they are bound form a fused 6-membered oxygen containing ring according to formula D2:

it is understood that various other rings may be formed when two independently occurring substituents are taken together with one or more atoms to which each substituent is bonded, and the above detailed examples are not intended to be limiting.

In some embodiments, the alkyl or aliphatic chain may optionally be interrupted by another atom or group. This means that the methylene units of the alkyl or aliphatic chain may optionally be replaced by said further atom or group. Unless otherwise specified, optionally substituted to form chemically stable compounds. Optionally the intercalation may occur within and/or at either end of the strand, i.e. at one or more attachment points to the rest of the molecule and/or at the terminus. The two optional substitutions may also be adjacent to each other within the chain, as long as a chemically stable compound is obtained. Unless otherwise specified, if a substitution or an insertion occurs at the end of the chain, the substituting atom is bonded to H at the end. For example, if-CH₂CH₂CH₃Optionally interrupted by-O-, the resulting compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂And (5) OH. In another example, if the divalent linking group-CH₂CH₂CH₂Optionally interrupted by-O-, the resulting compound may be-OCH₂CH₂-、-CH₂OCH₂-or-CH₂CH₂O-is formed. The optional substitution may also completely replace all carbon atoms in the chain. E.g. C₃The aliphatic groups may optionally be replaced by-N (R ') -, -C (O) -, and-N (R') -, to form-N (R ') C (O) N (R') - (urea).

In general, the term "adjacent" refers to a substituent being placed on a group comprising two or more carbon atoms, wherein the substituent is attached to an adjacent carbon atom.

In general, the term "geminal" means that the substituents are disposed on a group comprising two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

The terms "terminal" and "internal" refer to the position of a group within a substituent. A group is terminal when it is present at the end of a substituent, not further bonded to the rest of the chemical structure. Carboxyalkyl radicals or R^XO (O) C-alkyl is an example of a carboxyl group used at the end. A group is internal when it is present in the middle of a substituent at the end of the substituent that is bonded to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C (O) O-or alkyl-O (CO) -) and alkylcarboxylaryl (e.g., alkyl-C (O) O-aryl-or alkyl-O (CO) -) are examples of internally used carboxyl groups.

As described herein, a bond drawn from a substituent to the center of one ring in a polycyclic ring system (as shown below) represents substitution of the substituent at any substitutable position in any ring of the polycyclic ring system. For example, formula D3 represents a possible substitution in any of the positions shown in formula D4:

this also applies to polycyclic ring systems fused to optional ring systems (this can be indicated by dashed lines). For example, in formula D5, X is an optional substituent for ring a and ring B.

However, if two rings in a polycyclic ring system each have different substituents depicted from the center of each ring, each substituent represents only a substitution on the ring to which it is attached, unless otherwise specified. For example, in formula D6, Y is an optional substituent for only ring a, and X is an optional substituent for only ring B.

As used herein, the term "alkoxy" or "alkylthio" refers to an alkyl group as previously defined attached to a molecule or another chain or ring through an oxygen ("alkoxy", i.e., -O-alkyl) or sulfur ("alkylthio", i.e., -S-alkyl) atom.

Term C_n-m"alkoxyalkyl group", C_n-m"alkoxyalkenyl", C_n-m"Alkoxyaliphatic radical" and C_n-m"alkoxyalkoxy" means an alkyl, alkenyl, aliphatic, or alkoxy group, optionally substituted with one or more alkoxy groups, wherein the combined total number of carbons in the combination of alkyl and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy, or alkoxy and alkoxy is between the values n and m, as appropriate. E.g. C_4-6The total carbon number of the alkoxyalkyl group is 4 to 6, which is divided between the alkyl group and the alkoxy group, and may be, for example, -CH₂OCH₂CH₂CH₃、-CH₂CH₂OCH₂CH₃or-CH₂CH₂CH₂OCH₃。

When the moieties described in the preceding paragraph are optionally substituted, they may be substituted on either side of oxygen or sulfur in one or both of the moieties. For example, optionally substituted C₄Alkoxyalkyl may be, for example, -CH₂CH₂OCH₂(Me)CH₃or-CH₂(OH)OCH₂CH₂CH₃；C₅The alkoxyalkenyl group may be, for example, -CH ═ CHOCH₂CH₂CH₃or-CH ═ CHCH₂OCH₂CH3。

The terms aryloxy, arylthio, benzyloxy or benzylthio refer to compounds which are obtained by oxidation of an oxygen atom ("aryloxy", benzyloxy, e.g. -O-Ph, -OCH₂Ph) or sulfur ("arylthio", e.g. -S-Ph, -S-CH₂Ph) an aryl or benzyl group with the atom attached to the molecule or another chain or ring. In addition, the terms "aryloxyalkyl", "benzyloxyalkyl", "aryloxyalkenyl", and "aryloxyaliphatic" as the case may be, mean an alkyl, alkenyl, or aliphatic group, which is optionally substituted with one or more aryloxy or benzyloxy groups. In this case, the number of atoms of each aryl, aryloxy, alkyl, alkenyl or aliphatic group will be shown separately. Thus, 5-6 membered aryloxy (C)_1-4Alkyl) is a 5-6 membered aryl ring attached to C via an oxygen atom_1-4Alkyl chain, C_1-4The alkyl chain in turn is attached to the rest of the molecule via its terminal carbon.

As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. E.g. C_1-3The haloalkyl group can be-CFHCH₂CHF₂And C is_1-2The haloalkoxy group can be-OC (Br) HCHF₂. This term includes perfluorinated alkyl groups such as-CF₃and-CF₂CF₃。

The term "cyano," as used herein, refers to-CN or-C ≡ N.

The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic group" and "cyanoalkoxy" mean an alkyl, alkenyl, aliphatic group or alkoxy group, optionally substituted with one or more cyano groups. E.g. C_1-3Cyanoalkyl may be-C (CN)₂CH₂CH₃And C is_1-2Cyanoalkenyl may be ═ chc (cn) H₂。

As used herein, "amino" refers to-NH₂。

The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic group" and "aminoalkoxy" mean an amino groupAlkyl, alkenyl, aliphatic or alkoxy, optionally substituted with one or more amino groups. E.g. C_1-3Aminoalkyl may be-CH (NH)₂)CH₂CH₂NH₂And C is_1-2The aminoalkoxy group can be-OCH₂CH₂NH₂。

The term "hydroxy" or "hydroxyl" refers to-OH.

The terms "hydroxyalkyl", "hydroxyalkenyl", "hydroxyalkanoyl" and "hydroxyalkoxy" mean an alkyl, alkenyl, aliphatic or alkoxy group, optionally substituted with one or more-OH. E.g. C_1-3Hydroxyalkyl may be-CH₂(CH₂OH)CH₃And C is₄The hydroxyalkoxy group may be-OCH₂C(CH₃)(OH)CH₃。

As used herein, "carbonyl", used alone or in combination with another group, refers to-c (o) -or-c (o) H. For example, as used herein, "alkoxycarbonyl" refers to a group such as-c (O) O (alkyl).

As used herein, "oxo" refers to ═ O, where oxo is typically, but not always, attached to a carbon atom (e.g., it may also be attached to a sulfur atom). The aliphatic chain being optionally interrupted by a carbonyl group or optionally substituted by an oxo group, and both expressions referring to the same thing, e.g. -CH₂-C(O)-CH₃。

As used herein, the term "linker" in the context of resin chemistry (e.g., using solid resins or soluble resins or beads) refers to a bifunctional chemical moiety that attaches a compound to a solid support or a soluble support.

In all other cases, as used herein, "linker" refers to a divalent group in which the two free valencies are on different atoms (e.g., carbon or a heteroatom) or on the same atom, but may be substituted with two different substituents. For example, the methylene group may be C₁Alkyl linking group (-CH)₂-) which may be two differentOne in each free valence state (e.g. in Ph-CH)₂-Ph, wherein the methylene group acts as a linker between the two phenyl rings). The ethylene group may be C₂Alkyl linking group (-CH)₂CH₂-) wherein the two free valencies are on different atoms. When placed in a position within the chain, an amide group, for example, may serve as a linking group (e.g., -CONH-). The linking group may be the result of an aliphatic chain being interrupted by certain functional groups or a methylene unit on the chain being replaced by the functional group. For example, the linking group can be C_1-6Aliphatic chains in which up to two methylene units are replaced by-C (O) -or-NH- (e.g. in-CH)₂-NH-CH₂-C(O)-CH₂-or-CH₂-NH-C(O)-CH₂-in (b) is substituted. Define the same-CH₂-NH-CH₂-C(O)-CH₂-and-CH₂-NH-C(O)-CH₂-substitution of the group is C₃An alkyl chain optionally interrupted by up to two-C (O) -or-NH-moieties. Cyclic groups may also form a linker, e.g., 1, 6-cyclohexanediyl may be a linker between two R groups, e.g., as inIn (1). The linker may additionally be optionally substituted in any moiety or position.

In which both free valences are in the same atom and are attached to the same substituent₂Divalent radicals of the type C are also possible. In this case, it will be referred to by the IUPAC accepted nomenclature. For example, the definition of a linker in this disclosure would not include an alkylidene group (e.g., such as methine (═ CH)₂) Or ethylidene (═ CH-CH)₃))。

As used herein, the term "protecting group" refers to a reagent used to temporarily block one or more desired reactive sites in a polyfunctional compound. In certain embodiments, the protecting group has one or more, preferably all of the following characteristics: a) selectively reacting in good yield to yield a protected substrate that is stable to reactions occurring at one or more other reaction sites; and b) selectively removed in good yield by a reagent that does not attack the regenerating functional group. Exemplary protecting Groups are described in Greene, T.W. et al, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, New York:1999, the entire contents of which are hereby incorporated by reference. As used herein, the term "nitrogen protecting group" refers to a reagent used to temporarily block one or more desired nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen-protecting Groups also possess the characteristics exemplified above, and certain exemplary nitrogen-protecting Groups are described in detail in Greene, T.W., Wuts, P.G. "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, New York:1999, Chapter 7, the entire contents of which are hereby incorporated by reference.

As used herein, the term "displaceable moiety" or "leaving group" refers to a group that is associated with an aliphatic or aromatic group as defined herein and is displaced by nucleophilic attack by a nucleophile.

As used herein, "amide coupling reagent" or "amide coupling reagent" means a compound that reacts with the hydroxyl moiety of a carboxyl moiety, rendering it susceptible to nucleophilic attack. Exemplary amide coupling agents include DIC (diisopropylcarbodiimide), EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate), pyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), and the like.

The compounds of the present invention are defined herein by their chemical structure and/or chemical name. When a compound is referred to by chemical structure and chemical name, and the chemical structure conflicts with the chemical name, the chemical structure determines the identity of the compound.

Compound embodiments

In a first aspect, the present invention relates to a compound according to formula I' or a pharmaceutically acceptable salt thereof:

wherein each X¹Selected from N, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl, and CF;

X²is selected from N or C;

W

i) is absent, wherein J^BDirectly to a carbon atom bearing two J groups, each J being independently selected from hydrogen or methyl, n is 1 and J^BIs C optionally substituted by up to 9 fluorine_1-7Alkyl chain, wherein optionally said C_1-7one-CH of an alkyl chain₂-units may be replaced by-O-or-S-;

ii) is ring B, which is phenyl or a 5 or 6 membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, O or S; wherein ring B is phenyl or a 5 or 6 membered heteroaryl ring; each J is hydrogen; n is an integer selected from 0 to 3; and each J^BIndependently selected from halogen, -CN, C_1-6Aliphatic radical, -OR^BOr C_3-8A cycloaliphatic group; wherein each of said C_1-6Aliphatic radical and each of said C_3-8Cycloaliphatic radical being optionally and independently substituted by up to 3R³Substituted, each R^BIndependently selected from hydrogen, C_1-6Aliphatic radicals or C_3-8A cycloaliphatic radical, in which is C_1-6Each of said R of the aliphatic radical^BAnd is C_3-8Each of said R of the cycloaliphatic ring^BOptionally and independently up to 3 instances of R^3aSubstitution;

each R³Independently selected from halogen, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl);

each R^3aIndependently selected from halogen, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl);

o is an integer selected from 1 to 3;

each J^DIndependently selected from J^AHalogen, -CN, -NO₂、-OR^D、-SR^D、-C(O)R^D、-C(O)OR^D、-OC(O)R^D、-C(O)N(R^D)₂、-N(R^D)₂、-N(R^d)C(O)R^D、-N(R^d)C(O)OR^D、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂、-SO₂R^D、-SO₂N(R^D)₂、-N(R^d)SO₂R^D、C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^D、C_3-8A cycloaliphatic ring, a 6-to 10-membered aryl ring, a 4-to 8-membered heterocyclic ring, or a 5-to 10-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-to 10-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^DEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8A cycloaliphatic ring, each said 6-to 10-membered aryl ring, each said 4-to 8-membered heterocyclic ring, and each said 5-to 10-membered heteroaryl ring are optionally and independently substituted with up to 5R^5dSubstitution;

J^Aselected from hydrogen, halogen, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a Wherein R is^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring; or wherein R is^aAnd R^bTaken together with the nitrogen atom to which they are both attached to form a 4-8 membered heterocyclic ring, or a 5-membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S, wherein the 4-8 membered heterocyclic ring and 5-membered heteroaryl ring are each optionally and independently substituted with up to 6 fluoro;

each R^DIndependently selected from hydrogen, C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^f、C_3-8A cycloaliphatic ring, a 4-to 10-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring;wherein each said 4-to 10-membered heterocyclic ring and each said 5-to 6-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^fEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 10-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5aSubstitution; wherein when any R is^DIs C_1-6Aliphatic radical or- (C)_1-6Aliphatic radical) -R^fWhen one of the radicals is present, the C is formed_1-6One or two-CH of aliphatic chain₂-the units may optionally be replaced by groups independently selected from: -N (R)^d) -, -CO-or-O-;

each R^dIndependently selected from hydrogen, C_1-6Aliphatic radical, - (C)_1-6Aliphatic radical) -R^f、C_3-8A cycloaliphatic ring, a 4-to 8-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein each of said C_1-6Aliphatic group, said- (C)_1-6Aliphatic radical) -R^fEach of C of the moiety_1-6Aliphatic moiety, each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 8-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5bSubstitution; wherein when any R is^dIs C_1-6Aliphatic radical or- (C)_1-6Aliphatic radical) -R^fWhen one of the radicals is present, the C is formed_1-6One or two-CH of aliphatic chain₂-the units may optionally be replaced by groups independently selected from: -N (R)^d) -, -CO-or-O-;

each R^fIndependently selected from C_1-3Alkyl radical, C_3-8A cycloaliphatic ring, a 4-to 10-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 10-membered heterocyclic ring and each said 5-to 6-membered heteroaryl ring contains 1 to 4 heteroatoms independently selected from O, N or S; and wherein each of said C_3-8Optionally and independently substituted with up to 5R for a cycloaliphatic ring, each said 4-to 10-membered heterocyclic ring, each said phenyl and each said 5-to 6-membered heteroaryl ring^5cSubstitution;

when J is^Dis-C (O) N (R)^D)₂、-N(R^D)₂、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂or-SO₂N(R^D)₂When the two R are^DGroups and attachment to the two R^DThe nitrogen atoms of a group together may form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein except for the two R^DEach said 4-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 3 additional heteroatoms independently selected from N, O or S, other than the nitrogen atom to which group is attached; and wherein each said 4-to 8-membered heterocycle and each said 5-membered heteroaryl ring are optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)C(O)R^DWhen R is in the above-mentioned range^DGroup and attachment to the R^DCarbon atom of a group, and the group attached to said R^dNitrogen atom of a group and^dgroups may form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein except for said R^dEach of said 4-to 8-membered heterocyclic rings and each of said 5-membered heteroaryl rings optionally contain up to 2 additional heteroatoms independently selected from N, O or S, other than the nitrogen atom to which group is attached; and wherein each said 4-to 8-membered heterocycle and each said 5-membered heteroaryl ring are optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)C(O)OR^DWhen R is in the above-mentioned range^DGroup and attachment to the R^DThe oxygen atom of the group, and the-N (R)^d)C(O)OR^DThe carbon atom of the-C (O) -moiety of group, and the group attached to the R^dThe nitrogen atom of the group and the group R^dThe groups may form a 4 to 8 membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or SAnd optionally and independently up to 5 instances of R⁵Substitution;

when J is^Dis-N (R)^d)C(O)N(R^D)₂When said R is attached to said nitrogen atom^DOne of the radicals with the nitrogen atom and with the R attached thereto^dThe N atom and the R of a group^dThe groups may form a 4 to 8 membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S and is optionally and independently substituted with up to 5R⁵Substitution;

when J is^Dis-N (R)^d)SO₂R^DWhen R is in the above-mentioned range^DGroup and said R^DThe sulfur atom to which a group is attached, and the R^dThe nitrogen atom to which a group is attached and with the R^dThe groups can combine to form a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S and is optionally and independently substituted with up to 5R⁵Substitution;

each R⁵Independently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶、-OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-C(O)N(R⁶)SO₂R⁶、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂OH、-SO₂NHOH、-SO₂N(R⁶)₂、-SO₂N(R⁶)COOR⁶、-SO₂N(R⁶)C(O)R⁶、-N(R⁶)SO₂R⁶、-(C＝O)NHOR⁶、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contain up to 4 independently selected fromN, O and the ring heteroatom of S; and wherein said C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶Part C_1-6Alkyl moiety, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

attached to J^DTwo instances of R of the same or different atoms⁵Optionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -CONH₂-OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5aAnd each R^5bIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) R^6a、-OR^6a、-SR^6a、-COR^6a、-OC(O)R^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-C(O)N(R^6a)SO₂R^6a、-N(R^6a)C(O)R^6a、-N(R^6a)C(O)OR^6a、-N(R^6a)C(O)N(R^6a)₂、-N(R^6a)₂、-SO₂R^6a、-SO₂OH、-SO₂NHOH、-SO₂N(R^6a)₂、-SO₂N(R^6a)COOR^6a、-SO₂N(R^6a)C(O)R^6a、-N(R^6a)SO₂R^6a、-(C＝O)NHOR^6a、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl, - (C)_1-6Alkyl) R^6aPart C_1-6Alkyl moiety, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

are respectively attached to R^DOr R^dTwo instances of R of the same or different atoms^5aOr two cases of R^5bOptionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -C (O) NH₂、-NR(CO)O(C_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5cIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R^6b、-OR^6b、-SR^6b、-COR^6b、-OC(O)R^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-C(O)N(R^6b)SO₂R^6b、-N(R^6b)C(O)R^6b、-N(R^6b)C(O)OR^6b、-N(R^6b)C(O)N(R^6b)₂、-N(R^6b)₂、-SO₂R^6b、-SO₂OH、-SO₂NHOH、-SO₂N(R^6b)₂、-SO₂N(R^6b)COOR^6b、-SO₂N(R^6b)C(O)R^6b、-N(R^6b)SO₂R^6b、-(C＝O)NHOR^6b、C_3-8Cycloalkyl ring, 4-to 7-membered heterocycle, 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxoOr a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring and each said 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R^6bPart C_1-6Alkyl moiety, each of said C_3-8A cycloalkyl ring, each of said 4-to 7-membered heterocyclic rings, each of said 5-or 6-membered heteroaryl rings, each of said benzyl groups, and each of said phenyl groups are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic rings contain in a fused or bridged relationship a first ring which is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the second ring is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

is attached to R^fTwo instances of R of the same or different atoms^5cOptionally form C together with the atom or atoms to which it is attached_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -CONH₂、-NR(CO)O(C_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R^5dIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R⁶、-OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂OH、-SO₂NHOH、-SO₂N(R⁶)COR⁶、-SO₂N(R⁶)₂、-N(R⁶)SO₂R⁶、C_7-12Aralkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl or an oxo group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl, - (C)_1-6Alkyl) -R⁶Part C_1-6Alkyl moiety, C_7-12Aralkyl radical, C_3-8Each of the cycloalkyl ring, 4-to 7-membered heterocycle, 5-or 6-membered heteroaryl ring, or phenyl is optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(haloalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

attached to J^DTwo instances of R of the same or different atoms^5dWith J attached thereto^DTogether said one or more atoms of (a) may optionally form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship with each other; whereinThe 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -C (O) NH₂-OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein said 5 orEach of the 6-membered heteroaryl ring or the 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-C(O)N(C_1-6Alkyl radical)₂、-C(O)NH(C_1-6Alkyl), -C (O) N (C)_1-6Haloalkyl)₂、-C(O)NH(C_1-6Haloalkyl), C (O) N (C)_1-6Alkyl) (C_1-6Haloalkyl), -COO (C)_1-6Alkyl), -COO (C)_1-6Haloalkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S; wherein

Is linked to R⁵Or R^5dTwo examples of the same nitrogen atom of R⁶Are each independently of R⁵Or R^5dMay together form a 5-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

is linked to R^5aOr R^5bTwo examples of nitrogen atoms of R^6aTogether with the nitrogen atom may form a 5-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

is linked to R^5cTwo examples of nitrogen atoms of R^6bTogether with the nitrogen atom may form a 5-to 8-membered heterocyclic or 5-membered heteroaryl ring;wherein each said 5-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

two J's attached to two adjacent ring D atoms^DGroups together with the two adjacent ring D atoms may form a 5-to 7-membered heterocyclic or 5-membered heteroaryl ring fused to ring D; wherein the 5-to 7-membered heterocyclic ring or the 5-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from N, O or S; and wherein said 5-to 7-membered heterocyclic ring or said 5-membered heteroaryl ring is optionally and independently substituted with up to 3 oxo or- (Y) -R⁹Substitution;

wherein Y is absent or C_1-6A linkage in the form of an alkyl chain optionally substituted with up to 6 fluorines; and wherein when Y is said C_1-6In the case of alkyl chains, up to 3 methylene units of the alkyl chain may be replaced by a group selected from: -O-, -C (O) -or-N ((Y) -R)⁹⁰) -, wherein

i) When Y is absent, each R⁹⁰Independently selected from hydrogen, -COR¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution; and is

ii) when Y is present, each R⁹⁰Independently selected from hydrogen, halogen, -CN, -OR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution;

each R⁹Independently selected from hydrogen, halogen, -CN, -OR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl and each of said 5-to 6-membered heteroaryl rings are optionally and independently substituted with up to 3 instances of R¹¹Substitution;

each R¹⁰Independently selected from hydrogen, C_1-6Alkyl, - (C)_1-6Alkyl) -R¹³Phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R¹³Part C_1-6Alkyl moiety, each of said phenyl groups, each of said benzyl groups, each of said C groups_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3R^11aSubstitution;

each R¹³Independently selected from phenyl, benzyl, C_3-6A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said phenyl groups, each of said benzyl groups, each of said C groups_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3R^11bSubstitution;

each R¹¹Independently selected from halogen, oxo, C_1-6Alkyl, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution;

each R^11aIndependently selected from halogen, oxo, C_1-6Alkyl, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution; and is

Each R^11bIndependently selected from halogen, C_1-6Alkyl, oxo, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂or-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and/or 3R¹²Substitution;

each R¹²Selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-CONH₂、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo.

R^CIs composed of

i) Ring C; or

ii) is selected from halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R^N、-COR⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)C(O)R⁷、-N(R⁷)C(O)OR⁷、-N(R⁷)C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷、-SO₂N(R⁷)₂、-C(O)N(R⁷)SO₂R⁷、-SO₂N(R⁷)COOR⁷、-SO₂N(R⁷)C(O)R⁷or-N (R)⁷)SO₂R⁷Or- (C ═ O) NHOR⁷(ii) a Wherein each of said C_1-6Alkyl, said- (C)_1-6Alkyl) -R^NEach C of_1-6The alkyl moiety is optionally and independently substituted with up to 6 fluorines and up to 2 of the following groups: -CN, -OR⁸Oxo, -N (R)⁸)₂、-N(R⁸)C(O)R⁸、-N(R⁸)C(O)OR⁸、-N(R⁸)C(O)N(R⁸)₂、-SO₂R⁸、-SO₂N(R⁸)₂、-NHOR⁸、-SO₂N(R⁸)COOR⁸、-SO₂N(R⁸)C(O)R⁸、-N(R⁸)SO₂R⁸；

Wherein each R⁷Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, phenyl, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R⁸Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^NIndependently selected from a phenyl ring, a monocyclic 5 or 6 membered heteroaryl ring, a monocyclic C_3-6A cycloaliphatic ring or a monocyclic 4-to 6-membered heterocycle, wherein said monocyclic 5-or 6-membered heteroaryl ring or said monocyclic 4-to 6-membered heterocycle contains 1 to 4 heteroatoms selected from N, O or S; wherein the monocyclic 5 or 6 membered heteroaryl ring is not a1, 3, 5-triazinyl ring; and wherein said phenyl, said monocyclic 5-to 6-membered heteroaryl ring, said monocyclic C_3-6A cycloaliphatic ring or said monocyclic 4-to 6-membered heterocycle is optionally and independently substituted with up to 6 fluorines and/or up to 3J^MSubstitution;

each J^MIndependently selected from-CN, C_1-6Aliphatic radical, -OR^M、-SR^M、-N(R^M)₂、C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring contains 1 or 2 heteroatoms independently selected from N, O or S; wherein each of said C_1-6Aliphatic radical, each of said C_3-8The cycloaliphatic ring and each of said 4-to 8-membered heterocyclic rings are optionally and independently substituted with up to 3R^7cSubstitution;

each R^MIndependently selected from hydrogen, C_1-6Aliphatic radical, C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein each said 4-to 8-membered heterocyclic ring contains 1 to 3 heteroatoms independently selected from O, N or S; and wherein

Ring C is a phenyl ringA monocyclic 5 or 6 membered heteroaryl ring, a bicyclic 8 to 10 membered heteroaryl ring, a monocyclic 3 to 10 membered cycloaliphatic ring, or a monocyclic 4 to 10 membered heterocyclic ring, wherein said monocyclic 5 or 6 membered heteroaryl ring, said bicyclic 8 to 10 membered heteroaryl ring, or said monocyclic 4 to 10 membered heterocyclic ring contains 1 to 4 heteroatoms selected from N, O or S; wherein the monocyclic 5 or 6 membered heteroaryl ring is not a1, 3, 5-triazinyl ring; and wherein said phenyl, monocyclic 5-to 6-membered heteroaryl ring, bicyclic 8-to 10-membered heteroaryl ring, monocyclic 3-to 10-membered cycloaliphatic ring, or monocyclic 4-to 10-membered heterocyclic ring is optionally and independently substituted by up to p and J^C' substitution wherein p is 0 or an integer selected from 1 to 3;

each J^C' is independently selected from halogen, -CN, -NO₂、C_1-6Aliphatic radical, -OR^H、-SR^H、-N(R^H)₂、C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein the 4-to 8-membered heterocyclic ring contains 1 or 2 heteroatoms independently selected from N, O or S; wherein each of said C_1-6Aliphatic radical, each of said C_3-8The cycloaliphatic ring and each of said 4-to 8-membered heterocyclic rings are optionally and independently substituted with up to 3R^7dSubstitution; or

Or, two J's attached to two adjacent ring C atoms^C' A group taken together with the two adjacent ring C atoms forms a 5 to 7 membered heterocyclic ring which is a new ring fused to ring C; wherein the 5-to 7-membered heterocyclic ring contains 1 to 2 heteroatoms independently selected from N, O or S;

each R^HIndependently selected from hydrogen, C_1-6Aliphatic radical, C_3-8A cycloaliphatic ring or a 4-to 8-membered heterocyclic ring; wherein each said 4-to 8-membered heterocyclic ring contains 1 to 3 heteroatoms independently selected from O, N or S; or, to-N (R)^H)₂Two examples of the same nitrogen atom of R^Hand-N (R)^H)₂Taken together to form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S;

each R^7cIndependently selected from hydrogenHalogen, -CN, -NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-8Cycloalkyl ring, -OR^8b、-SR^8b、-N(R^8b)₂、-C(O)O(C_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl) or oxo; wherein each said cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^7dIndependently selected from hydrogen, halogen, -CN, -NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-8Cycloalkyl ring, -OR^8c、-SR^8c、-N(R^8c)₂Or an oxo group; wherein each said cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^8bIndependently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^8cIndependently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring being optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

with the proviso that the compound is not a compound depicted below:

wherein J^DIs ethylene or-N (Me)₂，J^AIs hydrogen or methyl and J^BIs fluorine or C_1-2An alkoxy group.

In some embodiments of the compounds of formula I', W is absent. In some of these embodiments, wherein W is absent, the compound is represented by formula II' a:

wherein Q represents C_1-7Alkyl optionally substituted with up to 9 fluorines. In other embodiments, Q is substituted with up to 5 fluoro.

In other embodiments of formula I 'where W is absent, the compound is represented by formula III' a:

wherein:

q' is C_1-5An alkyl chain optionally substituted with up to 6 fluoro. In some of these embodiments, X²Is N and the moiety-N (R)¹)(R²) Is absent. In other embodiments, X²Is C and the moiety-N (R)¹)(R²) Are present. In some of these embodiments:

R¹and R²Taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein the 4-to 8-membered heterocyclic or 5-membered heteroaryl ring is R-deleted¹And R²Optionally containing up to 3 ring heteroatoms independently selected from N, O or S in addition to the nitrogen atom attached and optionally substituted with up to 5R^5eSubstitution;

each R^5eIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-4Alkyl) -R⁶、C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR⁶、-SR⁶、-OCOR⁶、-COR⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-N(R⁶)C(O)R⁶、-N(R⁶)₂、-SO₂R⁶、-SO₂OH、-SO₂NHOH、-SO₂N(R⁶)COR⁶、-SO₂N(R⁶)₂、-N(R⁶)SO₂R⁶Benzyl, phenyl or oxo groups; wherein each said phenyl ring and each said benzyl group are optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_1-6Alkyl, said- (C)_1-4Alkyl) -R⁶Each C of the moiety_1-4Alkyl moieties and each of said C_3-8The cycloalkyl ring is optionally and independently substituted with up to 3 halogens, wherein

Each R⁶Independently selected from hydrogen, C_1-6Alkyl radical, C_2-4Alkenyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said C_2-4Alkenyl, each of said phenyl, each of said benzyl, and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

attached to R¹、R²And R¹And R²Two instances R of the same or different atoms of the ring formed by the nitrogen atom to which they are attached^5eOptionally together with said one or more atoms may form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -C (O) NH₂、-NR(CO)O(C_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group.

In some of these embodiments, either R or R is¹And R²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocycle, 5-or 6-membered heteroaryl, phenyl or C_1-6alkyl-R^Y(ii) a Wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl, each of said C_1-6alkyl-R^YPart C_1-6Alkyl moiety, C_3-8Cycloalkyl ring, 4-to 8-membered heterocyclic group, 5-or 6-membered heteroaryl, phenyl and C_1-6alkyl-R^YEach optionally and independently of the other up to 5R^5fSubstitution;

R^Yis selected from C_3-8A cycloalkyl ring, a 4-to 8-membered heterocyclic ring, phenyl, or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains 1 and 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-8A cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl groups, and each of said 5-to 6-membered hetero ringsAryl rings optionally substituted with up to 5R^5gSubstitution;

each R^5fIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-4Alkyl) -R^6a、C_7-12Aralkyl radical, C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR^6a、-SR^6a、-OCOR^6a、-COR^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-N(R^6a)C(O)R^6a、-N(R^6a)₂、-SO₂R^6a、-SO₂N(R^6a)₂、-N(R^6a)SO₂R^6a、-SO₂OH、-SO₂NHOH、-SO₂N(R^6a)COR^6aPhenyl or oxo; wherein each said phenyl is optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NO₂、-CN、C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_7-12Aralkyl radical, C_1-6Alkyl, each of the above- (C)_1-4Alkyl) -R^6aC of (A)_1-4Alkyl moieties and each of said C_3-8Cycloalkyl is optionally and independently substituted with 3 halogen;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl radical, C_2-4Alkenyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said C_2-4Alkenyl, each of said phenyl, each of said benzyl, and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^5gIndependently selected from halogen, -CN, C_1-6Alkyl, - (C)_1-4Alkyl) -R^6bBenzyl, C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR^6b、-SR^6b、-OCOR^6b、-COR^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-N(R^6b)C(O)R^6b、-N(R^6b)₂、-SO₂R^6b、-SO₂N(R^6b)₂、-N(R^6b)SO₂R^6b、-SO₂OH、-SO₂NHOH、-SO₂N(R^6b)COR^6bPhenyl or oxo; wherein each said phenyl and each said benzyl is optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NO₂、-CN、C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_1-6Alkyl, each of (C)_1-4Alkyl) -R^6bPart C_1-4Alkyl moieties and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl radical, C_2-4Alkenyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said C_2-4Alkenyl, each of said phenyl, each of said benzyl, and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens.

In some embodiments, or attached to R^YTwo instances of R of the same or different ring atoms^5gTaken together with said one or more ring atoms to form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -C (O) NH₂、-NR”(CO)O(C_1-4Alkyl), -OH or halogen, wherein R "is hydrogen or C_1-2An alkyl group.

In those embodiments, when R¹Or R²Is one of up to 5 cases R^5fSubstituted C_3-8A cycloalkyl ring, a 4-to 8-membered heterocycle, or a 5-or 6-membered heteroaryl, to said R¹Or R²Of the same or different ring atoms^5fAre taken together with said atom or atoms to form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocycle, phenyl, or a 5-or 6-membered heterocycle to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4-to 6-membered heterocycle or the 5-or 6-membered heteroaryl ring contains up to 2 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, phenyl or a 5-or 6-membered heterocyclic ring optionally substituted with up to 2 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, oxo, - (CO) O (C)_1-4Alkyl), -NR' (CO) O (C)_1-4Alkyl) or halogen, wherein R' is hydrogen or C_1-2An alkyl group.

In some embodiments, two J's attached to two adjacent ring D atoms^DGroups taken together with the two adjacent ring D atoms may optionally form a 5-to 6-membered heterocyclic or 5-membered heteroaryl ring fused to ring D; wherein the 5-to 6-membered heterocyclic ring or the 5-membered heteroaryl ring contains 1 to 3 heteroatoms independently selected from N, O or S; and wherein said 5-to 6-membered heterocyclic ring or said 5-membered heteroaryl ring is optionally and independently substituted with up to 3 oxo or- (Y) -R⁹Is substituted in which R^YAs defined above;

in some embodiments of the first aspect, two instances X¹And X²Is N. In other embodiments, X¹And X²One example of these is N and the other is C. In other embodiments, X²Is C on ring D and optionally J^DAnd (4) substitution.

In some embodiments of the compounds of formula I ', the compounds are represented by formula IV':

J^Aselected from hydrogen, halogen, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a In some of these embodiments, R^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring; or R^aAnd R^bTaken together with the nitrogen atom to which both are attached may form a 4-8 membered heterocyclic ring, or a 5 membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S; wherein said 4-8 membered heterocyclic ring and 5-membered heteroaryl ring are each optionally and independently substituted with up to 6 fluoro, J^DSelected from hydrogen or fluorine, and R¹And R²As defined above.

In other embodiments of the compounds of formula I ', the compounds are represented by formula II' b:

in some of these embodiments, ring B is phenyl. In other embodiments, ring B is a 5 or 6 membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, O or S.

In some embodiments of the compounds of formula II' b, X on ring D²Is carbon, optionally substituted by J^DAnd (4) substitution. In other embodiments, X on ring D²Is nitrogen.

In some embodiments of the compounds of formula II' b, each J^DIndependently selected from J^AHalogen, C_1-6Aliphatic radical, -N (R)^D)₂、-N(R^d)COR^D、-N(R^d)COOR^D、-OR^D、-N(R^d)SO₂R^DOr optionally substituted C_3-8A cycloaliphatic ring. In other embodiments, o is 2 and each J is^DIndependently selected from halogen atoms or-N (R)^D)₂、-N(R^d)COR^D、-OH、-N(R^d)COOR^Dor-N (R)^d)SO₂R^D. In other embodiments, o is 2 and 1 case J^DIs fluorine or chlorine, and another example J^Dis-OH. In other embodiments of formula II' b, o is 2 and 1 case J^Dis-NH₂And the other is independently selected from-N (R)^D)₂Wherein at least 1 instance of R^DIs not hydrogen, or is-NHCOR^D、-N(R^d)COOR^Dor-N (R)^d)SO₂R^D. In other embodiments, o is 2 and 1 case J^DIndependently selected from-N (R)^D)₂or-NHCOR^DAnd another example J^DSelected from fluorine or chlorine. In other embodiments, o is 1 and J^DIs an amino group.

In some embodiments of the compounds of formula I 'or formula II' b, the compound is represented by one of formulae III 'b or III' c:

in other embodiments of the compounds of formula I 'or formula II' b, the compounds are represented by formula IV 'b or formula IV' c:

in some embodiments of the compounds of formula IV 'b or IV' c, X²Is nitrogen and is partially-NR₁R₂Is absent. In other embodiments, X²Is carbon and is partly-NR₁R₂Are present.

In some embodiments of any of the above-depicted formulae wherein W is ring B, the compound is represented by formula V' B:

wherein J^ASelected from hydrogen, halogen, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a In some of these embodiments, R^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring; or in other embodiments, R^aAnd R^bTaken together with the nitrogen atom to which they are both attached to form a 4-8 membered heterocyclic ring, or a 5 membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S; wherein the 4-8 membered heterocyclic ring and the 5-membered heteroaryl ring are each optionally and independently substituted with up to 6 fluoro; and J^DAbsent or fluorine.

In some embodiments of the compounds of formula I 'or formula II' B, ring B is phenyl. In other embodiments of the compounds of formula I 'or formula II' B, ring B is a 6 membered heteroaryl ring. In some of these embodiments, n is an integer selected from 1,2, or 3 and each J is^BIndependently selected from halogen, C_1-6Aliphatic radicals OR-OR^B. In other embodiments, each J is^BIndependently selected from halogens. In other embodiments, each J is^BIndependently selected from fluorine or chlorine. In other embodiments, J^BIs fluorine. In other embodiments, J^BIs methyl or ethyl. In other embodiments, n is 1. In some of these embodiments, where n is 1, J^BSelected from halogens. In other embodiments, J^BIs fluorine or chlorine. In other embodiments, J^BIs fluorine.

In other embodiments of formula I 'or formula II' b, at least one J^BOrtho to the attachment point of the methylene linker between ring B and ring a. At least one J therein^BAt the position ofIn some of these embodiments, the methylene linker is ortho to the attachment point between ring B and ring a, at least one J of the ortho positions^BIndependently selected from halogens. In other embodiments, the at least one J is^BIndependently selected from fluorine or chlorine. In other embodiments, the at least one J is^BIs fluorine. In other embodiments, n is 1 and the at least one J ortho to the attachment point of the methylene linkage between ring B and ring a^BIs fluorine.

In other embodiments of the compounds of formula I 'or formula II' B, ring B is a 6 membered heteroaryl ring. In some of these embodiments, ring B is a pyridyl ring. In other embodiments, ring B is a pyrimidinyl ring.

In some embodiments of the compounds of formula I 'or formula II' a or formula II 'b or formula III' c, o is an integer selected from 1,2, and 3. In some of these embodiments, where o is selected from 1,2, and 3, each J is^DIndependently selected from halogen, C_1-6Aliphatic radical, -N (R)^D)₂、-N(R^d)C(O)R^D、-N(R^d)C(O)OR^D、-N(R^d)C(O)N(R^D)₂、-SO₂R^D、-SO₂N(R^D)₂、-N(R^d)SO₂R^D、-OR^DOr optionally substituted C_3-8A cycloaliphatic ring.

In other embodiments of the compounds of formula I 'or formula II' a or formula II 'b or formula III' c, o is 1 or 2 and each J is^DIndependently selected from halogen atoms or-N (R)^D)₂、-N(R^d)COR^D、-OH、-N(R^d)COOR^Dor-N (R)^d)SO₂R^D. In some of these embodiments, where o is 1 or 2, each R is^dIndependently selected from hydrogen or C_1-4An alkyl group. In other embodiments where o is 1 or 2, at least 1 instance J^DIndependently selected from fluoro, chloro, oxo, hydroxy or amino.

In some embodiments of the compounds of formula I ' or formula II ' a, the compound is represented by one of formulae Va or VI ' a:

wherein ring E is a 5 or 6 membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; and wherein each J^EIndependently selected from oxo or- (Y) -R⁹。

In some embodiments of the compounds of formula I 'or formula II' b, the compound is represented by one of formula VI 'b or formula VII' b:

wherein ring E is a 5 or 6 membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; and wherein each J^EIndependently selected from oxo or- (Y) -R⁹。

In some embodiments of the compounds of formula V ' a, formula VI ' b, or formula VII ' b, J^ASelected from halogen, -NH₂-OH or hydrogen.

In some embodiments of the compounds of formula V ' a, formula VI ' b, or formula VII ' b, ring E is a heterocyclic ring containing one nitrogen ring atom and at least 1 example J^EIs oxo. In some of these embodiments, one J^EIs oxo and the other two cases J^EIndependently selected from- (Y) -R⁹。

In other embodiments of the compounds of formula V ' a, formula VI ' b, or formula VII ' b, each- (Y) -R⁹Independently selected from C_1-6An alkyl group; a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O or S and optionally substituted with one or more C_1-6Alkyl or halogen substitution; and-C (O) NH-R¹⁰. In some of these embodiments, R¹⁰Is C_3-6A cycloalkyl ring.

In some embodiments of the compounds of formula I ' or formula II ' a, the compounds are represented by formula VII ' a:

in these embodiments, ring E is a 5 or 6 membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; and each J^EIndependently selected from oxo or- (Y) -R⁹。

In some embodiments of the compounds of formula I ' or formula II ' b, the compound is represented by formula VIII ' b:

wherein ring E is a 5 or 6 membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; and each J^EIndependently selected from oxo or- (Y) -R⁹。

In some embodiments of the compounds of formula VII 'a and VIII' b, an example is J^EIs oxo and the other two cases J^EIndependently selected from C_1-6An alkyl group; a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from N, O or S and optionally substituted with one or more C_1-6Alkyl or halogen substitution; and- (CO) NH-R¹⁰. In some of these embodiments, R¹⁰Is C_3-6A cycloalkyl ring.

In some embodiments of the compounds of formula I 'or formula VII' a, the compounds are represented by formula VIII 'a or formula VIII'd:

it is fully clear that two- (Y) -R⁹Substituents can be attached to any available ring carbon, but to the same carbon.

In some embodiments of the compounds of formula I 'or formula VIII' b, the compounds are represented by formula XIX 'b or formula XIX'd:

as above, two- (Y) -R⁹Substituents can be attached to any available ring carbon, but to the same carbon.

In some of the compounds of formula I ', the compounds are represented by one of formula XIX ' a or X ' a:

in these embodiments, each J^AIndependently selected from-NH₂Or hydrogen. In some embodiments, each J is^DIs absent or in R¹And R²And halogen when not all hydrogen. In other embodiments, R¹And R²Are all simultaneously hydrogen, and each J^DIndependently selected from-C (O) R^D、-C(O)OR^D、-OC(O)R^D、-C(O)N(R^D)₂、-N(R^D)₂、-N(R^d)C(O)R^D、-N(R^d)C(O)OR^D、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂、-SO₂R^D、-SO₂N(R^D)₂or-N (R)^d)SO₂R^D。

In some of the compounds of formula I ', the compound is represented by one of formulae X ' b or XI ' b:

in these embodiments, each J^AIndependently selected from-NH₂Or hydrogen. In some embodiments, each J is^DIs absent or in R¹And R²And halogen when not all hydrogen. In other embodiments, R¹And R²Are all simultaneously hydrogen and each J^DIndependently selected from-C (O) R^D、-C(O)OR^D、-OC(O)R^D、-C(O)N(R^D)₂、-N(R^D)₂、-N(R^d)C(O)R^D、-N(R^d)C(O)OR^D、-N(R^d)C(O)N(R^D)₂、-OC(O)N(R^D)₂、-SO₂R^D、-SO₂N(R^D)₂or-N (R)^d)SO₂R^D。

In some embodiments of the compounds of formula I ', formula XIX' a, formula X 'b, or formula XI' b, J^DIs selected from-NH₂OH and hydrogen.

In some embodiments, R^CNot a ring. In some of these embodiments, R^CIs halogen, -CN, C_1-6Alkyl, - (C)_1-6Alkyl) -R^N、-COOR⁷、-COR⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)C(O)R⁷、-N(R⁷)C(O)OR⁷、-N(R⁷)C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷、-SO₂N(R⁷)₂or-N (R)⁷)SO₂R⁷. In some embodiments, when R^CIs C_1-6Alkyl or- (C)_1-6Alkyl) -R^NWhen, C_1-6Alkyl or- (C)_1-6Alkyl) -R^NOf (C)_1-6Alkyl) moiety may optionally and independently be substituted with up to 6 fluorines and/or up to 2R^7cAnd (4) substitution. In other embodiments, R^Cis-CN, C_1-6Alkyl, -COR⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷or-SO₂N(R⁷)₂. In some embodiments, when R^CIs C_1-6Alkyl or- (C)_1-6Alkyl) -R^NWhen, C_1-6Alkyl or- (C)_1-6Alkyl) -R^NOf (C)_1-6Alkyl) moiety may optionally and independently be substituted with up to 6 fluorines and/or up to 2R^7cAnd (4) substitution. In other embodiments, R^Cis-COR⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷or-SO₂N(R⁷)₂。

In some embodiments, R^CIs a ring.

The present invention is further directed to compounds of formula I:

wherein:

wherein X is selected from N, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl, and CF;

ring B is phenyl or a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms, or ring B is thiophene;

n is 0 or an integer selected from 1 to 3;

each J^BIndependently selected from halogen, -CN, C_1-6Aliphatic radical, -OR^BOr C_3-8A cycloaliphatic ring; wherein each of said C_1-6Aliphatic radical and each of said C_3-8The cycloaliphatic radical being optionally substituted with up to 3 halogens;

each R^BIndependently selected from hydrogen, C_1-6Aliphatic radicals or C_3-8Cycloaliphatic ring, in which is C_1-6Aliphatic radicalEach of the R^BAnd is C_3-8Each of said R of the cycloaliphatic ring^BOptionally substituted with up to 3 halogens;

J^Aselected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^bWherein R is^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring;

J^Dabsent or selected from halogen, -CN, -CF₃Methoxy, trifluoromethoxy, nitro, amino or methyl;

R¹and R²Taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclic ring or a 5-or 6-membered heteroaryl ring, wherein said 4-to 8-membered heterocyclic ring or 5-or 6-membered heteroaryl ring optionally contains up to 3 ring heteroatoms independently selected from N, O or S in addition to said nitrogen atom and is optionally substituted with up to 5R⁵Substitution; or

Or, R¹And R²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocycle, 5-or 6-membered heteroaryl or C_1-6alkyl-R^Y(ii) a Wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocyclic group, 5-or 6-membered heteroaryl group and said C_1-6alkyl-R^YC of (A)_1-6Each alkyl moiety is optionally and independently substituted with up to 5R^5aSubstitution; with the proviso that R¹And R²Never simultaneously hydrogen; or

Or, J^DAnd R¹Or R²Can form a 5-6 membered heterocyclic ring containing up to two heteroatoms selected from O, N and S and optionally being oxo or- (Y) -R for up to 3 times⁹Substitution;

wherein Y is absent or C_1-6A linkage in the form of an alkyl chain optionally substituted with up to 6 fluorines；

Each R⁹Independently selected from hydrogen, fluorine, -CN, -OR¹⁰、-SR¹⁰、-COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(iii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings and each of said 5-to 6-membered heteroaromatic rings are optionally substituted with up to 3R¹¹Substitution;

each R¹¹Independently selected from halogen, C_1-6Alkyl, -CN, -OR¹²、-SR¹²、-COR¹²、-OC(O)R¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-C(O)N(R¹²)SO₂R¹²、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂、-SO₂N(R¹²)COOR¹²、-SO₂N(R¹²)C(O)R¹²、-N(R¹²)SO₂R¹²and-N ═ OR¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 3 of the following groups: fluorine, -OH, -O (C)_1-4Alkyl), phenyl and-O (C)_1-4Fluoroalkyl groups);

wherein each R¹⁰Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo; and is

Wherein each R¹²Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo;

R^Yis selected from C_3-8A cycloalkyl ring, a 4-to 8-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaromatic ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-8(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl groups, and each of said 5-to 6-membered heteroaromatic rings are optionally substituted with up to 5R^5cSubstitution;

each R^5cIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6b、-SR^6b、-COR^6b、-OC(O)R^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-C(O)N(R^6b)SO₂R^6b、-N(R^6b)C(O)R^6b、-N(R^6b)C(O)OR^6b、-N(R^6b)C(O)N(R^6b)₂、-N(R^6b)₂、-SO₂R^6b、-SO₂N(R^6b)₂、-SO₂N(R^6b)COOR^6b、-SO₂N(R^6b)C(O)R^6b、-N(R^6b)SO₂R^6b、-(C＝O)NHOR^6b、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring and each said 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said C_3-8A cycloalkyl ring, each of said 4-to 7-membered heterocyclic rings, each of said 5-or 6-membered heteroaryl rings, each of said benzyl groups, and each of said phenyl groups are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic rings contain in a fused or bridged relationship a first ring which is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the second ring is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

Is attached to R^YTwo instances of R of the same or different ring atoms^5cTogether with the ring atom or atoms may form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR' (CO) CO (C)_1-4Alkyl), -OH or halogen, wherein R "is hydrogen or C_1-2An alkyl group;

each R^5aIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6a、-SR^6a、-COR^6a、-OC(O)R^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-C(O)N(R^6a)SO₂R^6a、-N(R^6a)C(O)R^6a、-N(R^6a)C(O)OR^6a、-N(R^6a)C(O)N(R^6a)₂、-N(R^6a)₂、-SO₂R^6a、-SO₂N(R^6a)₂、-SO₂N(R^6a)COOR^6a、-SO₂N(R^6a)C(O)R^6a、-N(R^6a)SO₂R^6a、-(C＝O)NHOR^6a、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-C(O)N(C_1-6Alkyl radical)₂、-C(O)NH(C_1-6Alkyl), -C (O) N (C)_1-6Haloalkyl)₂、-C(O)NH(C_1-6Haloalkyl), C (O) N (C)_1-6Alkyl) (C_1-6Haloalkyl), -COO (C)_1-6Alkyl), -COO (C)_1-6Haloalkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S; or

When R is¹Or R²Is one of up to 5 cases R^5aSubstituted C_3-8A cycloalkyl ring, a 4-to 8-membered heterocycle, or a 5-or 6-membered heteroaryl, to said R¹Or R²Of the same or different ring atoms^5aOptionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocycle, phenyl, or a 5-or 6-membered heterocycle to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4-to 6-membered heterocycle or the 5-or 6-membered heteroaryl ring contains up to 2 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, phenyl or a 5-or 6-membered heterocyclic ring optionally substituted with up to 2 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, oxo, - (CO) CO (C)_1-4Alkyl), -NR' (CO) CO (C)_1-4Alkyl) or halogen, wherein R' is hydrogen or C_1-2An alkyl group;

each R⁵Independently selected from halogen, -CN, C_1-6Alkyl, -OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-C(O)N(R⁶)SO₂R⁶、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂N(R⁶)₂、-SO₂N(R⁶)COOR⁶、-SO₂N(R⁶)C(O)R⁶、-N(R⁶)SO₂R⁶、-(C＝O)NHOR⁶、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein said bicyclic ring comprises a ring one and a ring two in a fused or bridged relationship, said ring one is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, or a 4-to 7-membered heterocyclic ring, 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

R when attached to the nitrogen atom¹And R²Form up to 5 cases of R⁵When said 4-to 8-membered heterocyclic ring or 5-or 6-membered heteroaryl ring is substituted, these radicals R attached to the same or different atoms of said ring⁵Optionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

p is an integer selected from 0, 1 or 2;

ring C is a monocyclic 5-membered heteroaryl ring containing up to 4 ring heteroatoms selected from N, O or S, wherein the monocyclic 5-membered heteroaryl ring is not a1, 3, 5-triazinyl ring;

each J^CIndependently selected from halogen or C_1-4An aliphatic group optionally and independently substituted with up to 3 of the following groups: c_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) CO (C)_1-4Alkyl), -OH or halogen; or

Or, ring C is absent, p is 1 and J^CSelected from halogen, -CN, C_1-6Alkyl, -OR⁷、-SR⁷、-COR⁷、-OC(O)R⁷、-C(O)OR⁷、-C(O)N(R⁷)₂、-N(R⁷)C(O)R⁷、-N(R⁷)C(O)OR⁷、-N(R⁷)C(O)N(R⁷)₂、-N(R⁷)₂、-SO₂R⁷、-SO₂N(R⁷)₂、-C(O)N(R⁷)SO₂R⁷、-SO₂N(R⁷)COOR⁷、-SO₂N(R⁷)C(O)R⁷、-N(R⁷)SO₂R⁷、-(C＝O)NHOR⁷Or oxo radical, wherein C_1-6Alkyl is optionally and independently substituted with up to 6 fluorines and up to 2 of the following groups: -CN, -OR⁸Oxo, -N (R)⁸)₂、-N(R⁸)C(O)R⁸、-N(R⁸)C(O)OR⁸、-N(R⁸)C(O)N(R⁸)₂、-SO₂R⁸、-SO₂N(R⁸)₂、-NHOR⁸、-SO₂N(R⁸)COOR⁸、-SO₂N(R⁸)C(O)R⁸、-N(R⁸)SO₂R⁸；

Wherein each R⁷Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl radical, C_3-8A cycloalkyl ring, phenyl, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; and is

Wherein each R⁸Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Fluoroalkyl group,C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each said phenyl, each said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, n is an integer selected from 1 or 2, and each J is^BIndependently selected from halogen, C_1-4Alkyl OR-OR^B. In other embodiments, each J is^BIndependently selected from halogen atoms. In other embodiments, each J is^BIndependently selected from fluorine or chlorine. In other embodiments, each J is^BIs fluorine.

In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, each J is^BIs C_1-4An alkyl group. In some of these embodiments, J^BIs ethyl or methyl. In some embodiments, J is^BIs methyl.

In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, n is 1.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, n is 1 and each J is^BIndependently selected from halogen, C_1-4Alkyl OR-OR^B. In some of these embodiments, J^BIs halogen. In some embodiments, J is^BIs chlorine or fluorine. In other embodiments, J^BIs fluorine. Alternatively, in other embodiments, J^BIs C_1-4An alkyl group. In other embodiments, J^BIs methyl or ethyl.

In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, at least one J is^BIn the methylene linkage at ring B and carrying X¹Ortho to the attachment point between the rings of (a). In some of these embodiments, the at least one J is^BIndependently selected from halogen atoms. In other embodiments, each at least one J^BIndependently selected from fluorine or chlorine. In other embodiments, each at least one J^BIs fluorine. In other embodiments, n is 1 and is in the methylene linkage between ring B and the ring carrying X¹J ortho to the attachment point between the rings of (a)^BIs fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, n is an integer selected from 1 or 2, and each J is^BIndependently selected from halogen, C_1-4Alkyl OR-OR^BWherein at least one J^BIn the methylene linkage at ring B and carrying X¹Ortho to the attachment point between the rings of (a). In some of these embodiments, the halogen may be chlorine or, preferably, fluorine. In other embodiments, at least one J^BIs halogen. Or, at least one J^BIs C_1-4Alkyl groups, such as methyl or ethyl. In some of these embodiments, n is 1. In some embodiments, the methylene linkage is at ring B and carries X¹J ortho to the attachment point between the rings of (a)^BIs fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, n is 2 and each J is^BIs a halogen atom. In some embodiments, each J is^BIndependently selected from chlorine or fluorine. In other embodiments, one J^BIs fluorine and the other J^BIs chlorine. In other embodiments, each J is^BIs fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, ring B is phenyl. In some of these embodiments, n is 1 or 2. In some of these embodiments, J^BIn methylene linkage at ring BAnd carry X¹Ortho to the attachment point between the rings of (a), and J^BIs halogen, for example chlorine or preferably fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, ring B is a 6-membered heteroaryl ring or a thiophene ring. In other embodiments, ring B is a pyridyl ring. In other embodiments, ring B is a pyrimidinyl ring. In other embodiments, ring B is a thiophene ring.

In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, J^DChlorine, fluorine or absent. In some embodiments, J is^DIs fluorine.

In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, J^AIs hydrogen.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, ring C is a monocyclic 5-membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, O or S. In some of these embodiments, ring C is an oxazole or isoxazole ring. In some of these compounds, or pharmaceutically acceptable salts thereof, ring C is unsubstituted, and in other embodiments, ring C is an unsubstituted oxazole or isoxazole ring.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is N. In some of these embodiments, ring C is an oxazole or isoxazole ring. In other embodiments, ring C is unsubstituted, and in other embodiments, ring C is an unsubstituted oxazole or isoxazole ring. In some of these embodiments, ring B is phenyl. In some of these embodiments, J^BIs halogen, for example chlorine or preferably fluorine. In other embodiments, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these compounds or pharmaceutically acceptable salts thereof, n is 1. In some of these compounds, or pharmaceutically acceptable salts thereof, wherein n is 1, J^BIs in carrying with X¹Of methylene bridges between the ring(s) and ring BOrtho position. In some of these embodiments, J^DIs halogen, for example chlorine or preferably fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is N and p is 0. In some of these embodiments, ring C is an oxazole or isoxazole ring. In some of these embodiments, ring B is phenyl. In some of these embodiments, J^BIs halogen, for example chlorine or preferably fluorine. In other embodiments, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these embodiments, n is 1. In some of these embodiments, n is 1, J^BIs in carrying with X¹Ortho to the methylene bridge between the ring(s) and the ring B and J^DIs halogen, for example chlorine or preferably fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is N and ring C is an isoxazolyl ring. In some of these embodiments, ring B is phenyl. In some of these embodiments, where ring B is phenyl, J^BIs halogen, for example chlorine or preferably fluorine. In other embodiments, where ring B is phenyl, n is 1. In other embodiments, where ring B is phenyl and n is 1, J^BIs halogen, preferably fluorine. In other embodiments, where ring B is phenyl, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In other embodiments, where ring B is phenyl, J^BIs in carrying with X¹Ortho to the methylene bridge between the ring(s) and the ring B and J^BPreferably halogen, such as chlorine or fluorine. In some of these compounds or pharmaceutically acceptable salts thereof, J^DIs halogen. In some of these compounds or pharmaceutically acceptable salts thereof, J^DIs fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is C with substituents (giving, for example, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl or CF). In theseIn some of the embodiments, ring C is an oxazole or isoxazole ring. In some of these embodiments, ring C is unsubstituted, and in other embodiments, ring C is an unsubstituted oxazole or isoxazole ring. In some of these embodiments, ring B is phenyl. In some of these compounds or pharmaceutically acceptable salts thereof, J^BIs halogen, for example chlorine or preferably fluorine. In some of these embodiments, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these compounds or pharmaceutically acceptable salts thereof, n is 1. In some of these compounds, or pharmaceutically acceptable salts thereof, wherein n is 1, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these compounds or pharmaceutically acceptable salts thereof, J^DIs halogen, for example chlorine or preferably fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is C with substituents (giving, for example, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl or CF) and p is 0. In some of these embodiments, ring C is an oxazole or isoxazole ring. In some of these embodiments, ring B is phenyl. In some of these embodiments, J^BIs halogen, for example chlorine or preferably fluorine. In other embodiments, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these compounds or pharmaceutically acceptable salts thereof, n is 1. In some of these compounds, or pharmaceutically acceptable salts thereof, wherein n is 1, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In some of these compounds or pharmaceutically acceptable salts thereof, J^DIs halogen, for example chlorine or preferably fluorine.

In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X¹Is C with substituents (giving, for example, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl or CF) and ring C is isoxazolyl. In these embodimentsIn some of (3), ring B is phenyl. In some of these embodiments, where ring B is phenyl, J^BIs halogen, for example chlorine or preferably fluorine. In other embodiments, where ring B is phenyl, n is 1. In other embodiments, where ring B is phenyl and n is 1, J^BIs halogen, preferably fluorine. In other embodiments, where ring B is phenyl, J^BIs in carrying with X¹Ortho to the methylene bridge between ring B. In other embodiments, where ring B is phenyl, J^BIs in carrying with X¹Ortho to the methylene bridge between the ring(s) and the ring B and J^BPreferably halogen, such as chlorine or fluorine. In some of these embodiments, J^DIs halogen. In some of these compounds or pharmaceutically acceptable salts thereof, J^DIs fluorine.

The present invention also relates to certain embodiments of compounds of formula I, or pharmaceutically acceptable salts thereof, having the structure depicted in formula IIa or IIb:

wherein each J^BIs halogen; and ring C is an unsubstituted oxazole or isoxazole ring.

The present invention also relates to certain embodiments of compounds of formula II having the structures depicted in formulae IIIa through IIId:

wherein each J^BIs halogen; and ring C is an unsubstituted oxazole or isoxazole ring.

The present invention also relates to certain embodiments of compounds of formulae IIIa and IIIb, or pharmaceutically acceptable salts thereof, having the structures depicted in formulae IVa and IVb:

wherein each J^BIs halogen;

and ring F is a monocyclic or bicyclic 4-to 10-membered heterocycle or a monocyclic or bicyclic 5-to 10-membered heteroaryl ring; wherein the 4-to 10-membered heterocyclic or 5-to 10-membered heteroaryl ring optionally contains up to 3 ring heteroatoms independently selected from N, O or S, and is optionally and independently substituted with up to 3R⁵And (4) substitution.

In some embodiments of the compound of formula IVa or formula IVb, or a pharmaceutically acceptable salt thereof, ring F is substituted with:

(i)3 example R⁵Wherein at least two of the examples are the same, or

(ii)0, 1 or 2 cases R⁵Wherein at ring F is substituted by 2R⁵When substituted, then the example R⁵Each independently selected;

wherein each R⁵Selected from fluorine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, C_1-6(hydroxy) alkyl, oxo, -CN, -O (C)_1-6Alkyl) -COOR^Z、-NH(C_1-6Alkyl) -COOR^Z、-(C_1-6Alkyl) -COOR^Z、-COOR^Z、-COR^Z、-CON(R^Z)₂、-NHCOOR^Z、-NHCON(R^Z)₂、-CONHSO₂R^Z、-NHCOR^Z、-NH(C_1-6Alkyl) -CON (R)^Z)₂、-N(R^Z)₂、-SO₂R^Z、-SO₂N(R^Z)₂、-SO₂NHCOR^Z、-SO₂NHCOOR^ZPhenyl, benzyl or a 5-or 6-membered heterocyclic or heteroaryl ring, wherein the phenyl, benzyl or 5-6-membered heteroaryl or heterocyclic ring is each optionally substituted with 1 or 2R^ZaSubstitution;

wherein each R^ZIndependently selected from hydrogen, C_3-6Cycloalkyl radical, C_1-6Alkyl radical, C_1-6A fluoroalkyl group; and is

Wherein each R^ZaIndependently selected from hydrogen, halogen, C_3-6Cycloalkyl radical, C_1-6Alkyl radical, C_1-6Fluoroalkyl, oxo, and-COOH.

In some embodiments of the compound of formula IVa or formula IVb or a pharmaceutically acceptable salt thereof, at least one instance of R is a-COOH moiety or at least one instance of R⁵Substituted with a-COOH moiety.

The present invention also relates to certain embodiments of compounds of formula IVa or formula IVb having the structure depicted in formula Va or formula Vb:

wherein F is a ring comprising a nitrogen attached to a pyrimidine and wherein ring F is optionally and independently substituted with 1 or 2R⁵And (4) further substituting.

The present invention also relates to certain embodiments of compounds of formula I, or pharmaceutically acceptable salts thereof, having the structure depicted in formula VIa or formula VIb:

wherein each J^BIs halogen;

R¹is hydrogen or C_1-6An alkyl group;

and ring G is a monocyclic or bicyclic 4-to 10-membered heterocycle or a monocyclic or bicyclic 5-to 10-membered heteroaryl ring; wherein the 4-to 10-membered heterocyclic or 5-to 10-membered heteroaryl ring optionally contains up to 3 ring heteroatoms independently selected from N, O or S, and is optionally and independently substituted with up to 3R^5aAnd (4) substitution.

In these compounds or their pharmaceuticals mayIn some of the acceptable salts, each R^5aSelected from fluorine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, C_1-6(hydroxy) alkyl, oxo, -CN, -O (C)_1-6Alkyl) -COOR^Zb、-NH(C_1-6Alkyl) -COOR^Zb、-(C_1-6Alkyl) -COOR^Zb、-COOR^Zb、-COR^Zb、-CON(R^Zb)₂、-NHCOOR^Zb、-NHCON(R^Zb)₂、-CONHSO₂R^Zb、-NHCOR^Zb、-NH(C_1-6Alkyl) -CON (R)^Zb)₂、-N(R^Zb)₂、-SO₂R^Zb、-SO₂N(R^Zb)₂、-SO₂NHCOR^Zb、-SO₂NHCOOR^ZbPhenyl, benzyl or a 5-or 6-membered heterocyclic or heteroaryl ring, wherein the phenyl, benzyl or 5-6-membered heteroaryl or heterocyclic ring is each optionally substituted with 1 or 2R^ZcSubstituted, wherein each R^ZbIndependently selected from hydrogen, C_1-4Alkyl radical, C_1-4A fluoroalkyl group; and wherein each R^ZcIndependently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Fluoroalkyl, oxo, and-COOH.

In some of these compounds or pharmaceutically acceptable salts thereof, at least one instance of R^5aIs a-COOH moiety or at least one instance of R^5aComprising a-COOH moiety.

The present invention also relates to certain embodiments of compounds of formula VIa or formula VIb having the structures depicted in formula VIIa or formula VIIb, or pharmaceutically acceptable salts thereof:

wherein ring G is optionally and independently further substituted with 1 or 2R^5aAnd (4) substitution.

The present invention also relates to certain embodiments of compounds of formula IIIa or formula IIIc, or pharmaceutically acceptable salts thereof, having the structure depicted in formula VIIIa or formula VIIIb:

wherein J^BIs halogen, R¹Is hydrogen or C_1-6Alkyl, L is optionally and independently substituted with up to 3R^5aSubstituted C_1-6Alkyl, and ring R^YIs a monocyclic or bicyclic 4-to 10-membered heterocycle or a monocyclic or bicyclic 5-to 10-membered heteroaryl ring; wherein the 4-to 10-membered heterocyclic or 5-to 10-membered heteroaryl ring optionally contains up to 3 additional heteroatoms independently selected from N, O or S, and is optionally and independently substituted with up to 3R^5bAnd (4) substitution.

The present invention also relates to certain embodiments of compounds of formula VIIIa or formula VIIIb having the structure depicted in formula IXa or IXb or one of formulae Xa or Xb, or a pharmaceutically acceptable salt thereof:

wherein in formula IXa or formula IXb the linker L is further optionally and independently substituted by up to 2R^5aSubstitution; and in formula Xa or Xb, the ring R^YFurther optionally and independently up to 2 instances of R^5bAnd (4) substitution.

The present invention also relates to certain embodiments of compounds of formula IIIa or IIIb having the structure depicted in formula XIa or formula XIb, or a pharmaceutically acceptable salt thereof:

wherein J^BIs halogen, R¹Is hydrogen or C_1-6An alkyl group; and R is²Is optionally and independently substituted with up to 3R^5aSubstituted C_1-6An alkyl group.

In some embodiments, the compound of formula I is selected from those listed in table 1A, table 1B, table 1C, and table 1D.

TABLE 1A

TABLE 1B

TABLE 1C

Table ID

Process for preparing compounds

The compounds of formulae I to XI can be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available compounds, or prepared using well-known synthetic methods. Another aspect of the invention is a process for the preparation of a compound of formula I as disclosed herein.

The general synthetic procedures for the compounds of the present invention are described below. The synthetic schemes are presented as examples and in no way limit the scope of the invention.

General procedure A

Step 1:

diketone enolate formation:LiHMDS (e.g., 0.9 equiv., 1.0M in toluene) is added dropwise via syringe to a solution of ketone A in THF cooled to-78 ℃. The reaction was allowed to warm to 0 ℃ and diethyl oxalate (1.2 eq) was charged. At this point, the reaction is allowed to warm to room temperature and stirred at that temperature until judged complete (e.g., using TLC or LC/MS analysis). Once the reaction is complete (reaction time is typically 45 minutes), the product diketoenolate B is used "as is" in step 2, the cyclization step, without any further purification.

Step 2:

pyrazole formation:diketoenolate B was diluted with ethanol and charged successively with HCl (e.g., 3 equivalents, 1.25M solution in ethanol) and arylhydrazine hydrate (e.g., 1.15 equivalents). The reaction mixture is heated to 70 ℃ and stirred at this temperature until cyclization is deemed complete (e.g. by LC/MS analysis, typically 30 minutes). Once complete, the reaction mixture is carefully treated with solid sodium bicarbonate (e.g., 4 equivalents) and diluted with dichloromethane and water. The layers were separated and further diluted with waterThe aqueous layer was then extracted with dichloromethane (3 ×). The combined organics were washed with brine, MgSO₄Dried, filtered and concentrated in vacuo. Then, passing through SiO₂Chromatography the resulting pyrazole C was purified using a suitable EtOAc gradient in hexane.

And step 3:

amidine formation:to NH via injector₄Suspension of Cl (e.g. 5 equiv.) in toluene cooled to 0 ℃ AlMe was added dropwise₃(e.g., 5 equivalents in a 2.0M solution in toluene). The reaction was allowed to warm to room temperature and stirred at this temperature until no more bubbles were observed. 1 part pyrazole C is added to the reaction mixture, heated to 110 ℃ and stirred at this temperature until judged complete (e.g. using TLC or LC/MS analysis). Once complete, the reaction was cooled, treated with excess methanol and stirred vigorously at room temperature for 1 hour. The viscous slurry was filtered and the resulting solid cake was washed with methanol. The filtrate was concentrated in vacuo and the resulting solid was resuspended in a 5:1 solvent mixture of ethyl acetate and isopropyl alcohol. The reaction was further treated with saturated sodium carbonate solution and stirred for 10 minutes, after which the layers were separated. The aqueous layer was extracted with ethyl acetate-5: 1 solvent mixture (3 ×), and the combined organics were washed with brine. Over MgSO₄The organics were further dried, filtered and the solvent removed in vacuo. The product amidine D was used as such in the subsequent steps without further purification.

And 4, step 4:

pyrimidinone formation:amidine D was suspended in ethanol and stirred vigorously at 23 ℃ to promote complete solvation. The reaction was further treated with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (e.g. 3 equivalents) and the flask was equipped with a reflux condenser. The reaction was placed in a pre-heated oil bath maintained at 90 ℃ and stirred until complete consumption of starting material was observed on LC/MS (reaction time typically 1 h). The contents are cooled to 23 ℃, and the reaction mixture is acidified with HCl (e.g., 3 equivalents, 1.25M solution in EtOH). The mixture was stirred for 30 minutes and,and most of the solvent was removed in vacuo. The contents were resuspended in ether and water (1:1 mixture) and the resulting slurry was stirred for 20 min. The suspension was filtered under vacuum and the solid cake was washed with additional water and ether and dried under high vacuum overnight. The resulting pyrimidinone E was used as such in the subsequent step without further purification.

General procedure B

A solution of the amino nucleophile (3 equivalents), triethylamine (10 equivalents) and intermediate 1(1 equivalent) was stirred in dioxane and water (2:1 ratio) at 90 ℃ until complete consumption of the starting material was observed by LC/MS. The solution was diluted with 1N aqueous hydrochloric acid and dichloromethane. The layers were then separated and the aqueous layer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification to give the desired product.

General procedure C

A mixture of intermediate 2 (this intermediate was previously described in published patent application WO 2012/3405A 1; 1 equivalent) and carboxylic acid (1.1 equivalent) in N, N-dimethylformamide was treated with triethylamine (4 equivalents) followed by a solution of 50% propylphosphonic anhydride (T3P, 1.4 equivalents) in ethyl acetate. The reaction was heated to 80 ℃ for 24h, after which the reaction was diluted with water and 1N hydrochloric acid solution. The contents were extracted with dichloromethane and then ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification to give the desired product.

Pharmaceutically acceptable salts of the invention

As used herein, the phrase "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compound of formula I or formula I'. Pharmaceutically acceptable salts of the compounds of formula I or formula I' are useful in medicine. However, pharmaceutically unacceptable salts may be used to prepare compounds of formula I or formula I' or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, succinate ion or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, the pharmaceutically acceptable salts may have more than one charged atom in the structure. The case where the plurality of charged atoms are part of a pharmaceutically acceptable salt may have a plurality of counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

Pharmaceutically acceptable salts of the compounds described herein include those derived from the compounds with inorganic acids, organic acids or bases. In some embodiments, the salts may be prepared in situ during the final isolation and purification of the compounds. In other embodiments, salts may be prepared in a separate synthetic step from the free form of the compound.

When a compound of formula I or formula I' is acidic or contains a sufficiently acidic bioisostere, suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, ketone, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Particular embodiments include ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine (hydrabamine), isopropylamine, lysine, methyl reduced glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compounds of formula I or formula I' are basic or contain sufficiently basic bioisosteres, salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1' -methylene-bis (2-hydroxy-3-naphthoate)).

Berg et al, "Pharmaceutical Salts," J.pharm.Sci.,1977:66:1-19, which are incorporated herein by reference in their entirety, more fully describe the preparation of the pharmaceutically acceptable Salts and other typical pharmaceutically acceptable Salts described above.

In addition to the compounds described herein, pharmaceutically acceptable salts thereof may also be used in compositions to treat or prevent the conditions identified herein.

Pharmaceutical compositions and methods of administration

The compounds disclosed herein and pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions or "formulations".

Typical formulations are prepared by admixing a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient employed will depend upon the manner and purpose of formulation of the compounds of formula I and formula I'. Solvents are generally selected based on solvents that one of skill in the art would consider safe (GRAS, generally regarded as safe) for administration to mammals. Generally, the safe solvent is a non-toxic aqueous solvent, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulations may also contain other types of excipients, such as one or more buffers, stabilizers, anti-attachment agents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (e.g., enteric or sustained release) protectants, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other additives known to provide elegant presentation of a drug (i.e., a compound of formula I and formula I' or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (i.e., a medicament).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, a quantity of the drug substance (i.e., a compound of formula I and formula I', pharmaceutically acceptable salts thereof, or stabilized forms of the compound, such as complexes with cyclodextrin derivatives or other known complexing agents) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound having the desired purity is optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient or stabilizer, in the form of a lyophilized formulation, a milled powder or an aqueous solution. The formulation can be carried out by mixing with a physiologically acceptable carrier at ambient temperature, at a suitable pH and at the desired purity. The pH of the formulation depends primarily on the particular use and concentration of the compound, but can range from about 3 to about 8. When the reagents described herein are solid amorphous dispersions formed by a solvent process, the additives may be added directly to the spray-dried solution as the mixture is formed, such as by dissolving or suspending the additives in the solution as a slurry that may then be spray-dried. Alternatively, additives may be added after the spray drying process to help form the final formulated product.

The compounds of formula I and formula I', or pharmaceutically acceptable salts thereof, are typically formulated in pharmaceutical dosage forms to provide easily controllable dosages of the drug and to enable patient compliance with prescribed regimens. Pharmaceutical formulations of the compounds of formula I and formula I' or pharmaceutically acceptable salts thereof may be prepared for various routes and forms of administration. Various dosage forms of the same compound may exist, as different medical conditions may require different routes of administration.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, time-release formulations intended for oral administration to humans may contain from about 1 to 1000mg of the active material compound compounded with an appropriate and inexpensive amount of a carrier material which may vary from about 5 to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide readily measurable amounts for administration. For example, aqueous solutions intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per mL of solution so that an appropriate volume of infusion can be made at a rate of about 30 mL/h. As a general proposition, the initial pharmaceutically effective amount of inhibitor administered will be in the range of about 0.01-100mg/kg per dose, i.e., about 0.1 to 20mg/kg patient body weight per day, with a typical initial range of 0.3 to 15 mg/kg/day for the compound used.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. A therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more symptoms thereof.

The pharmaceutical compositions of formula I and formula I' will be formulated, administered and administered in a manner consistent with good medical practice, i.e., the amount, concentration, regimen, course, vehicle and route of administration. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site at which the agent is delivered, the method of administration, the administration regimen, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.

The term "prophylactically effective amount" refers to an amount effective to prevent or substantially reduce the chance of acquiring a disease or condition, or reduce the severity of a disease or condition prior to acquiring it, or reduce the severity of one or more symptoms thereof prior to the development of the symptoms. In general, preventive measures are divided into primary prevention (to prevent disease development) and secondary and methods (whereby the disease has developed and the patient is protected from worsening of the process).

Acceptable diluents, carriers, excipients, and stabilizers are those that are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; sheetSugars, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEEN^TM、PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be encapsulated in microcapsules prepared, for example by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively; encapsulated in a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are also disclosed in Remington's, The Science and Practice of Pharmacy, 21 st edition, University of The sciences in Philadelphia,2005 edition (hereinafter "Remington").

A "controlled drug delivery system" supplies drugs to the body in a precisely controlled manner to accommodate the drugs and the condition being treated. The main objective is to achieve a therapeutic drug concentration at the site of action for the desired duration. The term "controlled release" is often used to refer to a variety of methods of modifying the release of a drug from a dosage form. This term includes preparations labeled "extended release", "delayed release", "modified release" or "sustained release". In general, controlled release of the agents described herein can be provided through the use of a wide variety of polymeric carriers and controlled release systems including: erodible and non-erodible matrices, permeability control devices, various reservoir devices, enteric coatings, and multi-particle control devices.

"sustained release preparations" are the most common application of controlled release. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methyl methacrylate) or poly (vinyl alcohol)), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ -ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D- (-) -3-hydroxybutyric acid.

"immediate release preparations" may also be prepared. The goal of these formulations is to get the drug into the bloodstream and site of action as quickly as possible. For example, for fast dissolution, most tablets are designed to rapidly disintegrate into granules and subsequently deaggregate into fine particles. This provides a larger exposed surface area for the dissolution media, resulting in a faster dissolution rate.

The agents described herein may be incorporated into an erodible or non-erodible polymeric matrix controlled release device. Erodable matrix means water erodable or water swellable or water soluble in the sense that it is erodable or swellable or soluble in pure water or requires the presence of an acid or base to ionize the polymer matrix sufficiently to cause erosion or dissolution. Upon contact with an aqueous environment of use, the erodible polymeric matrix imbibes water and forms a water-swollen gel or matrix in which the agents described herein are encapsulated. The water-swellable matrix gradually erodes, swells, disintegrates, or dissolves in the environment of use, thereby controlling the release of the compounds described herein to the environment of use. One component of this water-swellable matrix is a water-swellable, erodible or soluble polymer, which can be generally described as an osmopolymer, hydrogel or water-swellable polymer. Such polymers may be linear, branched or crosslinked. These polymers may be homopolymers or copolymers. In certain embodiments, it may be a synthetic polymer derived from: vinyl, acrylate, methacrylate, urethane, ester, and oxide monomers. In other embodiments, it may be a derivative of a naturally occurring polymer, such as polysaccharides (e.g., chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan), starches (e.g., dextrin and maltodextrin), hydrocolloids (e.g., pectin), phospholipids (e.g., lecithin), alginic acidSalts/esters (e.g. ammonium, sodium, potassium or calcium alginate, propylene glycol alginate), gelatin, collagen and cellulosics. Cellulosic products are cellulosic polymers that have been modified by reacting at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form ester-linked or ether-linked substituents. For example, cellulosic ethylcellulose has ether-linked ethyl substituents attached to the saccharide repeat units, while cellulosic cellulose acetate has ester-linked acetate substituents. In certain embodiments, cellulosic articles for use in the erodable matrix include water-soluble and water-erodable cellulosic articles, which may include, for example, Ethyl Cellulose (EC), Methyl Ethyl Cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), Cellulose Acetate (CA), Cellulose Propionate (CP), Cellulose Butyrate (CB), Cellulose Acetate Butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). In certain embodiments, the cellulosic article comprises various grades of low viscosity (MW less than or equal to 50,000 daltons, e.g., Dow Methocel^TMSeries E5, E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000 daltons, e.g. E4MCR, E10MCR, K4M, K15M and K100M and Methocel^TMK series) HPMC. Other commercially available types of HPMC include Shin Etsu Metholose 90SH series.

Other materials that may be used as the erodible matrix material include, but are not limited to, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ethacrylic acid, or methacrylic acid (ii)Rohm America, Inc., Piscataway, New Jersey) with other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl acrylate, 2-dimethylaminoethyl methacrylate and methacrylic acid (trimethylaminoethyl methacrylate)Polyester) chloride homopolymers and copolymers.

Alternatively, the agents of the present invention may be applied by or incorporated into a non-erodible matrix device. In such devices, the reagents described herein are distributed in an inert matrix. The agent is released by diffusion into an inert matrix. Examples of materials suitable for the inert matrix include insoluble plastics (e.g., methyl acrylate-methyl methacrylate copolymer, polyvinyl chloride, polyethylene), hydrophilic polymers (e.g., ethyl cellulose, cellulose acetate, cross-linked polyvinylpyrrolidone (also known as crospovidone)), and fatty compounds (e.g., carnauba wax, microcrystalline wax, and triglycerides). Such devices are further described in Remington, The Science and Practice of Pharmacy, 20 th edition (2000).

As noted above, the reagents described herein may also be incorporated into an osmotic control device. Such devices generally comprise a core containing one or more agents as described herein and a water permeable, non-dissolving and non-eroding coating surrounding the core that controls the flow of water from an aqueous environment of use into the core so as to release the drug to the environment of use by squeezing some or all of the core. In certain embodiments, the coating is polymeric, water permeable, and has at least one delivery opening. The core of the osmotic device optionally includes an osmotic agent that functions to imbibe water from the surrounding environment through such a semi-permeable membrane. The osmotic agent (osmoagent) contained in the core of this device may be a water-swellable hydrophilic polymer or it may be an osmogen (osmogen), which is also known as an osmotic agent (osmogen). Pressure is generated internally within the device that forces the reagent(s) out of the device via an orifice (sized to minimize solute diffusion while preventing hydrostatic head buildup). Non-limiting examples of osmotic control devices are disclosed in U.S. patent application No. 09/495,061.

The amount of water-swellable hydrophilic polymer present in the core may range from about 5 to about 80 wt% (including, for example, 10 to 50 wt%). Non-limiting examples of core materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone (PVP) and cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate, etc., hydrophilic polyurethanes containing large blocks of PEO, cross-linked sodium carboxymethylcellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, Gelatin, xanthan gum and sodium starch glycolate. Other materials include hydrogels comprising interpenetrating polymer networks, which polymers may be formed by addition or condensation polymerization, the components of which may comprise hydrophilic and hydrophobic monomers such as those just mentioned. Water swellable hydrophilic polymers include, but are not limited to, PEO, PEG, PVP, croscarmellose sodium, HPMC, sodium starch glycolate, polyacrylic acid, and cross-linked forms or mixtures thereof.

The core may also comprise an osmogen (or osmotic agent). The amount of osmogen present in the core may range from about 2 to about 70 wt% (including, for example, 10 to 50 wt%). A typical class of suitable osmogens are water-soluble organic acids, salts and sugars, which are capable of imbibing water to thereby achieve an osmotic pressure gradient across the barrier surrounding the coating. Typical useful osmogens include, but are not limited to, magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid, and mixtures thereof. In certain embodiments, the osmogen is glucose, lactose, sucrose, mannitol, xylitol, sodium chloride, including combinations thereof.

The drug delivery rate is controlled by such factors as: coating permeability and thickness, osmotic pressure of the drug-containing layer, degree of hydrophilicity of the hydrogel layer, and surface area of the device. One skilled in the art will appreciate that increasing the thickness of the coating will decrease the release rate, while any of the following will increase the release rate: increasing the permeability of the coating; increasing the hydrophilicity of the hydrogel layer; increasing the osmotic pressure of the drug-containing layer; or to increase the surface area of the device.

In certain embodiments, it is desirable to entrain particles of the agents described herein in the extrusion fluid during operation of such osmotic devices. For sufficiently entrained particles, the agent drug form is dispersed in the fluid before the particles have had a chance to settle in the core of the tablet. One means of achieving this is by the addition of a disintegrant which serves to break down the compressed core into its particle components. Non-limiting examples of standard disintegrants include materials such as: sodium starch glycolate (e.g., Explotab @)^TMCLV), microcrystalline cellulose (e.g., Avicel)^TM) Microcrystalline silicified cellulose (e.g. ProSoIv)^TM) And croscarmellose sodium (e.g., Ac-Di-Sol)^TM) And other disintegrants known to those skilled in the art. Depending on the particular formulation, some disintegrants are more effective than others. Several disintegrants tend to form gels when swollen with water, thus hindering drug delivery from the device. The non-gelling, non-swelling disintegrant provides for more rapid dispersion of the drug particles within the core as water enters the core. In certain embodiments, the non-gelling, non-swelling disintegrant is a resin, such as an ion exchange resin. In one embodiment, the resin is Amberlite^TMIRP 88 (available from Rohm and Haas, Philadelphia, Pa.). When used, the disintegrant is present in an amount in the range of about 1-25% of the core agent.

Another example of an osmotic device is an osmotic capsule. The capsule shell or a portion of the capsule shell may be semipermeable. The capsules may be filled with a powder or liquid consisting of: an agent as described herein, an excipient to imbibe water to provide an osmotic potential, and/or a water-swellable polymer or optionally a solubilizing excipient. The capsule core may also be prepared such that it has two layers or multiple layers of agents similar to the concentric geometries described for the two layers, three layers, or above.

Another type of osmotic device useful in the present invention comprises coated swellable tablets, for example as described in EP 378404. The coated swellable tablet comprises a tablet core comprising an agent as described herein and a swelling material, preferably a hydrophilic polymer, coated with a membrane containing holes or pores through which the hydrophilic polymer can extrude and carry the agent out in an aqueous use environment. Alternatively, the membrane may contain a polymer or low molecular weight water-soluble porous source. The porogens dissolve in the aqueous use environment, thereby providing pores through which the hydrophilic polymer and agent may be extruded. Examples of porogens are water soluble polymers such as HPMC, PEG and low molecular weight compounds such as glycerol, sucrose, glucose and sodium chloride. Alternatively, the holes may be formed by drilling holes in the coating using a laser or other mechanical means. In such osmotic devices, the membrane material may comprise any film-forming polymer, including water permeable or impermeable polymers, provided that the membrane deposited on the tablet core is porous or contains water-soluble porogens or possesses large pores for water ingress and drug release. Embodiments of such sustained release devices may also be multilayered, as described in, for example, EP 378404.

Where the agents described herein are liquids or oils, such as liquid vehicle formulations, for example as described in WO05/011634, the osmotic controlled release device may comprise a soft gel or gelatin capsule formed from a composite wall and comprising a liquid formulation, wherein the wall comprises a barrier layer formed on the outer surface of the capsule, an expandable layer formed on the barrier layer, and a semipermeable layer formed on the expandable layer. The delivery port connects the liquid formulation with an aqueous use environment. Such devices are described in, for example, US6419952, US6342249, US5324280, US4672850, US4627850, US4203440 and US 3995631.

As further described above, the reagents described herein may be provided in particulate form, typically ranging in size from about 10 μm to about 2mm (including, for example, from about 100 μm to 1mm in diameter). Such multiparticulates may be encapsulated, for example, in a capsule such as a gelatin capsule or a capsule formed from a water soluble polymer such as HPMCAS, HPMC or starch; administered as a suspension or slurry in a liquid; or it may be formed into tablets, troches, or pills by compression or other processes known in the art. Such multiparticulates can be prepared by any known process, such as wet and dry granulation processes, extrusion/spheronization, roller compaction, melt-condensation or by spray coating the seed core. For example, in wet and dry granulation processes, the agents described herein and optional excipients may be granulated to form multiparticulates of the desired size.

The active agent may be incorporated into a microemulsion, which is typically a thermodynamically stable, isotropic, transparent dispersion of two immiscible liquids such as oil and water stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology, New York: Marcel Dekker,1992, Vol. 9). For the preparation of microemulsions, surfactants (emulsifiers), cosurfactants (coemulsifiers), an oil phase and an aqueous phase are necessary. Suitable surfactants include any surfactant that can be used to prepare an emulsion, such as the emulsifiers typically used to prepare creams. Co-surfactants ("co-emulsifiers") are generally selected from the group consisting of polyglycerol derivatives, glycerol derivatives and fatty alcohols. Preferred emulsifier/co-emulsifier combinations are typically, but not necessarily, selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprylic and capric acid triglycerides and oleoyl macrogolglycerides. The aqueous phase will include not only water but typically also buffers, glucose, propylene glycol, polyethylene glycol, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400) and/or glycerol and the like, while the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono-, di-and triglycerides, mono-and diesters of PEG (e.g., oleoyl polyglycolyglycerides), and the like.

The compounds described herein can be incorporated into pharmaceutically acceptable nanoparticle, nanosphere, and nanocapsule formulations (Delie and Blanco-Prieto,2005, Molecule 10: 65-80). Nanocapsules generally encapsulate a compound in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, ultrafine particles (about 0.1 μm in size) can be designed using polymers capable of in vivo degradation (e.g., biodegradable polyalkyl-cyanoacrylate nanoparticles). Such particles are described in the prior art.

Implantable devices coated with a compound of the invention are another embodiment of the invention. The compounds may also be coated on implantable medical devices such as beads, or co-formulated with polymers or other molecules to provide a "drug reservoir," thus allowing the drug to be released over a longer period of time than when an aqueous drug solution is administered. General methods for the preparation of suitable coatings and coated implantable devices are described in U.S. patent nos. 6,099,562; 5,886,026 and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable outer coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart a controlled release profile in the composition.

Formulations include those suitable for the routes of administration detailed herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are commonly found in Remington. Such methods include the steps of: the active ingredient is associated with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

In reference to a compound, composition or formulation of the present invention, the term "administering (administers or administerations) means introducing the compound into an animal system in need of treatment. When a compound of the invention is provided in combination with one or more other active agents, "administering" and variations thereof is each understood to include the simultaneous and/or sequential introduction of the compound and the other active agent.

The compositions described herein may be administered systemically or locally, for example: orally (e.g., with capsules, powders, solutions, suspensions, tablets, sublingual tablets, etc.), by inhalation (e.g., with aerosols, gases, inhalers, nebulizers, etc.), applied to the ear (e.g., with ear drops), topically (e.g., with creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with ear drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., with enemas or suppositories), nasally, buccally, vaginally (e.g., with lavage, intrauterine devices, pessaries, vaginal rings or tablets, etc.), via implanted reservoirs, etc., or parenterally, depending on the severity and type of the condition being treated. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

The pharmaceutical compositions described herein may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerin; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. The tablets may be uncoated or may be coated by known techniques including microencapsulation to mask unpleasant tastes or to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax. Water soluble taste masking materials such as hydroxypropyl-methyl cellulose or hydroxypropyl cellulose may be used.

Formulations of the compounds of formula I and formula I' suitable for oral administration may be prepared as discrete units such as tablets, pills, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g. gelatin capsules, syrups or elixirs. The compound formulations intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin or olive oil.

The active compound may also be in microencapsulated form with one or more excipients as described above.

Where aqueous suspensions are desired for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents and antioxidants.

The compositions described herein in sterile injectable form (e.g., for parenteral administration) can be aqueous or oily suspensions. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butane diol. Acceptable vehicles and solvents that can be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as tweens, spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for injectable formulation purposes.

Oily suspensions may be formulated by suspending the compounds of formula I and formula I' in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.

Aqueous suspensions of the compounds of formula I and formula I' contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds described herein, it is often desirable to delay absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Thus, the rate of absorption of a compound will depend on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsulated matrices of the compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particulate polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Injectable solutions or microemulsions may be introduced into the bloodstream of a patient by means of local bolus injection. Alternatively, it may be advantageous to apply the solution or microemulsion in such a way that a constant circulating concentration of the compound of the invention is maintained. To maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is Deltec CADD-PLUS^TMModel 5400 intravenous pump.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.

The pharmaceutical compositions described herein may also be applied topically, particularly where the therapeutic target includes areas or organs that are readily accessible by topical application, including diseases of the eye, ear, skin, or lower intestinal tract. Suitable surface preparations can be readily prepared for each of these areas or organs.

Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, if desired, and with any preservatives or buffers required. Ophthalmic formulations, ear drops, and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application to the lower intestinal tract can be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Surface transdermal patches may also be used.

For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds provided herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as a fine suspension in isotonic, pH adjusted sterile saline, or preferably as a solution in isotonic, pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum. For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations may be applied as a topical ointment or cream containing one or more active ingredients in an amount of, for example, 0.075 to 20 w/w%. When formulated in an ointment, the active ingredient may be used with an oil-based, paraffin, or water-miscible ointment base.

Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may comprise a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG 400), and mixtures thereof. The topical formulations may desirably contain a compound that enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsions prepared using the compounds of formula I and formula I' may be composed of known ingredients in a known manner. Although the phase may comprise only emulsifiers, alternatively known as emulsifiers (emulgents), it desirably comprises a mixture of at least one emulsifier with a fat or oil or both a fat and an oil. Hydrophilic emulsifiers may be included with lipophilic emulsifiers that act as stabilizers. In some embodiments, the emulsifier comprises both oil and fat. The emulsifier or emulsifiers together, with or without stabilizer or stabilizers, form the so-called emulsifying wax, which together with the oils and fats forms the so-called emulsifying ointment base, which forms the oily disperse phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the compounds of formula I and formula I' include Tween^TM-60、Span^TM-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.

The pharmaceutical composition may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and employing fluorocarbons and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including in the range of 0.1 to 500 microns, with particles of incremental microns such as 0.5, 1, 30, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs.

Pharmaceutical compositions (or formulations) for use may be packaged in a variety of ways, depending on the method used to administer the drug. Generally, the article for distribution comprises a container in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as: bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-resistant component to prevent light access to the package contents. In addition, the container has a label placed thereon that describes the contents of the container. The label may also include appropriate warnings.

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier for injections, for example water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily or unit daily dose (as described herein above) of the active ingredient or an appropriate fraction thereof.

In another aspect, the compounds of formula I and formula I', or pharmaceutically acceptable salts thereof, may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials that can be used for the purpose of administering the composition, and can be solid, liquid or gaseous materials that are otherwise inert or acceptable to formula I and formula I' in the veterinary field and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Method of treatment

In a third aspect, the present invention relates to the treatment of certain conditions in a patient in need thereof by using sGC stimulators or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same, alone or in combination.

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutical formulations thereof and their use, alone or in combination with one or more other agents, for the treatment and/or prevention of various diseases, where an increase in the concentration of NO or an increase in the concentration of cGMP may be desired. Treatable diseases include, but are not limited to, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis, erectile dysfunction, female sexual dysfunction, conditions associated with diabetes, ocular conditions, and other related cardiovascular conditions.

Increased concentrations of cGMP result in vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive effects, anti-remodeling effects, anti-apoptotic effects, anti-inflammatory effects, and nerve signaling effects. Thus, sGC stimulators may be used to treat and/or prevent a range of diseases and disorders, including but not limited to peripheral, pulmonary, hepatic, cardiac or cerebrovascular/endothelial disorders or conditions, genitourinary-gynecological or sexual dysfunction or disorder, thromboembolic disease, ischemic disease, fibrotic disorder, superficial or skin disorder, pulmonary or respiratory disorder, renal or hepatic disorder, metabolic disorder, atherosclerosis, or lipid-related disorder.

In other embodiments, the compounds disclosed herein are sGC stimulators that are useful for the prevention and/or treatment of diseases or conditions characterized by: an undesirable reduction in bioavailability and/or sensitivity to NO, such as those associated with oxidative stress or nitrification stress conditions.

Throughout this disclosure, the terms "hypertension", "arterial hypertension" or "Hypertension (HBP)" are used interchangeably and refer to an extremely prevalent and highly preventable chronic condition in which arterial Blood Pressure (BP) is higher than normal. If not properly controlled, it represents a significant risk factor for several serious cardiovascular and renal pathologies. Hypertension may be a primary disease, referred to as "essential hypertension" or "idiopathic hypertension", or it may be caused by other diseases, in which case it is classified as "secondary hypertension". Essential hypertension accounts for 90-95% of all cases.

As used herein, the term "refractory hypertension" refers to hypertension that remains above the target blood pressure (typically less than 140/90mmHg, but a lower target of less than 130/80mmHg is recommended for patients with concurrent diabetes or kidney disease) despite the concurrent use of three antihypertensive agents belonging to different classes of antihypertensive drugs. Persons requiring four or more drugs to control blood pressure are also considered to have refractory hypertension. Hypertension is a very common comorbid condition in diabetes, affecting about 20-60% of diabetics, depending on obesity, race and age. This type of hypertension is referred to herein as "diabetic hypertension". In type 2 diabetes, hypertension often occurs as part of the insulin resistance metabolic syndrome, and also includes central obesity and dyslipidemia. In type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy.

As used herein, Pulmonary Hypertension (PH) is a disease characterized by a sustained elevation of blood pressure in the pulmonary vasculature (pulmonary arteries, pulmonary veins, and pulmonary capillaries), which leads to right heart hypertrophy, ultimately leading to right heart failure and death. Common symptoms of PH include shortness of breath, dizziness, and fainting, all of which are exacerbated by exercise. Without treatment, the median life expectancy after diagnosis was 2.8 years. PH exists in a number of different forms, which can be classified according to etiology. Categories include Pulmonary Arterial Hypertension (PAH), PH with left heart disease, PH associated with pulmonary disease and/or hypoxemia, PH due to chronic thrombotic and/or embolic disease, and miscellaneous PH. PAH is rare in the general population, but the incidence is increased in association with certain common conditions such as HIV infection, scleroderma, and sickle cell disease. Other forms of PH are generally more common than PAH, and, for example, the association of PH with Chronic Obstructive Pulmonary Disease (COPD) is of particular concern. Current treatments for pulmonary hypertension depend on the stage and mechanism of the disease.

As used herein, "heart failure" is a progressive Left Ventricular (LV) myocardial remodeling disorder, ending with a complex clinical syndrome in which impaired cardiac function and circulatory congestion are defined features and result in inadequate delivery of blood and nutrients to body tissues. The condition occurs when the heart is damaged or over-worked and is unable to pump all of the blood that circulates back to it from the system. When less blood is pumped, the blood returning to the heart backs up and fluid accumulates in other parts of the body. Heart failure also impairs the ability of the kidneys to handle sodium and water, further complicating fluid retention. Heart failure is characterized by autologous dysfunction, neurohormonal activation, and overproduction of cytokines, which contribute to progressive circulatory failure. Symptoms of heart failure include: dyspnea (shortness of breath) due to sudden apneas (both indicative of emphysema) while exercising or resting and waking at night; general fatigue or weakness, foot, ankle and leg edema, rapid weight gain, chronic cough, including those producing mucus or blood. Depending on clinical manifestations, heart failure is classified as neonatal, transient or chronic. Acute heart failure, i.e., a rapid or gradual onset of symptoms requiring urgent treatment, can progress either neo-natally or as a result of chronic heart failure becoming decompensated. Diabetes is a common comorbidity in heart failure patients and is associated with poor outcomes and potentially compromises therapeutic efficacy. Other important comorbidities include systemic hypertension, chronic airflow obstruction, sleep apnea, cognitive dysfunction, anemia, chronic kidney disease, and arthritis. Chronic left heart failure is often associated with the development of pulmonary hypertension. The frequency of certain comorbidities varies with gender: in women, hypertension and thyroid disease are more common, while men are more commonly afflicted with Chronic Obstructive Pulmonary Disease (COPD), peripheral vascular disease, coronary artery disease, and renal insufficiency. Depression is a frequent co-morbidity of heart failure, and these two conditions can and often are concurrent with each other. Cachexia has long been recognized as a serious and frequent complication of heart failure affecting up to 15% of all heart failure patients and is associated with poor diagnosis. Cardiac cachexia is defined as the involuntary loss of at least 6% of body mass over a 6 month period.

The term "sleep apnea" refers to the most common disorder of sleep disordered breathing. It is characterized by the following pathologies: the flow may be intermittent, reduced in circulation, or stopped altogether, which may or may not involve upper airway obstruction. There are three types of sleep apnea: obstructive sleep apnea (the most common form), central sleep apnea and mixed sleep apnea.

"Central Sleep Apnea (CSA)" is caused by dysfunction of the brain's normal respiratory signals, rather than physical closure of the airways. The lack of respiratory effort results in an increase in carbon dioxide in the blood, which may awaken the patient. CSA is rare in the general population, but is relatively common in patients with systolic heart failure.

As used herein, the term "metabolic syndrome", "insulin resistance syndrome" or "syndrome X" refers to a group or cluster of metabolic conditions (abdominal obesity, elevated fasting glucose, "dyslipidemia" (i.e., elevated lipid levels), and Hypertension (HBP)) that occur more often together than by chance alone and together contribute to the development of type 2 diabetes and cardiovascular disease. Metabolic syndrome is characterized by a specific lipid profile with increased triglycerides, decreased high density lipoprotein cholesterol (HDL-cholesterol) and, in some cases, moderately elevated low density lipoprotein cholesterol (LDL-cholesterol) levels, and accelerated progression of "atherosclerotic disease" due to stress constituting risk factors. There are several types of dyslipidemia: "hypercholesterolemia" refers to elevated cholesterol levels. Familial hypercholesterolemia is a particular form of hypercholesterolemia due to a defect on chromosome 19 (19p 13.1-13.3). "hypertriglyceridemia" refers to elevated levels of glycerides (e.g., "hypertriglyceridemia" relates to elevated triglyceride levels). "hyperlipoproteinemia" refers to elevated lipoprotein levels (typically LDL, unless otherwise specified).

As used herein, the term "Peripheral Vascular Disease (PVD)", also commonly referred to as "Peripheral Arterial Disease (PAD)" or "Peripheral Arterial Occlusive Disease (PAOD)", refers to the occlusion of an aorta that is not in the coronary arteries, aortic arch vasculature or brain. PVD can be caused by atherosclerosis, inflammatory processes leading to stenosis, embolism or thrombosis. It causes acute or chronic "ischemia (lack of blood supply)". In general, PVD is a term used to refer to atherosclerotic occlusion seen in the lower extremities. PVD also includes a subset of diseases classified as microvascular disease caused by occasional narrowing of arteries (e.g., "raynaud's phenomenon") or their widening (erythromelalgia), i.e., vascular spasms.

The term "thrombosis" refers to the formation of blood clots ("thrombi") within the blood vessels that block the flow of blood through the circulatory system. When blood vessels are damaged, the body uses platelets (thrombocytes) and fibrin to form blood clots to prevent blood loss. Alternatively, even when the blood vessel is not damaged, blood clots may form in the body if the appropriate pathology manifests itself. If the clot is too severe and the clot breaks free, the advancing clot is now called an "embolism". The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism". When a thrombus occupies greater than 75% of the arterial luminal surface area, the blood flow supplied to the tissue is sufficiently reduced to cause a variety of symptoms due to reduced oxygen (hypoxia) and accumulation of metabolites such as lactic acid ("gout"). Greater than 90% of obstruction can lead to hypoxia, complete oxygen deprivation, and "infarction," a mode of cell death.

An "embolism" (multiple embolism) is an event in which an embolus (a detached intravascular mass capable of occluding the arterial capillary bed at a site remote from its origin) lodges in the narrow capillaries of the arterial bed, causing the distal part of the body to close (vessel occlusion). This should not be confused with a thrombus that is closed at the site of origin.

A "stroke" or cerebrovascular event (CVA) is a rapid loss of one or more brain functions due to disturbance of the blood supply to the brain. This can be attributed to "ischemia" (lack of blood flow) caused by occlusion (thrombosis, arterial embolism) or hemorrhage (blood leak). Thus, the affected area of the brain fails to function, which may result in the inability to move one or more limbs on one side of the body, the inability to understand or express language, or the inability to see one side of the visual field. Risk factors for stroke include aging, hypertension, previous stroke or Transient Ischemic Attack (TIA), diabetes, high cholesterol, smoking, and atrial fibrillation. Hypertension is the most important and manageable risk factor for stroke. "ischemic stroke" is sometimes treated in hospitals by thrombolysis (also known as "clot lysis agent"), and some hemorrhagic strokes benefit from neurosurgery. Preventing relapse may involve administration of antiplatelet drugs such as aspirin and dipyridamole (dipyridamole), control and reduction of hypertension, and the use of statins. Selected patients may benefit from carotid endarterectomy and the use of anticoagulants.

"ischemia" is a restriction of the blood supply to a tissue, causing a shortage of oxygen and glucose required for cellular metabolism (to keep the tissue alive). Ischemia is generally caused by vascular problems, resulting in tissue damage or dysfunction. It also means ischemia of a given part of the body, which is sometimes caused by congestion (such as vasoconstriction, thrombosis or embolism).

According to the American Psychiatric Association's Diagnostic and statistical Manual of Mental Disorders, fourth edition (DSM-IV), the term "sexual dysfunction" encompasses a series of conditions characterized by disturbances of libido and psychophysiological changes associated with the sexual response cycle; while this type of problem is common, sexual dysfunction is only thought to exist when the problem causes annoyance to the patient. Sexual dysfunction may be of physical or psychological origin. It may exist as a primary condition, generally hormonal in nature, but most often secondary to other medical conditions or drug treatments for such conditions. All types of sexual dysfunction can be further classified as terminal, acquired, episodic, or generalized (or combinations thereof).

DSM-IV-TR specifies five main classes of "female sexual dysfunction": disorders of libido/interest; "sexual arousal disorder (including reproductive, subjective, and combination)"; orgasmic disorder; feelings of uneasiness and vaginismus; and persistent excitability disorders.

"Female Sexual Arousal Disorder (FSAD)" is defined as persistent or recurrent inability to obtain or maintain a sufficient level of sexual arousal, thereby causing personal distress. FSAD involves a lack of subjective impulse sensation (i.e., subjective arousal disorder) and a lack of somatic reactions such as lubrication and uplift (i.e., reproductive/physical arousal disorder). FSAD may be strictly of psychological origin, but it is generally caused by or concurrent with medical or physiological factors. Hypoestrogenicity is the most common physiological condition associated with FSAD, which leads to urogenital atrophy and decreased vaginal lubrication.

As used herein, "Erectile Dysfunction (ED)" is male sexual dysfunction characterized by the inability to develop or maintain a penile erection during sexual activity. Penile erection is the hydraulic action of blood entering and remaining in the corpus cavernosum of the penis. This process is often initiated by sexual excitation as signals are transmitted from the brain to the nerves in the penis. Erectile dysfunction is indicated when erection is difficult to develop. The most important causes of the organism are cardiovascular diseases and diabetes, neurological problems (e.g., prostatectomy trauma), hormone deficiency (hypogonadism), and drug side effects.

As used herein, the term "bronchoconstriction" is used to define the contraction of the pulmonary airways due to tightening of the surrounding smooth muscles, resulting in coughing, wheezing and shortness of breath. The condition has multiple etiologies, with asthma being the most common cause of the condition. Exercise and allergies may cause symptoms in otherwise asymptomatic individuals. Other conditions such as Chronic Obstructive Pulmonary Disease (COPD) may also exhibit bronchoconstriction.

Specific diseases or conditions that can be treated and/or prevented by administration of sGC stimulators of the invention include, but are not limited to: hypertension (e.g., diabetic hypertension, arterial hypertension, pulmonary hypertension, refractory hypertension, peripheral arterial disease, etc.), heart failure (e.g., Left Ventricular Diastolic Dysfunction (LVDD) and Left Ventricular Systolic Dysfunction (LVSD), sleep apnea associated with heart failure), atherosclerotic diseases (e.g., atherosclerosis), thromboembolic disorders (e.g., chronic thromboembolic pulmonary hypertension, thrombosis, stroke, embolism, pulmonary embolism), Alzheimer's disease, renal diseases (e.g., renal fibrosis, ischemic renal disease, renal failure, renal insufficiency, chronic renal disease), hepatic diseases (e.g., hepatic fibrosis or cirrhosis), respiratory diseases (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, interstitial lung disease), sexual dysfunction (e.g., erectile dysfunction, male and female sexual dysfunction, refractory hypertension, peripheral arterial disease, etc.), cardiac failure (e.g., chronic thromboembolic pulmonary hypertension, thrombosis, stroke, embolism, pulmonary embolism), Alzheimer's disease, renal fibrosis, ischemic, Vaginal atrophy), sickle cell anemia, neuroinflammatory diseases or disorders, and metabolic disorders (e.g., lipid-related disorders).

Compounds of formula I and formula I' and pharmaceutically acceptable salts thereof are useful as sGC stimulators for the prevention and/or treatment of the following types of diseases, conditions and disorders that can benefit from sGC stimulation:

(i) peripheral, pulmonary, hepatic, renal, cardiac or cerebrovascular/endothelial disorders or conditions or diseases associated with other modes of circulation:

disorders related to: hypertension and reduced coronary vascular flow (such as acute and chronic increases in coronary blood pressure), arterial hypertension, and vascular disorders resulting from cardiac and renal complications (e.g., heart disease, stroke, cerebral ischemia, renal failure); refractory hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; cardiac arrhythmia; a reduction in ventricular preload; cardiac hypertrophy; heart failure/cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage;

thromboembolic disorders and ischemia, such as myocardial infarction, stroke, Transient Ischemic Attack (TIA); obstructive thrombotic vasculitis; stable or unstable angina; coronary artery spasm; variant angina pectoris; prinzmitos angina (Prinzmetal's angina); prevention of restenosis following thrombolytic therapy; thrombotic disorders;

alzheimer's disease; parkinson's disease; dementia; vascular cognitive disorders; cerebral vasospasm; traumatic brain injury;

peripheral arterial disease; peripheral obstructive arterial disease; peripheral vascular disease; the pressure is too high; raynaud's syndrome or phenomenon; critical limb ischemia; vasculitis; a peripheral plug; intermittent claudication; vascular occlusion crisis; duchenne and becker muscular dystrophy; a microcirculation abnormality; control of vascular leakage or permeability;

shock; septicemia; cardiogenic shock; controlling leukocyte activation; inhibiting or modulating platelet aggregation;

pulmonary/respiratory conditions such as pulmonary hypertension, pulmonary arterial hypertension, and associated pulmonary vascular remodeling (e.g., local thrombosis and right heart hypertrophy); excessive lung pressure; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, pre-capillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary artery disease, plexogenic pulmonary artery disease; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis; lung transplantation;

pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary venous malformation drainage, pulmonary vein obstructive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep disordered breathing, sleep apnea, alveolar hypoventilation disorders, chronic altitude disease, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other blood clotting disorders, chronic thromboembolism, pulmonary embolism (due to tumor, parasite or foreign material), connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangioma; histiocytosis X, lymphangiomatosis, and pulmonary vascular compression (such as due to adenosis, tumors, or fibrositis);

arteriosclerotic diseases or conditions such as atherosclerosis (e.g., associated with endothelial injury, platelet and monocyte attachment and aggregation, smooth muscle proliferation and migration); restenosis (e.g., development after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA), and bypass); inflammation;

cardiovascular diseases associated with: metabolic syndrome (e.g., obesity, dyslipidemia, diabetes, hypertension); lipid-related disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; pre-eclampsia; polycystic kidney disease progression; subcutaneous fat; obesity;

cirrhosis associated with: chronic liver disease, liver fibrosis, hepatic stellate cell activation, hepatic fibrocollagen and total collagen accumulation; a fatal inflammatory and/or immunogenic liver disease; and genitourinary system disorders such as renal fibrosis and renal failure resulting from chronic kidney disease or insufficiency (e.g., due to accumulation/deposition and tissue injury, progressive sclerosis, glomerulonephritis); prostatic hypertrophy, systemic sclerosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy;

(2) ischemia, reperfusion injury; ischemia/reperfusion associated with: organ transplantation, lung transplantation (lung transplantation), lung transplantation (pulmony transplantation), heart transplantation; preserving blood substitutes in trauma patients;

(3) sexual, gynecological and urological disorders or conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction (e.g., female sexual arousal disorder, hypoactive sexual arousal disorder); vaginal atrophy, feelings of uneasiness, atrophic vaginitis; benign Prostatic Hypertrophy (BPH) or overgrowth or enlargement, bladder outlet obstruction; bladder Pain Syndrome (BPS), Interstitial Cystitis (IC), overactive bladder, neurogenic bladder, and incontinence; diabetic nephropathy;

(4) ocular diseases or disorders: glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, sjogren's syndrome;

(5) a hearing disease or disorder: hearing impairment; partial or total hearing loss; partial or complete deafness; tinnitus; noise-induced hearing loss;

(6) topical or dermal disorders or conditions: dermal fibrosis, scleroderma, dermal fibrosis;

(7) wound healing, for example in diabetes; improvement in microvascular perfusion (e.g., post-injury to combat inflammatory reactions in perioperative care), anal fissures, diabetic ulcers; and

(8) other diseases or conditions: cancer metastasis, osteoporosis, gastroparesis; functional dyspepsia; diabetic complications, diseases associated with endothelial dysfunction, and neurological disorders associated with reduced nitric oxide production.

In other embodiments of the invention, the compounds of formula I and formula I' and pharmaceutically acceptable salts thereof are useful for the prevention and/or treatment of the following types of diseases, conditions, and disorders that may benefit from sGC stimulation:

hypertension, refractory hypertension, diabetic hypertension, Pulmonary Hypertension (PH), pulmonary arterial hypertension, PH associated with COPD, chronic airflow obstruction, asthma or pulmonary fibrosis, thrombosis, embolism, thromboembolic disorders, alzheimer's disease, atherosclerosis, right heart hypertrophy, heart failure, diastolic dysfunction, systolic dysfunction, sleep apnea associated with heart failure, liver cirrhosis, kidney fibrosis, renal failure resulting from chronic kidney disease or insufficiency, metabolic disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction, female sexual arousal disorder, and vaginal atrophy.

In some embodiments, the present invention relates to a method of treating a disease, health condition, or disorder in a subject, comprising administering to the subject in need of treatment a therapeutically effective amount of a compound of any one of the formulae depicted above, or a pharmaceutically acceptable salt thereof, wherein the disease, health condition, or disorder is selected from one of the diseases listed above.

In other embodiments, the disease, health condition or disorder is selected from a peripheral, pulmonary, hepatic, renal, cardiac, or cerebrovascular/endothelial disorder or condition or a disease otherwise associated with circulation selected from: acute and chronic coronary blood pressure increases, arterial hypertension and vascular disorders resulting from cardiac and renal complications, heart disease, stroke, cerebral ischemia, renal failure; refractory hypertension, diabetic hypertension, congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; cardiac arrhythmia; a reduction in ventricular preload; cardiac hypertrophy; heart failure/cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage; myocardial infarction; stroke or Transient Ischemic Attack (TIA); obstructive thrombotic vasculitis; stable or unstable angina; coronary artery spasm, variant angina, Prinzmett angina; restenosis as a result of thrombolytic therapy and thrombotic disorders.

In other embodiments, the disease, health condition or disorder is selected from a peripheral vascular/endothelial disorder or condition or a disease otherwise associated with circulation selected from: peripheral arterial disease, peripheral obstructive arterial disease; peripheral vascular disease; the pressure is too high; raynaud's syndrome or phenomenon; critical limb ischemia; vasculitis; a peripheral plug; intermittent claudication; vascular occlusion crisis; duchenne and becker muscular dystrophy; a microcirculation abnormality; and vascular leakage or permeability problems.

In other embodiments, the disease, health condition or disorder is a pulmonary disorder or a disease otherwise associated with circulation selected from: pulmonary hypertension; pulmonary arterial hypertension and associated pulmonary vascular remodeling; local thrombosis; right heart hypertrophy; excessive lung pressure; primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, pre-capillary pulmonary hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary artery disease, plexogenic pulmonary artery disease; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis and lung transplantation. In some of these embodiments, the pulmonary hypertension is pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary venous malformation drainage, pulmonary vein obstructive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep disordered breathing, sleep apnea, alveolar hypoventilation disorders, chronic altitude sickness, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease; blood coagulation disorders; chronic thromboembolism, pulmonary embolism due to tumor, parasite or exogenous material, connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangioma; histiocytosis X, lymphangiomatosis, and pulmonary vascular compression due to adenosis, tumors, or fibrositis.

In other embodiments, the health condition or disorder is a vascular or endothelial disorder or condition or disease otherwise associated with circulation selected from the group consisting of: arteriosclerotic diseases; atherosclerosis, atherosclerosis associated with endothelial injury, atherosclerosis associated with platelet and monocyte attachment and aggregation, atherosclerosis associated with smooth muscle proliferation and migration; restenosis, restenosis developed after thrombolytic therapy; restenosis that develops after percutaneous transluminal angioplasty; restenosis that develops after percutaneous transluminal coronary angioplasty and bypass; inflammation; cardiovascular disease associated with: metabolic syndrome, obesity, dyslipidemia, diabetes or hypertension; lipid-related disorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; pre-eclampsia; polycystic kidney disease progression; and subcutaneous fat.

In other embodiments, the disease, health condition, or disorder is selected from cirrhosis, cirrhosis associated with: chronic liver disease, hepatic fibrosis, hepatic stellate cell activation, hepatic fibrocollagen; total collagen accumulation; inflammatory or immunogenic liver disease.

In other embodiments, the disease, health condition, or disorder is a genitourinary disorder selected from renal fibrosis; renal failure due to chronic kidney disease or insufficiency; renal failure due to accumulation or deposition and tissue damage, progressive sclerosis or glomerulonephritis; and prostatic hypertrophy.

In other embodiments, the disease, health condition, or disorder is systemic sclerosis.

In other embodiments, the disease, health condition, or disorder is a cardiac condition selected from cardiac interstitial fibrosis; cardiac remodeling and fibrosis, and cardiac hypertrophy.

In other embodiments, the disease, health condition, or disorder is a CNS disorder or condition selected from: alzheimer's disease; parkinson's disease; dementia; vascular cognitive disorders; cerebral vasospasm; and traumatic brain injury.

In other embodiments, the disease, health condition, or disorder is selected from ischemia, reperfusion injury; ischemia/reperfusion associated with: organ transplantation, lung transplantation (lung transplantation), lung transplantation (pulmony transplantation) or heart transplantation; and preserving the blood substitute in the trauma patient.

In other embodiments, the disease, health condition or disorder is a sexual, gynecological, and urological disorder or condition selected from erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal disorder; hypofunction sexual excitation disorder; vaginal atrophy, feelings of uneasiness, atrophic vaginitis; benign Prostatic Hypertrophy (BPH) or overgrowth or enlargement; bladder outlet obstruction; bladder Pain Syndrome (BPS); interstitial Cystitis (IC); overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy.

In other embodiments, the disease, health condition or disorder is selected from vaginal atrophy, anhedonia, and atrophic vaginitis.

In other embodiments, the disease, health condition or disorder is selected from Benign Prostatic Hypertrophy (BPH) or overgrowth or enlargement, bladder outlet obstruction, Bladder Pain Syndrome (BPS), Interstitial Cystitis (IC), overactive bladder, neurogenic bladder, and incontinence.

In other embodiments, the disease, health condition, or disorder is a sexual condition selected from erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal disorder and hypoactive sexual arousal disorder.

In other embodiments, the disease or disorder is diabetic nephropathy.

In other embodiments, the disease, health disorder, or condition is duchenne and becker muscular dystrophy.

In other embodiments, the disease is an ocular disease or disorder selected from glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, and sjogren's syndromeSyndrome)。

In other embodiments, the disease is a hearing disease or disorder selected from the group consisting of hearing impairment; partial or total hearing loss; partial or complete deafness; tinnitus; and noise-induced hearing loss.

In other embodiments, the disease is a surface or skin disorder or condition selected from dermal fibrosis, scleroderma, and skin fibrosis.

In other embodiments, the treatment involves wound healing; wound healing in diabetes; improvement in microvascular perfusion; the microvascular perfusion problem is improved after injury; treating anal fissure; and treating diabetic ulcers.

In other embodiments, the disease or disorder is selected from the group consisting of cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; diseases associated with endothelial dysfunction and neurological disorders associated with reduced nitric oxide production.

In another embodiment, the compounds of the invention may be delivered in the form of an implantable device stent. Stents are reticulated "tubes" that are inserted into the natural passages/conduits of the body to prevent or counter disease-induced local flow constriction. The term may also refer to a tube used to temporarily hold open such natural ducts to allow access for surgery.

Drug Eluting Stents (DES) are peripheral or coronary stents (scaffolds) placed in stenotic peripheral or coronary arteries that slowly release drugs to block cell proliferation, typically smooth muscle cell proliferation. This prevents fibrosis, which together with the clot (thrombus) can block the supported artery, a process known as restenosis. Stents are typically placed within peripheral or coronary arteries during an angioplasty procedure by an interventional cardiologist or interventional radiologist. Drugs commonly used in DES to block cell proliferation include paclitaxel (paclitaxel) or rapamycin (rapamycin) analogues

In some embodiments of the invention, the sGC stimulators of the invention may be delivered by a drug eluting stent coated with the sGC stimulators. Drug-eluting stents coated with sGC stimulators of the invention may be used to prevent stent restenosis and thrombosis during percutaneous coronary interventions. Drug-eluting stents coated with sGC stimulators of the invention may be able to prevent smooth cell proliferation and help re-vascularization and regeneration of the endothelial tissue of the stented artery.

An alternative to percutaneous coronary intervention for the treatment of refractory angina due to coronary occlusive disease is a procedure known as Coronary Artery Bypass Graft (CABG). CABG provides only a palliation of the ongoing process, which is further complicated by the rapid development of graft atherosclerosis. Saphenous vein grafts are the most commonly used conduit in CABG procedures. The long-term clinical success of intravenous CABG is hampered by three main reasons: accelerated graft atherosclerosis, incomplete endothelialization and thrombosis.

In some embodiments, sGC stimulators of the invention may be used to prevent saphenous vein graft failure during CABG procedures. The compounds of the present invention may assist in the endothelialisation process and help prevent thrombosis. In this indication, the sGC stimulators are delivered locally in the form of a gel.

The terms "disease," "disorder," and "condition" are used interchangeably herein to refer to sGC, cGMP, and/or NO-mediated medical or pathological conditions.

As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., an avian species such as a chicken, quail or turkey, or a mammal), specifically a "mammal" that includes non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically a human. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

The present invention also provides a method for treating one of the above diseases, conditions or disorders in a subject comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I and formula I', or a pharmaceutically acceptable salt thereof. Alternatively, the present invention provides the use of a compound of formula I and formula I', or a pharmaceutically acceptable salt thereof, to treat one of these diseases, conditions or disorders in a subject in need thereof. The invention further provides a method of making or manufacturing a medicament useful for treating one of these diseases, conditions or disorders, comprising the use of a compound of formula I and formula I', or a pharmaceutically acceptable salt thereof.

As used herein, the term "biological sample" refers to an in vitro or ex vivo sample, and includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, lymph, intraocular fluid, vitreous humor or other body fluids or extracts thereof.

"treating" or "treatment" with respect to a disorder or disease refers to reducing or eliminating the cause and/or effect of the disorder or disease. As used herein, the term "treating" refers to reducing or ameliorating the progression, severity, and/or duration of an sGC, cGMP, and/or NO-mediated condition, or ameliorating one or more symptoms (preferably one or more discernible symptoms) of the condition (i.e., "managing" without "curing" the condition), which results from administration of one or more treatments (e.g., one or more therapeutic agents, such as a compound or composition of the invention). In particular embodiments, the term "treating" refers to ameliorating at least one measurable physical parameter of an sGC, cGMP, and/or NO-mediated condition. In other embodiments, the term "treating" refers to inhibiting the progression of sGC, cGMP, and/or NO-mediated pathology, either physically by, e.g., stabilizing discernible symptoms or physiologically by, e.g., stabilizing physical parameters, or both.

As used herein, the term "preventing" refers to the premature administration of an agent to avoid or prevent the appearance of one or more symptoms of a disease or disorder. One of ordinary skill in the medical arts recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood to refer to the possibility or severity of prophylactic administration of a drug to substantially impair a condition or symptoms of a condition, and this is what the present disclosure is intended to mean. The standard text Physician's Desk Reference in the art uses the term "prevent" hundreds of times. As used herein, the terms "prevent", "preventing" and "prevention" with respect to a disease or disorder refer to avoiding the cause, effect, symptom or progression of the disease or disorder before the disease or disorder itself is fully manifested.

In one embodiment, the method of the invention is a prophylactic or "preventative" measure against patients, particularly humans, having a predisposition (e.g., a genetic predisposition) to develop sGC, cGMP and/or NO-related diseases, disorders or symptoms.

In other embodiments, the methods of the invention are prophylactic or "preventative" measures against, in particular human, a patient suffering from a disease, disorder or condition that puts the patient at risk of developing a sGC, cGMP, and/or NO-related disease, disorder or condition.

The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of diseases or disorders mediated, modulated or otherwise affected by sGC, cGMP and/or NO.

The compounds and compositions disclosed herein are also useful for veterinary treatment of companion, exotic, and farm animals, including but not limited to dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs, and cattle.

In other embodiments, the present invention provides a method of stimulating sGC activity in a biological sample comprising contacting the biological sample with a compound or composition of the invention. The use of sGC stimulators in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays and biological sample storage.

Combination therapy

The compounds and pharmaceutical compositions described herein may be used in combination therapy with one or more other therapeutic agents. For combination therapy with more than one active agent, wherein the active agents are in separate dosage form formulations, the active agents may be administered alone or in combination. In addition, the administration of one element is before, simultaneously with, or after the administration of the other agent.

When co-administered with other agents, such as when co-administered with another pain medication, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and may be adjusted by one of skill in the art depending on the condition of the subject, the type of condition or conditions being treated, and the amount of the compound described herein being used. In the case where amounts are not explicitly indicated, an effective amount should be employed. For example, the compounds described herein may be administered to a subject in the following dosage ranges: about 0.01 to about 10,000mg/kg body weight/day, about 0.01 to about 5000mg/kg body weight/day, about 0.01 to about 3000mg/kg body weight/day, about 0.01 to about 1000mg/kg body weight/day, about 0.01 to about 500mg/kg body weight/day, about 0.01 to about 300mg/kg body weight/day, about 0.01 to about 100mg/kg body weight/day.

When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of formula I and formula I', or a pharmaceutically acceptable salt thereof, and a second amount of another suitable therapeutic agent.

In one embodiment of the invention, the compounds of formula I and formula I' and the additional therapeutic agent are each administered in an effective amount (i.e., each amount would be therapeutically effective if administered alone). In another embodiment, the compounds of formula I and formula I' and the additional therapeutic agent are each administered in an amount that alone does not provide a therapeutic effect (sub-therapeutic dose). In another embodiment, the compounds of formula I and formula I' may be administered in an effective amount, while the other therapeutic agent is administered in a sub-therapeutic dose. In another embodiment, the compounds of formula I and formula I' may be administered in sub-therapeutic doses, while another therapeutic agent, such as a suitable cancer therapeutic agent, is administered in an effective amount.

As used herein, the terms "combination" or "co-administration" are used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of these terms does not limit the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Co-administration comprises administering the first and second amounts of the compound in a substantially simultaneous manner, such as in a single pharmaceutical composition, e.g., a capsule or tablet having a solid ratio of the first and second amounts, or in multiple separate capsules or tablets for each. In addition, such co-administration also includes the use of each compound in either order in a sequential manner. When co-administration involves administering a first amount of a compound of formula I and formula I' separately and a second amount of another therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the time period between administrations that can result in a desired therapeutic effect can range from minutes to hours, and can be determined taking into account the characteristics of the compounds, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compounds of formula I and formula I' and the second therapeutic agent may be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered to a subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent).

Examples of other therapeutic agents that may be administered alone or in the same pharmaceutical composition in combination with the compounds of the present disclosure include, but are not limited to:

(1) endothelial Derived Release Factor (EDRF);

(2) NO donors such as nitrosothiols, nitrites, sydnonimine, NONONOate, N-nitrosamines, N-hydroxynitrosamines, nitrosoimines, nitrotyrosine, diazacyclobutene dioxide, oxatriazole 5-imine, oximes, hydroxyamines, N-hydroxyguanidines, hydroxyureas or furazolidone. Some examples of these types of compounds include glyceryl trinitrate (also known as GTN, nitroglycerin, and triglycerol), the nitrate ester of glycerol; sodium Nitroprusside (SNP), in which one molecule of nitric oxide coordinates to metallic iron, forming a tetragonal bipyramid complex; 3-morpholino-sydnonimine (SIN-1), an amphoteric compound formed by combining morpholine and sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative having a nitrosothiol functional group; diethylenetriamine/NO (DETA/NO), a compound in which nitric oxide is covalently bonded to diethylenetriamine; and NCX4016, m-nitroxymethylphenyl ester of acetylsalicylic acid. More specific examples of some of these classes of NO donors include: classical nitrovasodilators such as organic nitrates and nitrites, including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide esterFK 409 (NOR-3); FR 144420 (NOR-4); 3-morpholino sydnonimine; linsidomine (Linsidomine) chloride hydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); AZD3582(CINOD lead compound), NCX4016, NCX 701, NCX 1022, HCT 1026, NCX1015, NCX 950, NCX 1000, NCX 1020, AZD 4717, NCX 1510/NCX 1512, and mixtures thereof,NCX 2216 and NCX4040 (both from NicOx s.a.), S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione monoethyl ester (GSNO ester), 6- (2-hydroxy-1-methyl-nitrosohydrazino) -N-methyl-1-hexylamine (NOC-9), or diethylamine NONOate. Nitric oxide donors are also disclosed in U.S. Pat. Nos. 5,155,137, 5,366,997, 5,405,919, 5,650,442, 5,700,830, 5,632,981, 6,290,981, 5,691,423, 5,721,365, 5,714,511, 6,511,911 and 5,814,666, Chrysselis et al (2002) J Med chem.45:5406-9 (such as NO donors 14 and 17) and Nitic oxid donors for Pharmaceutical and Biological Research, Peng George Wang, TingweiBill Cai, Naoyuki Taniguchi eds, Wiley, 2005;

(3) other cGMP concentration-enhancing substances such as protoporphyrin (protoporphyrin) IX, arachidonic acid, and phenylhydrazine derivatives;

(4) nitric oxide synthase substrate: for example, N-hydroxyguanidino analogs such as N [ G ] -hydroxy-L-arginine (NOHA), 1- (3, 4-dimethoxy-2-chlorobenzylideneamino) -3-hydroxyguanidine, and PR5(1- (3, 4-dimethoxy-2-chlorobenzylideneamino) -3-hydroxyguanidine); l-arginine derivatives (such as homoarg, homonoha, N-tert-butyloxy-and N- (3-methyl-2-butenyl) oxy-L-arginine, canavanine (canavanine), epsilon-guanidine-hexanoic acid, herring spermine (agmatine), hydroxy-herring spermine, and L-tyrosyl-L-arginine); N-alkyl-N ' -hydroxyguanidines (such as N-cyclopropyl-N ' -hydroxyguanidine and N-butyl-N ' -hydroxyguanidine), N-aryl-N ' -hydroxyguanidines (such as N-phenyl-N ' -hydroxyguanidine and its para-substituted derivatives having-F, -Cl, -methyl, -OH substituents, respectively); guanidine derivatives such as 3- (trifluoromethyl) propylguanidine; and other nitric oxide synthase substrates reviewed in Cali et al (2005, Current Topics in Medicinal Chemistry 5: 721-;

(5) compounds that enhance eNOS transcription: for example those described in WO 02/064146, WO 02/064545, WO 02/064546 and WO 02/064565 and corresponding patent documents such as US2003/0008915, US2003/0022935, US2003/0022939 and US 2003/0055093. Other eNOS transcription enhancers, including US20050101599 (e.g. 2, 2-difluorobenzo [1,3 ]]Dioxole-5-carboxylic acid indan-2-ylamide and 4-fluoro-N- (indan-2-yl) -benzylamide) and Sanofi-Aventis compounds AVE3085 and AVE9488(CA accession No. 916514-70-0;etc., Journal of Thrombosins and Homeostasis 2005; volume 3, supplement 1: abstract number P1487);

(6) NO-independent heme-independent sGC activators, including but not limited to: BAY 58-2667 (see patent publication DE19943635)

HMR-1766 (Ataciguat sodium, see patent publication WO2000002851)

S3448 (2- (4-chloro-phenylsulfonylamino) -4, 5-dimethoxy-N- (4- (thiomorpholine-4-sulfonyl) -phenyl) -benzylamide (see patent publications DE19830430 and WO2000002851)

HMR-1069(Sanofi-Aventis)。

(7) Heme-dependent sGC stimulators, including but not limited to:

YC-1 (see patent publications EP667345 and DE19744026)

Riociguat (Riociguat) (BAY 63-2521, Adempas, commercial product, described in DE 19834044)

Neliciguat (BAY 60-4552, described in WO 2003095451)

Virgiguat (Vericiguat) (BAY 1021189, clinical stand-by of Riociguat)

BAY 41-2272 (described in DE19834047 and DE 19942809)

BAY 41-8543 (described in DE 19834044)

Itraciguat (Etriciguat) (described in WO 2003086407)

CFM-1571 (see patent publication WO2000027394)

A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935.

Compounds disclosed in one of the following publications: US20090209556, US8455638, US20110118282(WO2009032249), US20100292192, US20110201621, US7947664, US8053455(WO2009094242), US20100216764, US8507512(WO2010099054), US20110218202(WO2010065275), US20130012511(WO2011119518), US20130072492(WO2011149921), US20130210798(WO2012058132), and other compounds disclosed in Tetrahedron Letters (2003),44(48): 8661-.

(8) Compounds that inhibit cGMP degradation, such as:

PDE5 inhibitors, such as sildenafil for exampleAnd other related agents such as Avanafil (Avanafil), lotrafil (Lodenafil), milonafil (Mirodenafil), sildenafil citrateTalanafil (Tadalafil) ((r))Or) Vardenafil (Vardenafil)And Udenafil (Udenafil); alprostadil (Alprostadil); and dipyridamole;

(9) calcium channel blockers, such as:

dihydropyridine calcium channel blockers: amlodipine (Amlodipine) (collaterals (Norvasc)), Aranidipine (Aranidipine) (saprosta (Sapresta)), azedipine (Azelidipine) (Calblock (Calblock)), Barnidipine (Barnidipine) (Hypoca)), Benidipine (Benidipine) (Benidipine) (Coneil), Cilnidipine (Cinidipine) (Atelec), cilnaloxonone (Cinalong), ciscar (Siscad)), Clevidipine (Clevidipine) (Clividipine (Clipirex)), Diltiazem (Ditiazem), Efonidipine (Efonidipine) (Landol (Landelel)), Felodipine (Felodipine) (Polidipine) (Plendine (Plundine) (Lacidipine (Mocils), Lacilnidipine (Morcinidipine), Lanidipine (Cardipine) (Cardipine (Zidipine)), and Caridipine (Cardidipine) (Cardidipine (Caridipine (Cardinal)), Manidipine (Cardidipine) (Cardidipine (My)), and/Cardidipine (Cardidipine) (Cardidipine (Zeidipine (Cardidipine)), and/Cardidipine (Cardidipine) (Cardidipine (Caridipine (Zeidipine)), and Zeidipine) (Matidipine (Caridipine) (Cardidipine (S)), and Car, Nifedipine (Nifedipine) (procaldia), adaratide (Adalat)), Nilvadipine (Nilvadipine) (Nivadil), Nimodipine (Nimodipine) (Nimotop), Nisoldipine (Nisoldipine) (berocard), sula (Sular), cisco (Syscor)), Nitrendipine (Nitrendipine) (gardif), stributipine (Nitrepin), new dellotensin (baytenin)), pralidipine (prandine) (acaradipine (Acalas)), Isradipine (Isradipine) (Lomir));

phenylalkylamine calcium channel blockers: verapamil (Verapamul) (kalan, Eiboltin (Isoptin))

Galopamid (Gallopamil) (Procorum, D600);

benzothiazepines: diltiazem (cardiozem);

non-selective calcium channel inhibitors, such as: miazinil (mibefradil), bepridil (bepridil), and fluspirilene (flupirilene), fendiline (fendiline);

(10) endothelin Receptor Antagonist (ERA): e.g. dual (ET)_AAnd ET_B) Endostatin receptor antagonist Bosentan (Bosentan) (asSold); sitaxentan (Sitaxentan), under the nameSelling the product; ambrisentan (Ambrisentan), as a drug in the United statesSelling; dual/non-selective endothelin antagonist acket-1, which entered clinical trials in 2008;

(11) prostacyclin derivatives or analogs: such as prostacyclin (prostaglandin I)₂) Epoprostenol (Epoprostenol) (synthetic prostacyclin asSold); treprostinil (Treprostinil)Iloprost (Iloprost)Iloprost (asSold); in the form of oral and inhalation forms under developmentBeraprost (Beraprost), an oral prostanoid available in japan and south korea;

(12) antihyperlipidemic drugs such as: bile acid sequestrants (e.g., Cholestyramine (Cholestyramine), Colestipol (Colestipol), Colestilan (Colesevelam), and Colesevelam (Colesevelam)); statins such as atorvastatin (Pitavastatin), Simvastatin (Simvastatin), Lovastatin (Lovastatin), Fluvastatin (Fluvastatin), Pitavastatin (Pitavastatin), Rosuvastatin (Rosuvastatin), and Pravastatin (Pravastatin); cholesterol absorption inhibitors such as Ezetimibe (Ezetimibe); other lipid lowering agents such as ethyl itaconate (Icosapent), ethyl omega-3-carboxylate, Reducol; fibric acid derivatives such as Clofibrate (Clofibrate), Bezafibrate (Bezafibrate), Clinofibrate (Clinofibrate), Gemfibrozil (Gemfibrozil), chloronicotinate (Ronifibrate), Binifibrate (Binifibrate), fenofibrate (fenofibrate), Ciprofibrate (Ciprofibrate), choline fenofibrate (fenofibrate); nicotinic acid derivatives such as Acipimox (Acipimox) and Niacin (Niacin); and combinations of: statins, nicotinic acid, intestinal cholesterol absorption inhibitory supplements (ezetimibe and others), and fibrates; antiplatelet therapies such as Clopidogrel (Clopidogrel) bisulfate;

(13) anticoagulants, such as the following types:

coumarin (courmarine) (vitamin K antagonist):(Coumadin)), most used in the united states and uk;and PhenprocouMainly used in other countries;

heparin and derived substances, such as: heparin; low molecular weight heparin, Fondaparinux (Fondaparinux) and heparin-epirubicin (Idraparinux);

direct thrombin inhibitors such as: argatroban (Argatroban), recombinant hirudin (Lepirudin), Bivalirudin (Bivalirudin) and Dabigatran (dabigastran); simelatant (Ximelagatran)Not approved in the united states;

tissue plasminogen activators, used to dissolve blood clots and open arteries, such as Alteplase (Alteplase);

(14) antiplatelet drugs, for example thienopyridines such as Lopidogrel (Lopidogrel) and Ticlopidine (Ticlopidine); dipyridamole; aspirin;

(15) ACE inhibitors, for example of the following types:

mercapto group-containing reagents, such as Captopril (Captopril) (trade name)) A first ACE inhibitor, and Zofenopril (Zofenopril);

dicarboxylic ester-containing reagents, such as Enalapril (Enalapril) (Vasotec @)) (ii) a Ramipril (Ramipril) (Alpace/Tripace/Ramace @) (ii) a Quinapril (Quinapril)Perindopril (Perindopril) (Coversyl @)) (ii) a Lisinopril (Lisinopril) (Lisodur/Lopril/Novatec/Prinivil) And Benazepril (Benazepril)

Phosphonate-containing agents such as: fosinopril (Fosinopril);

naturally occurring ACE inhibitors such as: casein (Casokinin) and lactokinin (lactokinin), which are breakdown products of casein and occur naturally after ingestion of dairy products, in particular fermented milks; the lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by Lactobacillus helveticus or derived from casein also have ACE inhibitory and antihypertensive functions;

other ACE inhibitors such as Alacepril (Alacepril), Delapril (Delapril), Cilazapril (Cilazapril), Imidapril (Imidapril), quadolapril (Trandolapril), Temocapril (Temocapril), Moexipril (Moexipril), Spirapril (Spirapril);

(16) oxygen supplementation therapy;

(17) β retarding agents, such as the following types:

non-selective agents:(with additional α -blocking Activity),(with additional α -blocking Activity),(having intrinsic sympathomimetic activity),(with intrinsic sympathomimetic activity), alprenolol (Oxprenolol), Acebutolol (Acebutolol), Sotalol (Sotalol), pindolol (Mepindolol), Celiprolol (Celiprolol), arolol (Arotinolol), tetanolol (Tertatolol), Amosulalol (Amosulalol), Nipradilol (Nipradilol),And

·β₁-a selective agent:(having intrinsic sympathomimetic activity),Dobutamine (Dobutamine) hydrochloride, elsodipine (Irsogladine) maleate, Carvedilol (Carvedilol), Talinolol (Talinolol), and salts thereof,And

·β₂-a selective agent:(Weak α-adrenergic agonist activity);

(18) antiarrhythmic agents, such as the following types:

type I (sodium channel blocker): quinidine (Quinidine), Lidocaine (Lidocaine), Phenytoin (Phenytoin), propylamine propiophenone (Propafenone)

Type III (potassium channel blocker): amiodarone (Amiodarone), Dofelide (Dofetilide), Sutalol (Sotalol)

Form V: adenosine (Adenosine), Digoxin (Digoxin)

(19) Diuretics, such as: thiazide diuretics, such as chlorothiazide, chlorothiadone and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, Polythiazide, Quinethazone (Quinethazone), Xipamide (Xipamide), Metolazone (methazone), Indapamide (Indapamide), cilostanin (Ciclinine); loop diuretics such as Furosemide (Furosemide) and Toresamide (torsemide); potassium sparing diuretics such as Amiloride (amioride), Spironolactone (Spironolactone), potassium canephonate (Canrenoate), Eplerenone (Eplerenone), and methotrexate (Triamterene); and combinations of these agents; other diuretics, such as acetazolamide (Acetazolamide) and Carperitide (Carperitide)

(20a) Direct acting vasodilators such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, cadrazine (Cadralazine); other vasodilators such as isosorbide dinitrate and isosorbide 5-mononitrate;

(20b) exogenous vasodilators, such as:

·an adenosine agonist, useful primarily as an antiarrhythmic agent;

α blocker (which blocks the vasoconstrictive action of epinephrine):

α -1-adrenoceptor antagonists such as guaiazoline (Prazosin), indoperamine (Indamin), Urapidil (Urapidil), Bunazosin (Bunazosin), Terazosin (Terazosin), Doxazosin (Doxazosin)

Atrial Natriuretic Peptide (ANP);

ethanol;

histamine inducers, these complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophils;

tetrahydrocannabinol (THC), the major active chemical in cannabis, which has a small vasodilating effect;

papaverine, an alkaloid found in poppy flowers;

(21) bronchodilators there are two main types of bronchodilators, β₂Agonists and anticholinergics, as exemplified below:

·β₂agonist(s):or albuterol (albuterol) (commonly known under the trade name salbutamol (Ventolin)) andshort acting β for quick relief of COPD symptoms₂Agonist long-acting β₂Agonists (LABA), such asAnd

anticholinergic agents:short acting anticholinergics are the most widely prescribed.Long-acting cholinergic agents that are most commonly prescribed in COPD;

·a bronchodilator and a phosphodiesterase inhibitor;

(22) corticosteroid: such as beclomethasone, methylprednisone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolone, flunisolide and hydrocortisone, and corticosteroid analogs such as budesonide

(23) Dietary supplements such as, for example, omega-3 oil; folic acid, nicotinic acid, zinc, copper, Korean red ginseng root, ginkgo biloba, pine bark, Tribulus terrestris (Tribulus terrestris), arginine, oat (Avena sativa), aegilops (Horny goat weed), maca root, muira puama (muira puama), serenoa repens, and swiss pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patches; levoxel (Zorraxel), Naltrexone (Naltrexone), Bremelanotide (Bremelanotide) (formerly PT-141), Melanotan (Melanotan) II, hMaxi-K; prelox: proprietary mixtures/combinations of the naturally occurring components L-arginine aspartate and pycnogenol;

(24) PGD2 receptor antagonists including, but not limited to, those listed in U.S. published applications US20020022218, US20010051624 and US20030055077, PCT published applications W09700853, W09825919, WO03066046, WO03066047, WO03101961, WO03101981, WO04007451, WO0178697, WO04032848, WO03097042, WO03097598, WO03022814, WO03022813 and WO04058164, European patent applications EP945450 and EP944614 as having PGD2 antagonistic activity, and Torsiu et al Bioorg Med Chem Lett 14:4557, Torsiu et al 2004Bioorg Med Chem Lett 200414: 4891 and Torsiu et al 2004Bioorg & Chem 200412: 4685;

(25) immunosuppressive agents such as cyclosporine (cyclosporine),) Tacrolimus (FK-506,) Rapamycin (sirolimus),) And other FK-506 type immunosuppressive agents, and mycophenolate esters such as mycophenolate mofetil

(26) Non-steroidal anti-asthmatics such as β 2-agonists (e.g. terbutaline, isoproterol, fenoterol, isoetharine, salbutamol, salmeterol, bitolterol and pirbuterol) and β 2-agonist-corticosteroid combinations (e.g. salmeterol-flunisolide) and β -agonist-corticosteroid combinations (e.g. salmeterol-flunisolide)Formoterol-budesonide (budesonid)Ipratropium (ipratropium), ipratropium bromide, leukotriene biosynthesis inhibitors (seleuton, BAY 1005);

(27) non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (e.g. alminoprofen (alminoprofen), benoxaprofen (benoxaprofen), bucloxic acid (bucloxic acid), carprofen (carprofen), fenbufen (fenbufen), fenoprofen (fenoprofen), fluprofen (fluprolen), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indoprofen (indoprofen), ketoprofen (ketoprofen), miroprofen (miroprofen), naproxen (naproxen), oxaprozin (oxaprozin), pirprofen (pirprofen), pranoprofen (pranoprofen), suprofen (suprofen), tiaprofenic acid (tiaprofenic acid) and thioprofen (tioxaprofen)); acetic acid derivatives (e.g. indomethacin (indomethacin), acemetacin (acemetacin), alclofenac (alclofenac), clidanac (clinanac), diclofenac (diclofenac), fenac (fenclofenac), fenclofenac (fencloxacacic), fentiazac (fentiazac), furofenac (furofenac), ibufenac (ibufenac), isoxepac (isoxepac), oxicerac (oxypinacac), sulindac (sulindac), thiofenac (tiopinac), tolmetin (tolmetin), zidometacin (zidometacin), and zomepirac (zomepirac)); fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid); biphenylcarboxylic acid derivatives (such as diflunisal (diflunisal) and flufenisal), oxicams (oxicams) (such as isoxicam (isooxicam), piroxicam (piroxicam), sudoxicam (sudoxicam), and tenoxicam (tenoxican)); salicylates (e.g., acetylsalicylic acid and sulfasalazine) and pyrazolones (e.g., azapropazone (apazone), pyrafluzone (bezpiperylon), feprazone (feprazone), mofetizone (mofebutazone), oxyphenylbutyrone (phenbutazone), and phenylbutazone);

(28) cyclooxygenase-2 (COX-2) inhibitors such as celecoxibRofecoxib (rofecoxib)Valdecoxib (valdecoxib), etoricoxib (etoricoxib), parecoxib (parecoxib), and lumiracoxib (lumiracoxib);opioid analgesics such as codeine (codeine), phenytol (fentanyl), hydromorphone (hydromorphone), levorphanol (levorphanol), meperidine (meperidine), methadone (methadone), morphine (morphine), oxycodone (oxycodone), oxymorphone (oxymorphone), propoxyphene (propofol), buprenorphine (buprenorphine), butorphanol (butorphanol), dezocine (dezocine), nalbuphine (nalbuphine), and pentazocine (pentazocine); and

(29) antidiabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., glibenclamide (Glyburide), Glyburide (Glybenclamide), Glipizide (Glipizide), Gliclazide (Gliclazide), Gliquidone (Gliquidone), Glimepiride (Glimepiride), meglumine (meglitinide), Tolbutamide (Tolbutamide), Chlorpropamide (chlorparamide), acetophencyclylcyclohexamide (Acetohexamide), Tolazamide (Tolazamide)); biguanides, for example metformin (metformin)α -glucosidase inhibitors (such as Acarbose (Acarbose), Epalrestat (Epalrestat), volibose (Voglibose), Miglitol (Miglitol)); thiazolidone compounds such as rosiglitazone (rosiglitazone)Troglitazone (troglitazone)Ciglitazone (ciglitazone), pioglitazone (pioglitazone)And englitazone (englitazone); insulin sensitizers such as pioglitazone and rosiglitazone; insulin secretagogues such as Repaglinide (Repaglinide), Nateglinide (Nateglinide), and Mitiglinide (Mitiglinide); secretin mimetics such as exenatide (Exanatide) and liraglutide; amylin analogs such as Pramlintide (Pramlintide); descendSugar agents such as chromium picolinate (optionally in combination with biotin); dipeptidyl peptidase IV inhibitors such as Sitagliptin (Sitagliptin), Vildagliptin (Vildagliptin), Saxagliptin (Saxagliptin), Alogliptin (Alogliptin), and Linagliptin (Linagliptin); vaccines currently developed for the treatment of diabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS 01; cytokine-targeted therapies are being developed for the treatment of diabetes, such as Anakinra (Anakinra), conatinumab (Canakimab), Diacerein (Diakerein), Gevokizumab (Gevokizumab), LY-2189102, MABP-1, GIT-027; drugs being developed for the treatment of diabetes:

(30) HDL cholesterol increasing agents such as anaqupi (Anacetrapib), MK-524A, CER-001, DRL-17822, Dacetrapib (Dalcetrrapib), JTT-302, RVX-000222, TA-8995;

(31) anti-obesity drugs such as methamphetamine hydrochloride, bupropion hydrochloride (Amfepramone)Fenterming (Phentermine)Benzphetamine hydrochloride (Benzfetamine)Benzyltrazine tartrate (Phenimetrazine)Molindol (Mazindol)Orlistat (Orlistat)Sibutramine hydrochloride monohydrateRimonabant (Rimonabant)Amfepramone, chromium picolinate, RM-493, TZP-301; combinations such as phentermine/Topiramate (Topiramate), Bupropion (Bupropion)/naltrexone, sibutramine/metformin, Bupropion SR/Zonisamide (Zonisamide) SR, salmeterol xinafoate/fluticasone propionate; rotocillin hydrochloride (Lorcaserin), phentermine/topiramate, bupropion/naltrexone, Cetilistat (Cetilistat), Exenatide (Exenatide), KI-0803, linagliptin, metformin hydrochloride, sibutramine/metformin, 876167, ALS-L-1023, amfetanone SR/Zonisamide SR, CORT-108297, canagliflozin, chromium picolinate, GSK-1521498, LY-377604, Metreleptin (Metreleptin), obicin (Obinepitide), P-57AS3, PSN-821, salmeterol xinafoate/fluticasone propionate, sodium tungstate, growth hormone (recombinant), TM-30339, TTP-435, temorelin (Tesamorelin), Tesofensine (Tesofensine), Welfite (Velperi), zoneitine (Velpenimide), Zornide (AThapamine), Zymidone-830216, SABMS-46 127158, HX-465926, HX-5926, HX-7, Haliotropine (Zymosin), Halofenit-4656, Haliotropine, Halifen-1030, Haliotropine (Zymidine), Halifen-46105, Haliotropine, Halipen, AZD-2820, AZD-8329, Beloranib hemioxalate (Pololanzi)) CP-404, HPP-404, ISIS-FGFR4Rx, insulinotropic peptide (Insulinotropin), KD-3010PF, 05212389, PP-1420, PSN-842, peptide YY3-36, Resveratrol (Resveratrorol), S-234462, S-234462, sobetimer, TM-38837, Tetrahydrocannabivarin (Tetrahydrocannabivarin), ZYO-1, β -Lapachone (Lapacchone);

(32) angiotensin receptor blockers such as Losartan (Losartan), Valsartan (Valsartan), Candesartan cilexetil (Candesartan cilexetil), eprosartan (Eprosaran), Irbesartan (Irbesartan), Telmisartan (Telmisartan), olmesartan medoxomil (olmesartan medoxomil), Azilsartan medoxomil (Azilsartan medoxomil);

(33) renin inhibitors such as Aliskiren hemifumarate (alikiren);

(34) central action α -2-adrenoceptor agonists such as Methyldopa (Methyldopa), Clonidine (Clonidine), Guanfacine (Guanfacine);

(35) adrenergic neuron blockers such as Guanethidine (Guanethidine), Guanadrel (Guanadrel);

(36) imidazoline I-1 receptor agonists such as Rimenidine (Rimenidine) dihydrogen phosphate and Moxonidine hydrochloride (Moxonidine) hydrate;

(37) aldosterone antagonists such as spironolactone and eplerenone

(38) Potassium channel activators such as Pinacidil (Pinacidil)

(39) Dopamine D1 agonists such as Fenoldopam mesylate (Fenoldopam); other dopamine agonists such as Ibopamine (Ibopamine), pexamine (Dopexamine), and polycarbobamine (docapamine);

(40)5-HT2 antagonists such as ketosertrin (Ketansera);

(41) drugs currently under development for the treatment of arterial hypertension:

(42) vasopressin antagonists such as Tolvaptan (Tolvaptan);

(43) calcium channel sensitizers such as Levosimendan (Levosimendan) or activators such as nicorandil;

(44) PDE-3 inhibitors such as amirone (Amrinone), Milrinone (Milrinone), Enoximone (Enoximone), Vesnarinone (Vesnarinone), Pimobendan (Pimobendan), eplerenone (Olprinone);

(45) adenylate cyclase activators such as forskolin daprate (Colforsin daprate) hydrochloride;

(46) positive inotropic agents such as digoxin and meglumine (Metildigoxin); metabolic cardiotonic agents such as Ubidecarenone (Ubidecarenone); brain natriuretic peptides such as Nesiritide (Nesiritide);

(47) drugs currently under development for the treatment of heart failure:

(48) drugs currently under development for the treatment of pulmonary hypertension:

(49) drugs currently under development for the treatment of female sexual dysfunction:

(50) drugs for the treatment of erectile dysfunction such as alprostadil, Aviptadil (Aviptadil), Phentolamine mesylate (Phentolamine), warfarin (Weige), alprostadil;

(51) drugs currently under development for the treatment of male sexual dysfunction:

(51) drugs are being developed for the treatment of sleep apnea:

(52) drugs currently under development for the treatment of metabolic syndrome:

(53) anti-obesity drugs:

(54) drugs for the treatment of Alzheimer's disease: for example, cholinesterase inhibitors, including those formulated for mild to moderate Alzheimer's disease(galantamine)),(rivastigmine) and(donepezil)), (donepezil),(tacrine);(memantine), an N-methyl D-aspartic acid (NMDA) antagonist, andprescribed for the treatment of moderate to severe alzheimer's disease; vitamin E (antioxidant).

(55) Antidepressants: tricyclic antidepressants such as amitriptylineDesipramine (desipramine)Imipramine (imipramine)Amoxicapine (amoxapine)Nortriptyline (nortriptyline); selective Serotonin Reuptake Inhibitors (SSRI) such as paroxetine (parooxetine)Fluoxetine (fluooxetine)Sertraline (sertraline)And citalopram (citalopram)And other antidepressants such as doxepin (doxepin)And trazodone (trazodone)SNRI (e.g., venlafaxine (venlafaxine) and reboxetine (reboxetine)); dopaminergic antidepressants (e.g., bupropion and amitriptyline).

(56) Neuroprotective agents: such as memantine, L-dopa, bromocriptine (bromocriptine), pergolide (pergolide), talipexole (talipexol), pramipexol (pramipexol), cabergoline (cabergoline), and neuroprotective agents currently under investigation including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroid (lazaroid), bioenergetic agents, anti-glutamatergic agents, and dopamine receptors. Other clinically evaluated neuroprotective agents are for example the monoamine oxidase B inhibitors selegiline (selegiline) and rasagiline (rasagiline), dopamine agonists and the complex I mitochondrial enhancer coenzyme Q10.

(57) An antipsychotic agent: such as ziprasidone (ziprasidone) (Geodon)^TM) Risperidone (risperidone) (Risperdal)^TM) And olanzapine (olanzapine) (Zyprexa)^TM)。

Reagent kit

The compounds and pharmaceutical formulations described herein are available in kit form. The kit may include two or more reagents packaged or formulated individually, each in a single dose or multiple doses, or two or more reagents packaged or formulated in a combination of a single dose or multiple doses. Thus, one or more reagents may be present in a first container, and the kit may optionally comprise one or more reagents in a second container. The one or more containers are placed within a package, and the package may optionally include instructions for administration or dosing. The kit may include additional components, such as a syringe or other device for administering the agent or diluent or other device for formulation. Thus, a kit may comprise a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle, or diluent; and b) a container or package. The kit can optionally include instructions describing a method of use of the pharmaceutical composition in one or more methods described herein (e.g., preventing or treating one or more diseases or disorders described herein). The kit may optionally include a second pharmaceutical composition comprising one or more additional agents, pharmaceutically acceptable carriers, vehicles, or diluents described herein for use in co-therapy. The pharmaceutical composition comprising a compound described herein and the second pharmaceutical composition contained in the kit may optionally be combined in the same pharmaceutical composition.

Kits include containers or packages for containing the pharmaceutical compositions, and may also include separate containers, such as separate bottles or separate foil pouches. The container may be, for example, a paper or cardboard box, a glass or plastic bottle or can, a resealable bag (e.g., to contain "refill" tablets for placement in different containers), or a blister pack with individual doses for extrusion packaging according to a treatment protocol. It is possible that more than one container may be used together in a single package to sell a single dosage form. For example, the tablets may be contained in bottles, which in turn are contained in cassettes.

An example of a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a relatively stiff sheet of material covered with a foil of preferably transparent plastic material. During the packaging process, a pocket is formed in the plastic film. The pockets may be of the size and shape of an individual tablet or capsule to be encapsulated or may be of the size and shape to accommodate a plurality of tablets or/and capsules to be encapsulated. Next, the tablet or capsule is placed in the recess according to this and the sheet of relatively hard material is sealed against the plastic foil on the side of the foil opposite to the direction in which the recess is formed. As a result, the tablets or capsules are individually or collectively sealed in the pockets between the plastic foil and the sheet layer as desired. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the location of the recesses. The tablet or capsule may then be removed through the opening.

It may be desirable to provide a physician, pharmacist or subject with a written memory aid and/or instructions containing information regarding when to take a medication. The "daily dose" may be a single tablet or capsule or several tablets or capsules taken on a given day. When the kit contains separate compositions, a daily dose of one or more of the compositions of the kit may consist of one tablet or capsule, while a daily dose of another one or more of the compositions of the kit may consist of several tablets or capsules. The kit may be in the form of a dispenser designed to dispense one daily dose at a time in the order of intended use. The dispenser may be fitted with a memory aid to further promote compliance with the protocol. An example of such a memory aid is a mechanical counter, which indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled with a liquid crystal reader or audible reminder signal, which for example reads the date of the last daily dose taken and/or reminds when the next dose is taken.

Examples

All references provided in the examples are incorporated herein by reference. As used herein, all abbreviations, symbols, and conventions are consistent with those used in the contemporary scientific literature. See, for example, Janet S.Dodd, The ACSStyle Guide, A Manual for Authors and Editors, second edition, Washington, D.C.: American chemical Society,1997, which is incorporated herein by reference in its entirety.

Example 1: compounds of Table 1A, Table 1B, Table IC and Table ID

General procedure A

Step 1:

diketone enolate formation:LiHMDS (e.g., 0.9 equiv., 1.0M in toluene) is added dropwise via syringe to a solution of ketone A in THF cooled to-78 ℃. The reaction was allowed to warm to 0 ℃ and diethyl oxalate (1.2 eq) was charged. At this point, the reaction is allowed to warm to room temperature and stirred at that temperature until judged complete (e.g., using TLC or LC/MS analysis). Once the reaction is finishedTo give (reaction time typically 45 minutes), the product diketoenolate B was used "as is" in step 2, the cyclisation step, without any further purification.

Step 2:

pyrazole formation:diketoenolate B was diluted with ethanol and charged successively with HCl (e.g., 3 equivalents, 1.25M solution in ethanol) and arylhydrazine hydrate (e.g., 1.15 equivalents). The reaction mixture is heated to 70 ℃ and stirred at this temperature until cyclization is deemed complete (e.g. by LC/MS analysis, typically 30 minutes). Once complete, the reaction mixture is carefully treated with solid sodium bicarbonate (e.g., 4 equivalents) and diluted with dichloromethane and water. The layers were separated and the aqueous layer was further diluted with water and then extracted with dichloromethane (3 ×). The combined organics were washed with brine, MgSO₄Dried, filtered and concentrated in vacuo. Then, passing through SiO₂Chromatography the resulting pyrazole C was purified using a suitable EtOAc gradient in hexane.

And step 3:

amidine formation:to NH via injector₄Suspension of Cl (e.g. 5 equiv.) in toluene cooled to 0 ℃ AlMe was added dropwise₃(e.g., 5 equivalents in a 2.0M solution in toluene). The reaction was allowed to warm to room temperature and stirred at this temperature until no more bubbles were observed. 1 part pyrazole C is added to the reaction mixture, heated to 110 ℃ and stirred at this temperature until judged complete (e.g. using TLC or LC/MS analysis). Once complete, the reaction was cooled, treated with excess methanol and stirred vigorously at room temperature for 1 hour. The viscous slurry was filtered and the resulting solid cake was washed with methanol. The filtrate was concentrated in vacuo and the resulting solid was resuspended in a 5:1 solvent mixture of ethyl acetate and isopropyl alcohol. The reaction was further treated with saturated sodium carbonate solution and stirred for 10 minutes, after which the layers were separated. The aqueous layer was extracted with ethyl acetate-5: 1 solvent mixture (3 ×), and the combined organics were washed with brine. Over MgSO₄Further drying the organic, filtering and removing the solvent in vacuo. The product amidine D was used as such in the subsequent steps without further purification.

And 4, step 4:

pyrimidinone formation:amidine D was suspended in ethanol and stirred vigorously at 23 ℃ to promote complete solvation. The reaction was further treated with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (e.g. 3 equivalents) and the flask was equipped with a reflux condenser. The reaction was placed in a pre-heated oil bath maintained at 90 ℃ and stirred until complete consumption of starting material was observed on LC/MS (reaction time typically 1 h). The contents are cooled to 23 ℃, and the reaction mixture is acidified with HCl (e.g., 3 equivalents, 1.25M solution in EtOH). The mixture was stirred for 30 minutes and most of the solvent was removed in vacuo. The contents were resuspended in ether and water (1:1 mixture) and the resulting slurry was stirred for 20 min. The suspension was filtered under vacuum and the solid cake was washed with additional water and ether and dried under high vacuum overnight. The resulting pyrimidinone E was used as such in the subsequent step without further purification.

General procedure B

A solution of the amino nucleophile (3 equivalents), triethylamine (10 equivalents) and intermediate 1(1 equivalent) was stirred in dioxane and water (2:1 ratio) at 90 ℃ until complete consumption of the starting material was observed by LC/MS. The solution was diluted with 1N aqueous hydrochloric acid and dichloromethane. The layers were then separated and the aqueous layer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification to give the desired product.

General procedure C

A mixture of intermediate 2 (this intermediate was previously described in published patent application WO 2012/3405A 1; 1 equivalent) and carboxylic acid (1.1 equivalent) in N, N-dimethylformamide was treated with triethylamine (4 equivalents) followed by a solution of 50% propylphosphonic anhydride (T3P, 1.4 equivalents) in ethyl acetate. The reaction was heated to 80 ℃ for 24h, after which the reaction was diluted with water and 1N hydrochloric acid solution. The contents were extracted with dichloromethane and then ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification to give the desired product.

Synthesis of intermediate 1

A suspension of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-ol (using 1- (isoxazol-3-yl) ethanone of step 1 and 2-fluorobenzylhydrazine of step 2, 11.5g, 32.4mmol, 1 eq) in phosphorus oxychloride (60.3mL, 647mmol, 20 eq) via general procedure a was heated at 60 ℃ for 3H. The solution was cooled to 23 ℃ and poured onto ice water (800mL) portion by portion over the course of 15min with stirring. After the addition was complete, the contents were stirred for a further 15min and diluted with dichloromethane (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2X 200 mL). The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give intermediate 1(12.5g, 103% yield) as a tan solid.

¹H NMR(500MHz,DMSO-d₆)δ9.11(d,1H),9.04(s,1H),7.71-7.68(m,1H),7.37-7.30(m,2H),7.25-7.20(m,1H),7.12(t,1H),6.92(td,1H),5.95(s,2H)。

Compound I-248

Following general procedure B, a mixture of intermediate 1(48mg, 1 eq), (R) -3-methyl-2- ((methylamino) methyl) butanoic acid, (99mg, TFA salt, 3 eq), and triethylamine (0.177mL, 10 eq) was heated as a solution in dioxane/water (2:1) to 100 ℃ forAnd then 20 h. The contents were treated with 3N HCl and partitioned between a 1:1 mixture of dichloromethane and water. The layers were separated and the aqueous layer was treated with a small amount of sodium chloride. The aqueous layer was then extracted with dichloromethane (× 3) and the organic portions were combined and washed with brine. Over MgSO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-248(20mg, 93%) as an off-white solid.

¹H-NMR(500MHz,MeOD)δ8.74(d,1H),8.09(d,1H),7.38(s,1H),7.29-7.23(m,1H),7.10-7.05(m,1H),7.02(td,1H),6.87-6.83(m,1H),6.83(d,1H),5.98-5.89(m,2H),4.15(dd,1H),3.81(dd,1H),3.33(d,3H),2.72-2.65(m,1H),1.94(dq,1H),1.09(d,3H),1.01(d,3H)。

Compound I-250

The title compound was prepared according to general procedure B except 1- ((methylamino) methyl) cyclopropanecarboxylic acid (as TFA salt) was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-250 as an off-white solid (40mg, 54%).

¹H-NMR(500MHz,MeOD)δ8.74(d,1H),8.07(d,1H),7.36(s,1H),7.29-7.23(m,1H),7.11-7.05(m,1H),7.03(td,1H),6.88(d,1H),6.85(td,1H),5.93(s,2H),4.14(s,2H),3.35(d,3H),1.30-1.25(m,2H),1.07-1.03(m,2H)。

Compound I-252

The title compound was prepared according to general procedure B except 2-ethyl-2- ((methylamino) methyl) butanoic acid (as TFA salt) was the amine reactant, the contents were heated at 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-252(33mg, 39%) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.80(d,1H),8.25(d,1H),7.50(s,1H),7.32-7.26(m,1H),7.12-7.06(m,1H),7.04(t,1H),6.94(t,1H),6.91(d,1H),5.97(s,2H),4.20(s,2H),3.46(d,3H),1.86-1.77(m,2H),1.68(dq,2H),0.91(t,6H)。

Compound I-253

The title compound was prepared according to general procedure B, except that (S) -3-methyl-2- ((methylamino) methyl) butanoic acid (as TFA salt) was the amine reactant, the contents were heated at 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-253(26mg, 64%) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.08(d,1H),7.37(s,1H),7.28-7.22(m,1H),7.10-7.05(m,1H),7.02(t,1H),6.84(t,1H),6.82(d,1H),5.97-5.88(m,2H),4.15(dd,1H),3.79(dd,1H),3.32(d,3H),2.70-2.64(m,1H),1.93(dq,1H),1.08(d,3H),1.01(d,3H)。

Compound I-260

The title compound was prepared according to general procedure B except 4-benzylpiperidine-4-carboxylic acid was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound I-260 as a white solid (26mg, 64%).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.11(d,1H),7.41(s,1H),7.29-7.22(m,3H),7.22-7.15(m,3H),7.11-7.06(m,1H),7.05-7.00(m,1H),6.91(d,1H),6.84-6.79(m,1H),5.96(s,2H),4.57(d,2H),3.29-3.23(m,2H),2.90(s,2H),2.19(d,2H),1.68-1.61(m,2H)。

Compound I-262

The title compound was prepared according to general procedure B except that ethyl 2-methylpiperidine-2-carboxylate was the amine reactant, the contents were heated to 100 ℃ for 19h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-262 as a white solid (1.1mg, 8%).

¹H-NMR(500MHz,CD₃OD)δ8.82(d,1H),8.33(d,1H),7.47(s,1H),7.32-7.26(m,1H),7.12-7.07(m,1H),7.05(t,1H),6.92(t,1H),6.88(d,1H),6.03-5.95(m,2H),4.32-4.24(m,1H),3.63(dt,1H),2.14(ddd,1H),2.01-1.79(m,5H),1.76(s,3H)。

Compound I-265

The title compound was prepared according to general procedure B except 3-phenylpyrrolidine-3-carboxylic acid was the amine reactant, the contents were heated to 100 ℃ for 24h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-265 as an off-white solid (29mg, 45%).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.11(d,1H),7.51-7.44(m,3H),7.40-7.36(m,2H),7.32-7.23(m,2H),7.12-7.06(m,1H),7.03(t,1H),6.92(s,1H),6.81(t,1H),5.96(s,2H),4.03-3.96(m,1H),3.91(d,1H),3.87(br.s.,1H),3.07-3.00(m,1H),2.41-2.32(m,1H)。

Compound I-267

The title compound was prepared according to general procedure B except 3, 3-dimethylpiperidine-2-carboxylic acid (as the HCl salt) was the amine reactant, the contents were heated to 100 ℃ for 18h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-267(15mg, 17%) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.81(d,1H),8.35(d,1H),7.57(s,1H),7.32-7.26(m,1H),7.12-7.07(m,1H),7.04(t,1H),6.94-6.90(m,2H),5.99(s,2H),4.99(s,1H),4.62(d,1H),3.86(td,1H),2.07-1.96(m,1H),1.95-1.87(m,1H),1.81-1.75(m,1H),1.50(d,1H),1.22(s,3H),1.17(s,3H)。

Compound I-269

The title compound was prepared according to general procedure B except 3-aminobicyclo [1.1.1] pentane-1-carboxylic acid (as the TFA salt) was the amine reactant, the contents were heated at 100 ℃ for 18h, and the aqueous layer was treated with sodium chloride during the treatment.

The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-269(11mg, 16%) as a white solid.

¹H-NMR(500MHz,CD₃ODδ8.76(d,1H),8.08(d,1H),7.36(s,1H),7.30-7.23(m,1H),7.12-7.06(m,1H),7.04(t,1H),6.96(d,1H),6.91(t,1H),5.94(s,2H),2.53(s,6H)。

Compound I-80

The title compound was prepared according to general procedure B, except L-phenylalanine was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (2:1) for 48 h. The contents were concentrated in vacuo and the crude material was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-80(1.3mg, 4%) as a white solid.

¹H-NMR(500MHz,CD₃ODMeOD)δ8.81(s,1H),8.20(d,1H),7.51-7.48(m,1H),7.34-7.26(m,3H),7.22(t,2H),7.17-7.03(m,3H),6.96(s,1H),6.90(t,1H),6.00(s,2H),5.36-5.29(m,1H),3.48(d,1H),3.24-3.18(m,1H)。

Compound I-81

The title compound was prepared according to general procedure B except L-tryptophan was the amine reactant and the contents were heated as a solution in THF/water (2:1) at 90 ℃ for 48 h. The contents were concentrated in vacuo and the residue was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-81(7.3mg, 18%) as a brown solid.

¹H-NMR(500MHz,CD₃OD)δ8.86-8.83(m,1H),8.16(d,1H),7.69(d,1H),7.33-7.27(m,1H),7.16(d,1H),7.13-7.04(m,4H),7.01-6.96(m,1H),6.95-6.88(m,3H),5.96(s,2H),5.51(dd,1H),3.74-3.67(m,1H),3.30-3.25(m,1H)。

Compound I-85

The title compound was prepared according to general procedure B except 1-aminocyclopropanecarboxylic acid was the amine reactant and the contents were heated as a solution in THF/water (2:1) at 90 ℃ for 48 h. The contents were concentrated in vacuo and the residue was purified via reverse phase HPLC with a 5-95% acetonitrile/water gradient to give the desired compound, compound I-85(7.3mg, 18%) as a clear oil.

¹H-NMR(500MHz,CD₃OD)δ8.83(d,1H),8.38(d,1H),7.47(s,1H),7.34-7.28(m,1H),7.13-7.04(m,2H),6.99-6.95(m,2H),6.02(s,2H),1.84-1.79(m,2H),1.43-1.38(m,2H)。

Compound I-93

The title compound was prepared according to general procedure B, except that (3-aminooxetan-3-yl) methanol was the amine reactant and the contents were heated in a microwave at 170 ℃ for 15min as a solution in THF/water (2: 1). The contents were concentrated in vacuo and the residue was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-93(0.6mg, 4%) as a clear oil.

¹H-NMR(500MHz,CD₃OD)δ8.85(d,1H),8.55(s,1H),7.69(s,1H),7.32-7.37(m,1H),7.09-7.17(m,3H),6.97(d,1H),6.01(s,2H),5.00(s,2H),3.76(q,4H)。

Compound I-102

The title compound was prepared according to general procedure B except that methyl 2-amino-2- (oxetan-3-yl) acetate was the amine reactant and the contents were heated as a solution in THF/water (2:1) at 100 ℃ for 42 h. The contents were concentrated in vacuo and the residue was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-102(0.6mg, 2%) as a clear oil.

¹H-NMR(500MHz,CD₃OD)δ8.80(d,1H),8.30(d,1H),7.50(s,1H),7.32-7.27(m,1H),7.12-7.03(m,2H),6.92(t,1H),6.89(d,1H),5.99(s,2H),5.23(d,1H),4.65(t,1H),4.31(t,1H),3.83-3.74(m,2H),3.02(dtd,1H)。

Compound I-109

The title compound was prepared according to general procedure B except that no amine reactant was used, DBU was used instead of triethylamine and the contents were heated as a solution in THF/water (2:1) at 100 ℃ for 18 h. The contents were concentrated in vacuo and the residue was purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound, compound I-109(7mg, 35%) as a clear oil.

¹H-NMR(500MHz,CD₃OD) Δ 8.84(d,1H),8.26(d,1H),7.67(s,1H),7.25-7.28(m,1H),7.14-7.05(m,2H),7.02(d,1H),7.01-6.97(m,1H),6.03(s,2H),3.79(t,2H),3.56-3.47(m,4H),2.56-2.50(m,2H),1.99 (quintuple, 2H),1.80-1.73(m,2H),1.72-1.61(m, 4H).

Compound I-108

The title compound was prepared according to general procedure B except D-tryptophan was the amine reactant and the contents were heated as a solution in THF/water (2:1) at 100 ℃ for 18 h. The contents were treated with 3N HCl solution, the solvent removed in vacuo, and H₂The resulting solid was washed and then purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound, compound I-108 as a clear oil (3.5mg, 16%).

¹H-NMR(500MHz,CD₃OD)δ8.85(d,1H),8.16(d,1H),7.69(d,1H),7.33-7.27(m,1H),7.17(d,1H),7.13-7.05(m,4H),7.01-6.96(m,1H),6.95-6.89(m,3H),5.97(s,2H),5.50(dd,1H),3.70(dd,1H),3.28(d,1H)。

Compound I-116

The title compound was prepared according to general procedure B, except D-phenylalanine was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (2:1) for 18 h. The contents were treated with 3N HCl solution, the solvent was removed in vacuo, and the resulting residue was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the desired compound, compound I-116(25mg, 61%) as a solid.

¹H-NMR(500MHz,CD₃OD,MeOD)δ8.77(s,1H),8.13(d,1H),7.43(s,1H),7.31(d,2H),7.28-7.18(m,3H),7.16-7.11(m,1H),7.09-7.03(m,1H),7.01(t,1H),6.91(s,1H),6.85(t,1H),5.94(s,2H),5.26(dd,1H),3.45(dd,1H),3.19(dd,1H)。

Compound I-117

The title compound was prepared according to general procedure B except L-phenylglycine was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (2:1) for 18 h. The contents were treated with 3N HCl solution, the solvent was removed in vacuo, and the resulting solid was purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound, compound I-117(26mg, 63%) as a solid.

¹H-NMR(500MHz,CD₃OD)δ8.81(s,1H),8.29(d,1H),7.61(d,2H),7.52(s,1H),7.46-7.36(m,3H),7.27(q,1H),7.10-7.05(m,1H),7.03(t,1H),6.95-6.90(m,2H),6.02(s,1H),5.97(s,2H)。

Compound I-118

The title compound was prepared according to general procedure B except D-phenylglycine was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (2:1) for 18 h. The contents were treated with 3N HCl solution, the solvent was removed in vacuo, and the resulting solid was purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound, compound I-118(22mg, 53%) as a solid.

¹H-NMR(500MHz,CD₃OD)δ8.81(s,1H),8.30(d,1H),7.60(d,2H),7.53(s,1H),7.46-7.37(m,3H),7.28(q,1H),7.11-7.06(m,1H),7.04(t,1H),6.96-6.91(m,2H),6.02(s,1H),5.99(s,2H)。

Compound I-142

The title compound was prepared according to general procedure B except N-methylphenylglycine was the amine reactant and the contents were heated to 100 ℃ for 18h as a solution in THF/water (2: 1). The contents were treated with 3N HCl solution, the solvent was removed in vacuo, and the resulting solid was purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound as a solid (15mg, 52%).

¹H-NMR(500MHz,MeOD)δ8.80(d,1H),8.45-8.39(m,1H),7.58-7.55(m,1H),7.50-7.44(m,5H),7.34-7.27(m,1H),7.14-7.04(m,2H),7.00-6.94(m,1H),6.90(d,1H),6.61-6.55(m,1H),6.02(s,2H),3.25-3.20(m,3H)。

Compound I-120

The title compound was prepared according to general procedure B, except 1- (aminomethyl) cyclopropanecarboxylic acid was the amine reagent, the contents were heated to 22h at 100 ℃, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-120(20mg, 42%) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.05(d,1H),7.39(s,1H),7.30-7.24(m,1H),7.12-7.06(m,1H),7.03(t,1H),6.89(d,1H),6.84(t,1H),5.95(s,2H),3.88(s,2H),1.25-1.20(m,2H),1.15-1.10(m,2H)。

Compound I-207

The title compound was prepared according to general procedure B, except that N-methyl-L-alanine was the amine reactant, the contents were heated to 100 ℃ for 22h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-207 as a white solid (20mg, 57%).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.16(d,1H),7.40(s,1H),7.29-7.23(m,1H),7.11-7.05(m,1H),7.02(t,1H),6.87(d,1H),6.82(t,1H),5.94(s,2H),5.10(q,1H),3.33(d,3H),1.59(d,3H)。

Compound I-217

The title compound was prepared according to general procedure B except 2- (aminomethyl) -2-ethylbutyric acid was the amine reactant, the contents were heated to 100 ℃ for 22h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified by silica gel chromatography using a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-217(20mg, 50%) as a clear oil.

¹H-NMR(500MHz,CD₃OD)δ8.76-8.72(m,1H),8.07-8.03(m,1H),7.42-7.39(m,1H),7.29-7.22(m,1H),7.11-7.04(m,1H),7.02(t,1H),6.89-6.81(m,2H),5.94(s,2H),3.91(s,2H),1.68(q,4H),0.98-0.90(t,6H)。

Compound I-224 and compound I-225

The title compound was prepared according to general procedure B except 2-amino-5, 5, 5-trifluoro-4-methylpentanoic acid was the amine reactant, the contents were heated to 100 ℃ for 18h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via reverse phase HPLC with a 5-75% acetonitrile/water gradient to give the diastereomers, compound I-224 as a white solid (3.3mg, 7%, eluting first on LCMS) and compound I-225 as a white solid (2mg, 5%, eluting second on LCMS).

Process for preparation of Compound I-224¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.15(d,1H),7.38(s,1H),7.29-7.24(m,1H),7.11-7.06(m,1H),7.03(t,1H),6.86(d,1H),6.83(t,1H),5.95(s,2H),4.94(t,1H),2.60(dd,1H),2.45-2.38(m,1H),1.96-1.89(m,1H),1.25(d,3H)。

Process for preparation of Compound I-225¹H-NMR(500MHz,CD₃OD)δ8.81(d,1H),8.34(d,1H),7.58(s,1H),7.33-7.27(m,1H),7.13-7.08(m,1H),7.06(t,1H),6.99-6.92(m,2H),6.01(s,2H),5.26(dd,1H),2.53-2.42(m,1H),2.42-2.33(m,1H),2.13(ddd,1H),1.24(d,3H)。

Compound I-226

The title compound was prepared according to general procedure B, except 2-amino-3-fluoro-3-methylbutyric acid was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-226 as a white solid (11mg, 42%).

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.16(d,1H),7.44(s,1H),7.30-7.22(m,1H),7.11-7.06(m,1H),7.02(t,1H),6.90(d,1H),6.81(t,1H),5.95(s,2H),5.13(d,1H),1.65-1.58(m,3H),1.58-1.51(m,3H)。

Compound I-227

The title compound was prepared according to general procedure B, except that (S) -2-amino-2-cyclopropylacetic acid was used as the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-227(21mg, 86%) as a white solid.

¹H-NMR(500MHz,MeOD)δ8.74(d,1H),8.10(d,1H),7.37(s,1H),7.28-7.22(m,1H),7.11-7.05(m,1H),7.02(t,1H),6.85(d,1H),6.82(t,1H),5.93(s,2H),3.96(d,1H),1.38-1.28(m,1H),0.75-0.64(m,3H),0.53-0.47(m,1H)。

Compound I-239

The title compound was prepared according to general procedure B, except that (S) -N-methyl-2-amino-2-cyclopropylacetic acid was used as the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-239(4mg, 20%) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.16(d,1H),7.39(s,1H),7.26(ddd,1H),7.08(ddd,1H),7.04-7.00(m,1H),6.86(d,1H),6.82(td,1H),5.94(s,2H),4.19(d,1H),3.48(d,3H),1.53-1.44(m,1H),0.91-0.83(m,1H),0.76-0.64(m,2H),0.44(dq,1H)。

Compound I-240

The title compound was prepared according to general procedure B, except that (R) -2-amino-2-cyclopropylacetic acid was used as the amine reactant, the contents were heated to 100 ℃ for 2h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-240 as a white solid (46mg, 93%).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.10(d,1H),7.36(s,1H),7.28-7.22(m,1H),7.07(ddd,1H),7.01(td,1H),6.84(d,1H),6.81(td,1H),5.93(s,2H),3.96(d,1H),1.38-1.30(m,1H),0.74-0.65(m,3H),0.52-0.47(m,1H)。

Compound I-241

The title compound was prepared according to general procedure B, except that (R) -N-methyl-2-amino-2-cyclopropylacetic acid (as the TFA salt) was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-241 as a white solid (20mg, 93%).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.15(d,1H),7.38(s,1H),7.28-7.22(m,1H),7.10-7.04(m,1H),7.04-6.99(m,1H),6.85(d,1H),6.82(t,1H),5.93(s,2H),4.18(d,1H),3.48(d,3H),1.53-1.44(m,1H),0.91-0.82(m,1H),0.76-0.64(m,2H),0.48-0.41(m,1H)。

Compound I-90

The title compound was prepared according to general procedure B, except that (S) -indoline-2-carboxylic acid was the amine reactant (1 equivalent), and the contents were heated as a solution in THF/water (1:1) at 90 ℃ for 12h, followed by heating in a microwave at 125 ℃ for 15 min. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified by reverse phase HPLC using 5 to 95% acetonitrile in water spiked with 0.1% trifluoroacetic acid to afford the desired compound, compound I-90 as an off white solid (3.9mg, 15% yield).

¹H-NMR(500MHz,DMSO-d₆)δ(ppm):9.10-9.21(d,1H),8.61-8.75(m,1H),8.47-8.57(d,1H),7.49-7.58(s,1H),7.33-7.41(m,1H),7.22-7.33(m,4H),7.10-7.20(m,2H),6.98-7.10(m,1H),5.95(s,2H),5.39-5.53(m,1H),3.64-3.74(dd,1H),3.20-3.32(dd,2H)。

Compound I-91

The title compound was prepared according to general procedure B, except that (R) -indoline-2-carboxylic acid was the amine reactant (1 equivalent), and the contents were heated to 90 ℃ as a solution in THF/water (1:1) for 12h, followed by heating in a microwave at 125 ℃ for 15 min. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified via reverse phase HPLC using a gradient of 5-95% acetonitrile in water (in 0.1% TFA) to afford the desired compound, compound I-91, obtained following the usual procedure (1.9mg, 7%).

¹H NMR(500MHz,CD₃CN)δ(ppm):8.68-8.75(d,1H),8.35-8.49(m,2H),7.42-7.49(m,1H),7.27-7.41(m,3H),7.05-7.24(m,4H),6.91-6.96(m,1H),5.97(s,2H),5.38-5.48(m,1H),3.65-3.79(dd,1H),3.31-3.44(dd,1H)。

Compound I-114

Purification was achieved by reverse phase HPLC using 5-75% acetonitrile in water over 30 minutes (spiked with 0.1% trifluoroacetic acid) to give the desired compound as a clear oil (1.6mg, 4% yield). Only the latter diastereomer (compound I-114) which ran out was purified from this reaction mixture.

¹H NMR(500MHz,500MHz,CD₃CN)δ(ppm):8.85(s,1H),8.33(d,1H),7.40-7.48(m,1H),7.28-7.38(m,1H),7.04-7.19(m,2H),6.90-7.00(m,2H),6.03(s,2H),3.13-3.17(m,1H),2.47-2.59(m,1H),2.36-2.42(m,1H),2.03-2.17(m,1H),1.77-1.85(m,1H),1.65-1.74(m,2H),1.49-1.60(m,2H),1.38-1.47(m,1H)。

Compound I-107

The title compound was prepared according to general procedure B except (1S,2S,5R) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid was the amine reactant (1 equivalent), 3 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in THF/water (10:1) for 14 h. The contents were extracted with ethyl acetate during work-up, dried, filtered and concentrated to give the desired compound. Compound I-107 was obtained as a light tan solid (38.3mg, 100% yield). This compound does not have to be purified.

¹H NMR(500MHz,CD₃OD) delta ppm 8.79(s,1H),8.23(d,1H),7.36-7.46(br.s,1H),7.25-7.31(m,1H),7.06-7.12(m,1H),7.01-7.06(m,1H),6.83-6.90(m,2H,2 displacement overlap), 5.96(s,2H),4.18(dd,1H),4.02-4.08(m,1H),1.93-2.02(m,1H),0.83-0.93(m, 4H).

Compound I-129

Purification was achieved by silica gel chromatography using 1 to 10% methanol in dichloromethane over 30 minutes to give compound I-129 as a white solid (21.7mg, 57% yield).

¹H NMR(400MHz,CDCl₃) Delta (ppm) 8.45-8.57(m,2H,2 synchro-shifts) 7.40-7.48(m,3H),7.24-7.40(m,1H),6.93-7.09(m,2H),6.58-6.68(m,1H),5.90(s,2H),3.74-3.90(m,2H),1.99-2.20(m,2H),1.70-1.89(m,4H),1.55-1.69(m, 2H).

Compound I-124

The title compound was prepared according to general procedure B except that 4-methylpiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant (1.1 equivalents), 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in THF/water (10:1) for 18 h. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified via silica gel chromatography using a gradient of 1-10% methanol in dichloromethane over 30 minutes to give the desired compound, compound I-124 as an off-white solid (36.1mg, 95% yield).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.49(s,1H),8.16-8.28(d,1H),7.35-7.44(m,1H),7.17-7.26(m,1H),6.95-7.10(m,2H),6.87(m,1H),6.62(s,1H),6.00(s,2H),4.34-4.48(m,1H),3.36-3.48(m,1H),2.36-2.41(m,1H),1.58-1.68(m,1H),1.34(s,3H),0.71-0.81(m,4H)。

Compound I-143

The title compound was prepared according to general procedure B except 3-methylpyrrolidine-3-carboxylic acid was the amine reactant (1.05 eq), 4 eq triethylamine was used, and the contents were heated to 80 ℃ as a solution in THF/water (10:1) for 4 h. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified via silica gel chromatography with a 1-10% methanol/dichloromethane gradient over 30 minutes to give the desired compound, compound I-143 as a white solid (18.9mg, 48% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.45(s,1H),8.12-8.19(d,1H),7.30(s,1H),7.27(s,1H),7.14-7.22(m,1H),6.98-7.05(m,1H),6.93-6.98(m,1H),6.80-6.87(m,1H),6.57(d,1H),5.96(s,2H),4.24-4.36(m,1H),3.84-4.00(m,2H),3.59-3.70(m,1H),2.45-2.58(m,1H),1.84-2.00(m,1H),1.47(s,3H)。

Compound I-152

The title compound was prepared according to general procedure B except 4, 4-dimethyl-pyrrolidine-3-carboxylic acid was the amine reactant (1.05 eq), 4 eq triethylamine was used and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 14 h. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified via silica gel chromatography using a gradient of 1-7% methanol in dichloromethane over 30 minutes to give the desired compound, compound I-152 as an off-white solid (14.3mg, 37% yield).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.45(s,1H),8.05-8.20(d,1H),7.29-7.34(m,1H),7.14-7.25(m,1H),6.91-7.08(m,2H),6.79-6.87(m,1H),6.56-6.63(m,1H),5.96(s,2H),4.01-4.23(m,2H),3.71-3.87(dd,1H),3.53-3.65(dd,1H),2.85-2.97(m,1H),1.34(s,3H),1.15(s,3H)。

Compound I-186

The title compound was prepared according to general procedure B except that 4-phenylpiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant (1.05 equivalents), 4 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in THF/water (10:1) for 24 h. During the treatment, the contents were extracted with ethyl acetate. The crude material was purified via silica gel chromatography using a 4-7% methanol/dichloromethane gradient over 40 minutes to give the desired compound, compound I-186 as a white solid (22.3mg, 51% yield).

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.46(s,1H),8.19(d,1H),7.44-7.49(m,2H,2 displacement overlap), 7.36-7.41(m,2H),7.29-7.34(m,2H),7.16-7.22(m,2H),6.99-7.05(m,1H),6.93-6.98(m,1H),6.81-6.86(m,1H),6.59(m,1H),5.97(s,2H),4.50-4.58(m,2H),3.42-3.50(m,2H),2.69-2.75(m,2H),2.07-2.14(m, 2H).

Compound I-194

This compound was prepared following the general procedure B described above, except that 4- (aminomethyl) tetrahydro-2H-pyran-4-carboxylic acid was the amine reactant (1.05 equivalents), 4 equivalents of triethylamine were used, and the contents were heated as a solution in THF/water (10:1) at 70 ℃ for 6H, followed by 90 ℃ for 12H. During work-up, the contents were extracted with ethyl acetate and purified by silica gel chromatography using 4 to 7% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-194 as a white solid (26.8mg, 66% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.46(s,1H),8.10(d,1H),7.28(s,1H),7.18-7.24(m,1H),6.94-7.07(m,3H),6.58(d,1H),5.95(s,2H),5.50-5.57(m,1H),3.86-3.94(m,2H),3.79-3.85(m,2H),3.51-3.60(m,2H),2.12-2.20(m,2H),1.53-1.62(m,2H)。

Compound I-228

The title compound was prepared in 4 steps:

step 1: 1- ((4-Methylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid

A slurry of 1- (aminomethyl) cyclopentanecarboxylic acid (316mg, 1.0 eq), p-toluenesulfonyl chloride (505mg, 1.2 eq) and 1M aqueous sodium hydroxide (6.62mL, 3.0 eq) was heated in water (10mL) at 90 ℃ for 1 hour, after which the reaction mixture was cooled to 0 ℃ and acidified by addition of 3M aqueous hydrochloric acid. The resulting white precipitate was filtered and then washed successively with water and ethanol to give 1- ((4-methylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid as a white solid (383mg, 58% yield).

¹H-NMR(500MHz,DMSO-d₆)δ(ppm):12.14-12.38(s,1H),7.64-7.75(d,2H),7.47-7.56(t,1H),7.33-7.45(d,2H),2.79-2.90(d,2H),2.38(s,3H),1.81-1.95(m,2H),1.47-1.65(m,6H)。

Step 2: 1- ((N, 4-dimethylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid

A solution of 1- ((4-methylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid (383mg, 1.0 equiv.), methyl iodide (0.254mL, 3.15 equiv.), and 1M aqueous sodium hydroxide (5.15mL, 4.0 equiv.) in water (5mL) was heated to 75 ℃ for 1.5 hours, after which LCMS analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature, washed with dichloromethane (3 × 30mL), acidified by addition of 3M aqueous hydrochloric acid, extracted with ether (3 × 30mL), dried (sodium sulfate), filtered and concentrated to give 1- ((N, 4-dimethylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid as a golden yellow solid (343mg, 86% yield). No purification is necessary.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.59-7.73(d,2H),7.30-7.41(d,2H),3.24-3.39(s,2H),2.71(s,3H),2.45(s,3H),2.06-2.22(m,2H),1.69-1.88(m,6H)。

And step 3: 1- ((methylamino) methyl) cyclopentanecarboxylic acid hydrobromide

A solution of 1- ((N, 4-dimethylphenylsulfonylamino) methyl) cyclopentanecarboxylic acid (343mg, 1.0 eq) was heated in a 33% solution of hydrogen bromide in glacial acetic acid (6.0mL, 30 eq) at 75 ℃ for 2 h. The reaction was then cooled to room temperature, diluted in water (10mL), and washed with diethyl ether (3 × 40 mL). The aqueous layer was concentrated to dryness and the resulting solid was recrystallized from acetone to give 1- ((methylamino) methyl) cyclopentanecarboxylic acid hydrobromide (127mg, 48% yield) as a crystalline white solid.

¹H-NMR(500MHz,DMSO-d₆)δ(ppm):12.76-13.15(s,1H),8.12-8.39(m,2H),2.98-3.11(m,2H),2.55(s,3H),1.86-2.01(m,2H),1.62(m,6H)。

Step 4 Compound I-228

The title compound was prepared according to general procedure B, except that 1- ((methylamino) methyl) cyclopentanecarboxylic acid (as the HBr salt) was the amine reactant (1.3 equivalents), 4 equivalents triethylamine was used, and the contents were heated as a solution in THF/water (10:1) at 90 ℃ for 6 h. During the treatment, the contents were extracted with ethyl acetate. Purification was achieved by silica gel chromatography using 2 to 5% methanol in dichloromethane over 40 minutes. The desired compound was obtained as a white solid (13.4mg, 45% yield).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.44(s,1H),8.08(d,1H),7.29(s,1H),7.15-7.25(m,1H),6.95-7.08(m,3H),6.55-6.58(m,1H),5.95(s,2H),4.02(s,2H),3.35(d,3H),2.18-2.29(m,2H),1.57-1.79(m,6H)。

Compound I-238

The title compound was prepared in 4 steps:

step 1: 4- ((4-Methylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid

A slurry of 4- (aminomethyl) tetrahydro-2H-pyran-4-carboxylic acid (500mg, 1.0 eq), p-toluenesulfonyl chloride (719mg, 1.2 eq) and 1M aqueous sodium hydroxide (9.4mL, 3.0 eq) was heated at 90 ℃ for 1 hour, after which the reaction mixture was cooled to 0 ℃ and acidified by addition of 3M aqueous hydrochloric acid. The resulting white precipitate was filtered and then washed successively with water and ethanol to give 4- ((4-methylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid (840mg, 85% yield) as a white solid. No purification is necessary.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):12.6(br.s,1H),7.68(d,2H),7.66(t,1H),7.39(d,2H),3.63-3.72(m,2H),3.27-3.32(m,2H),2.81(d,2H),2.38(s,3H),1.76-1.85(m,2H),1.33-1.46(m,2H)。

Step 2: 4- ((N, 4-dimethylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid

A suspension of 4- ((4-methylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid (840mg, 1.0 equiv) in 1M aqueous sodium hydroxide (10.7mL, 4.0 equiv) and iodomethane (0.528mL, 3.15 equiv) was heated to 100 ℃ for 2 hours, after which the reaction mixture was diluted in 3M aqueous hydrochloric acid, extracted with dichloromethane (3 × 30mL), dried (sodium sulfate), filtered and concentrated to give 4- ((N, 4-dimethylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid as a cream solid (197mg, 22% yield). No purification is necessary.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.63-7.72(d,2H),7.31-7.39(d,2H),3.87-3.97(m,2H),3.50-3.61(m,2H),3.25(s,2H),2.76(s,3H),2.45(s,3H),2.13-2.23(m,2H),1.62-1.74(m,2H)。

And step 3: 4- ((methylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid hydrobromide

A solution of 4- ((N, 4-dimethylphenylsulfonylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid (197mg, 1.0 equiv.) was heated in a 33% solution of hydrogen bromide in glacial acetic acid (1mL, 31 equiv.) at 85 ℃ for 3 hours, after which time LCMS analysis indicated that the starting material had been consumed. After the reaction mixture was cooled to room temperature, water was added and the reaction mixture was washed with diethyl ether (3 × 30 mL). The aqueous layer was concentrated to dryness and the resulting solid was recrystallized from acetone to give 4- ((methylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid hydrobromide salt (54.8mg, 36% yield) as a white solid.

¹H NMR(500MHz,D₂O)δ(ppm):3.71-3.89(m,2H),3.50-3.64(m,2H),3.17(s,2H),2.66(s,3H),1.96-2.09(m,2H),1.48-1.66(m,2H)。

And 4, step 4: compound I-238

This compound was prepared according to general procedure B, except that 4- ((methylamino) methyl) tetrahydro-2H-pyran-4-carboxylic acid (as HBr salt) was the amine reactant (1.05 equivalents), 4 equivalents triethylamine was used, and the reaction was carried out in dioxane/water (3:1) at 90 ℃ for 18 hours. Following the procedure described above, during workup, the contents were extracted with ethyl acetate and purified by silica gel chromatography using 2 to 7% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-238 as a white solid (31.0mg, 43% yield).

¹H NMR(400MHz,CDCl₃)δ(ppm):8.47(s,1H),8.06(d,1H),7.31(s,1H),7.23-7.27(m,1H),7.22(br.s,1H),7.00-7.09(m,3H),6.59(d,1H),5.96(s,2H),3.83-3.95(m,4H),3.47-3.56(m,2H),3.40(d,3H),2.20-2.26(m,2H),1.51-1.64(m,2H)。

Compound I-244

The title compound was prepared in 4 steps:

step 1: 4,4, 4-trifluoro-2- (4-methylphenylsulfonylamino) butanoic acid

A slurry of 2-amino-4, 4, 4-trifluorobutanoic acid (300mg, 1.0 eq), p-toluenesulfonyl chloride (437mg, 1.2 eq), and 1M aqueous sodium hydroxide (5.73mL,3.0 eq) was heated in water (4mL) at 90 ℃ for 1 hour, the reaction mixture was cooled to 0 ℃ and acidified by addition of 3M aqueous hydrochloric acid, extracted with dichloromethane (3 × 40mL), dried (sodium sulfate), filtered, and concentrated to give 4,4, 4-trifluoro-2- (4-methylphenylsulfonylamino) butanoic acid (175mg, 29% yield) as a white solid.

¹H NMR(500MHz,CDCl₃) Delta (ppm) 7.71-7.80(d,2H),7.28(d,2H, in chloroform), 5.72-5.91(br.s,1H),4.16-4.29(m,1H),2.64-2.76(m,1H),2.52-2.63(m,1H),2.43(s, 3H).

Step 2: 2- (N, 4-dimethylphenylsulfonylamino) -4,4, 4-trifluorobutanoic acid

A mixture of 4,4, 4-trifluoro-2- (4-methylphenylsulfonylamino) butyric acid (175mg, 1.0 equiv.) and methyl iodide (146. mu.L, 3.15 equiv.) in 1M aqueous sodium hydroxide (2.81mL, 4.0 equiv.) was heated at 85 ℃ for 2.5 hours, after which LCMS analysis indicated the presence of the desired product and the methyl ester of the desired product. The reaction mixture was acidified with 3M hydrochloric acid solution, extracted with dichloromethane (3 × 30mL), dried (sodium sulfate), filtered and concentrated to a residue. The residue was reconstituted in tetrahydrofuran (2mL) and then treated with 1M aqueous sodium hydroxide (0.5 mL). Stirring at room temperatureAfter 30min, the reaction mixture was acidified with 3M hydrochloric acid solution, extracted with dichloromethane (3 × 30mL), dried (sodium sulfate) and concentrated to give¹H NMR indicated 2- (N, 4-dimethylphenylsulfonylamino) -4,4, 4-trifluorobutanoic acid as a gum with a purity of about 90% (66mg, 36% yield). Used as such in the next step without further purification.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.60-7.70(d,2H),7.19(d,2H),4.90-4.99(m,1H),2.75-2.89(m,1H),2.66-2.72(s,3H),2.30-2.44(m,1H),2.29(s,3H)。

And step 3: 4,4, 4-trifluoro-2- (methylamino) butanoic acid hydrobromide

A solution of 2- (N, 4-dimethylphenylsulfonylamino) -4,4, 4-trifluorobutanoic acid (66mg, 1.0 equiv.) in 33% glacial acetic acid solution of hydrogen bromide (1.0mL, 91 equiv.) was heated to 85 ℃ for 2 hours. The starting material remains. Stirring was allowed at 60 ℃ for 72 hours, after which deprotection was almost complete. The reaction mixture was diluted in water, washed with diethyl ether (3 × 30mL), and the aqueous layer was concentrated to dryness. This crude material was used as such in the next step without any purification.

And 4, step 4: compound I-244

This compound was prepared following the general procedure B described above, except that 4,4, 4-trifluoro-2- (methylamino) butanoic acid (as HBr salt) was the amine reactant (1.2 equivalents), 4 equivalents of triethylamine was used and the reaction was carried out in dioxane/water (3:1) at 90 ℃ for 5 days. The crude material was purified via silica gel chromatography using a gradient of 2-10% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-244(24.7mg, 32% yield) as a tan solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.77(s,1H),8.21(d,1H),7.41(m,1H),7.24-7.33(m,1H),6.07-7.13(m,1H),7.02-7.07(m,1H),6.90(d,1H),6.82-6.88(m,1H),5.97(s,2H),3.38-3.46(m,2H),3.33-3.36(m,1H),3.03-3.19(m,3H)。

Compound I-94

The compound was prepared according to general procedure B, except that methyl 1-aminocyclobutanecarboxylate was the amine reactant, 5 equivalents of triethylamine were used and the reaction was heated as a solution in THF/water (10:1) at 90 ℃ for 14h, followed by heating in a microwave at 170 ℃ for 10 min. The contents were then treated with water and solid 1N HCl and dried in vacuo. The crude material was purified via preparative reverse phase HPLC to give the desired compound, compound I-94 as a white solid (0.30mg, 1.5% yield).

¹H NMR (500MHz, methanol-d 4). delta.ppm 8.81(d,1H),8.23(d,1H),7.34(s,1H),7.25-7.31(m,1H),7.01-7.13(m,2H),6.86-6.94(m,2H),5.97(s,2H),. 2.89(ddd,2H),2.45-2.54(m,2H),2.07-2.14(m,1H),1.95-2.03(m, 1H).

Compound I-138

This compound was prepared as above, except that methyl 1-aminocyclopentanecarboxylate (as the HCl salt) was the amine reactant, the mixture was heated in DMA (volume: 142. mu.l) at 140 ℃ for 5 hours to give the ester. The reaction mixture was then allowed to stir at room temperature (23 ℃) for 16 h. Sodium hydroxide (14.2mg) was added and the reaction was heated at 40 ℃ for 1h, then cooled, water was added, and the reaction was neutralized with 1N HCl and extracted with ethyl acetate (3 times). The organics were combined and dried and purified via reverse phase preparative HPLC to give the desired compound, compound I-138(0.5mg, 1.5% yield).

¹H NMR (500MHz, methanol-d 4). delta.ppm 8.84(s,1H),8.29(d,1H),7.40(s,1H),7.28-7.35(m,1H),7.04-7.16(m,2H),6.91-7.00(m,2H),6.01(s,2H),2.50-2.62(m,3H),2.17-2.26(m,2H),1.90(br.s., 3H).

Compound I-156

A mixture of intermediate 1(30.8mg), (1S,2R) -2-aminocyclopentanecarboxylic acid (31.9mg, 3 equivalents) and triethylamine (115. mu.l, 10 equivalents) was heated to 80 ℃ in a 10:1 mixture of THF/water for 16 h. The contents were concentrated in vacuo and purified via preparative reverse phase HPLC to give the desired compound, compound I-156 as a white solid (6.2mg, 16% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.52(s,1H),8.46(br.s.,1H),7.44(br.s.,2H),7.22-7.27(m,1H),7.15(t,1H),7.00-7.09(m,2H),6.66(s,1H),5.94(s,2H),4.88(br.s.,1H),3.13-3.21(m,1H),2.23(d,1H),2.15(br.s.,2H),1.85-2.03(m,2H),1.76(d,1H)。

Compound I-154

The title compound was prepared according to general procedure B, except cis-2-aminocyclohexanecarboxylic acid was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 24 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-154(8.5mg, 26% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm:8.62(d,1H),8.53(d,1H),7.79(br.s.,1H),7.45(s,1H),7.19-7.27(m,2H),7.00-7.10(m,2H),6.67(s,1H),5.94(s,2H),4.58(br.s.,1H),2.94(d,1H),2.33(d,1H),1.87(br.s.,2H),1.81(d,1H),1.61-1.74(m,2H),1.36-1.57(m,2H)。

Compound I-159

The title compound was prepared according to general procedure B except 3- (4-hydroxyphenyl) -L-alanine was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 18 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-159 as a brown oil.

¹H NMR(500MHz,CD₃OD)δppm:8.82(d,1H),8.22(d,1H),7.52(s,1H),7.25-7.33(m,1H),7.02-7.15(m,4H),6.97(d,1H),6.92(t,1H),6.64(d,2H),6.00(s,2H),5.29(dd,1H),3.40(dd,1H),3.09(dd,1H)。

Compound I-165

The title compound was prepared according to general procedure B except 3- (4-hydroxyphenyl) -D-alanine was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 90 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-165 as a brown oil (4.7mg, 13% yield).

¹H NMR(500MHz,CD₃OD)δppm:8.82(d,1H),8.24(d,1H),7.53(s,1H),7.26-7.38(m,1H),7.13(d,2H),7.04-7.11(m,2H),6.98(d,1H),6.93(t,1H),6.64(d,2H),6.01(s,2H),5.30(dd,1H),3.41(dd,1H),3.09(dd,1H)。

Compound I-179

The title compound was prepared according to general procedure B except (1S,3R) -3-aminocyclopentanecarboxylic acid was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 48 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-179(1.7mg, 5% yield).

¹H NMR(400MHz,CD₃OD)δppm:8.83(d,1H),8.23(d,1H),7.67(s,1H),7.26-7.35(m,1H),7.12(d,1H),7.05-7.10(m,1H),7.01(d,1H),)6.94-7.00(m,1H),6.03(s,2H),2.96-3.06(m,1H),2.42-2.54(m,1H),2.21(td,1H),1.97-2.15(m,4H),1.80-1.96(m,1H)。

Compound I-188

The title compound was prepared according to general procedure B except 4-fluoro-4-piperidinecarboxylic acid (as the HCl salt) was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 8h, followed by stirring at 23 ℃ for an additional 8 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-188 as a white solid (7mg, 18% yield).

¹H NMR(500MHz,CD₃OD)δppm:8.81(d,1H),8.32(d,1H),7.63(s,1H),7.26-7.33(m,1H),7.03-7.14(m,2H),6.91-6.98(m,2H),6.01(s,2H),4.82(br.s.,1H),3.59-3.73(m,2H),2.26-2.41(m,2H),2.16-2.23(m,2H),0.10(m,1H)。

Compound I-199

The title compound was prepared according to general procedure B, except that (S) -2-amino-4- (methylthio) butanoic acid was used as the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 16 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-199(4mg, 9% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm:8.82(d,1H),8.34(d,1H),7.58(s,1H),7.27-7.34(m,1H),7.04-7.14(m,2H),6.93-7.00(m,2H),6.02(s,2H),5.24(dd,1H),2.59-2.79(m,2H),2.36-2.46(m,1H),2.22-2.31(m,1H),2.12(s,3H)。

Compound I-192

The title compound was prepared according to general procedure B except 3- (methylsulfonyl) pyrrolidine was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 48 h. The contents were acidified with 1N hydrochloric acid, concentrated in vacuo, and purified via reverse phase HPLC to give the desired compound, compound I-192(6.3mg, 18% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm:8.81(d,1H),8.30(d,1H),7.61(s,1H),7.30(ddd,1H),7.03-7.14(m,2H),6.88-6.98(m,2H),6.01(s,2H),4.41-4.54(m,1H),4.27-4.38(m,1H),4.06-4.27(m,3H),3.11(s,3H),2.52-2.68(m,2H)。

Compound I-220

The title compound was prepared according to general procedure B except β -cyano-L-alanine was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 18 h.

¹H NMR(500MHz,CD₃OD)δppm:8.79(d,1H),8.30(d,1H),7.52(s,1H),7.25-7.31(m,1H),7.02-7.13(m,2H),6.86-6.95(m,2H),5.99(s,2H),5.34(dd,1H),3.15-3.25(m,2H)。

Compound I-198

The title compound was prepared according to general procedure B except trans-2-aminocyclohexanecarboxylic acid was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 16 h. The contents were acidified with 1N hydrochloric acid solution and the solid was filtered, resuspended in dichloromethane, and filtered to give the desired compound, compound I-198 as a white solid (14.5mg, 31% yield).

¹H NMR (500MHz, methanol-d 4) Δ ppm 8.75(d,1H),8.00(d,1H),7.42(s,1H),7.23-7.29(m,1H),7.05-7.11(m,1H),7.02(t,1H),6.89-6.92(m,1H),6.81(t,1H),5.95(s,2H),4.58(td,1H),2.56(td,1H),1.98-2.14(m,2H),1.78-1.90(m,2H),1.67(qd,1H),1.48-1.61(m,1H),1.28-1.47(m, 2H).

Compound I-208

The title compound was prepared according to general procedure B except that octahydrocyclopenta [ c ] pyrrole-3 a-carboxylic acid (4 equivalents) was the amine reactant and the mixture was heated as a solution in THF/water (10:1) at 80 ℃ for 5 h. The contents were blown dry with nitrogen and the crude mixture was resuspended in methanol and filtered to give the desired compound, compound I-208(37mg, 93% yield).

¹H NMR (500MHz, methanol-d 4) Δ ppm 8.74(d,1H),8.06-8.13(m,1H),7.39-7.45(m,1H),7.26(m,1H),7.09(m,1H),7.02(d,1H),6.91(d,1H),6.82(m,1H),5.96(s, 2H),4.40(d,1H),4.06(m,1H),3.79(d,2H),3.06(br.s.,1H),2.31(m,1H),2.11(m,1H),1.90(m,2H),1.64(m,1H),1.30(m, 1H).

Compound I-233

The title compound was prepared according to general procedure B except methyl L-cyclohexylglycine methyl ester (as HCl salt) was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 16 h. The contents were cooled, treated with solid sodium hydroxide and stirred at 23 ℃ for 2 h. After removal of the organic solvent from the reaction mixture and completion, the precipitate was filtered to give the desired compound, compound I-233(26.0mg, 0.047mmol, 70.7% yield) as a white solid.

¹H NMR (500MHz, methanol-d 4) Δ ppm 9.08(d,1H),8.12(d,1H),7.42(s,1H),7.29-7.35(m,1H),7.25(d,1H),7.18-7.24(m,1H),7.09(t,1H),6.93(t,1H),6.77(d,1H),5.82-5.92(dd,2H),4.17(br.s.,1H),3.30(s.,1H),1.79-1.91(m,2H),1.50-1.69(m,3H),0.89-1.24(m, 5H).

Compound I-243

A mixture of intermediate 1(25mg), (S) -2-amino-2-cyclohexylacetic acid methyl ester hydrochloride (41.7mg, 3 equivalents) and triethylamine (93. mu.l, 10 equivalents) was heated in a THF/water mixture at 90 ℃ for 16 h. The reaction mixture was cooled, NaOH (5.35mg, 2 equivalents) was added and the mixture was stirred at room temperature for 2 hours. The organic solvent was removed and the resulting precipitate was filtered to give (R) -2-cyclohexyl-2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) acetic acid as a white solid (26.0mg, 0.047mmol, 70.7% yield).

¹H NMR (500MHz, methanol-d 4) Δ ppm 8.75(d,1H),8.11(d,1H),7.41(s,1H),7.23-7.29(m,1H),7.00-7.11(m,1H),7.02(t,1H),6.88(d,1H),6.83(t,1H),5.95(s,2H),4.73(d,1H),1.97-2.04(m,1H),1.88(t,2H),1.80(d,2H),1.70(d,1H),1.17-1.39(m, 5H). The title compound was also prepared following general procedure B, except methyl D-cyclohexylglycine methyl ester (as the HCl salt) was the amine reactant (1 equivalent), and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 16 h. The contents were cooled, treated with solid sodium hydroxide, and stirred at 23 ℃ for 18 h. The contents were concentrated in vacuo and purified via reverse phase HPLC to give the desired compound, compound I-243 as a white solid (1mg, 3% yield).

Compound I-242

The title compound was prepared in 4 steps:

step 1:trans-2- (4-methylphenylsulfonylamino) cyclohexanecarboxylic acid

A slurry of trans-2-aminocyclohexanecarboxylic acid (318mg, 1.0 equiv.), p-toluenesulfonyl chloride (508mg, 1.2 equiv.), and 1M aqueous sodium hydroxide (6.7mL, 3.0 equiv.) was heated in water (5mL) at 90 ℃ for 1 hour. The reaction mixture was cooled to 0 ℃ and acidified by addition of 3M aqueous hydrochloric acid. The resulting white precipitate was filtered and washed successively with water and then ethanol to give racemic trans-2- (4-methylphenylsulfonylamino) cyclohexanecarboxylic acid as a white solid (179.6mg, 27% yield).

¹H NMR(400MHz,CDCl₃)δ(ppm):7.73(d,2H),7.27(d,2H),4.98-5.16(m,1H),3.24-3.46(br.s,1H),2.39(s,3H),2.23-2.34(m,1H),1.87-2.03(m,2H),1.58-1.78(m,2H),1.42-1.58(m,1H),1.08-1.35(m,3H)。

Step 2:synthesis of trans-2- (N, 4-dimethylphenylsulfonylamino) cyclohexanecarboxylic acid

A solution of trans-2- (4-methylphenylsulfonylamino) cyclohexanecarboxylic acid (187mg, 0.629mmol), methyl iodide (0.124mL, 3.0 equivalents) and 1M aqueous sodium hydroxide (2.52mL, 4.0 equivalents) in water (5mL) was heated at 75 ℃ for 1.5 hours, after which the reaction mixture was cooled to room temperature, washed with dichloromethane (2 × 30mL), acidified by addition of 3M aqueous hydrochloric acid, extracted with dichloromethane (3 × 30mL), dried (sodium sulfate), filtered and concentrated to give the crude N-methylamino acid product. Purification was achieved using silica gel chromatography with 2 to 5% methanol in dichloromethane as eluent over 40 min. Trans-2- (N, 4-dimethylphenylsulfonylamino) cyclohexanecarboxylic acid was obtained as a white foam (130mg, 66% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):7.69-7.76(d,2H),7.28(d,2H),4.03-4.16(m,1H),2.78(s,3H),2.49-2.61(m,1H),2.43(s,3H),2.02-2.13(m,1H),1.73-1.84(m,2H),1.63-1.73(m,1H),1.55-1.63(m,1H),1.35-1.45(m,2H),1.10-1.22(m,1H)。

Step 3: trans-2- (methylamino) cyclohexanecarboxylic acid hydrobromide salt

To a vial containing trans-2- (N, 4-dimethylphenylsulfonylamino) cyclohexanecarboxylic acid (130mg, 1.0 eq) was added a 33% solution of hydrogen bromide in glacial acetic acid (1.2ml, 53 eq). The suspension was heated at 85 ℃ for 2.5h before it was diluted in water and washed with diethyl ether (2 × 30mL) and then concentrated to give a golden foam residue. This material was recrystallized from acetone to give trans-2 (methylamino) cyclohexanecarboxylic acid hydrobromide (54.4mg, 55% yield) as a cream solid.

¹H NMR(500MHz,D₂O)δ(ppm):3.24-3.37(m,1H),2.65(s,3H),2.47-2.60(m,1H),2.06-2.20(m,2H),1.76-1.84(m,1H),1.15-1.51(m,5H)。

And 4, step 4: compound I-242

The title compound was prepared according to general procedure B, except that trans-2 (methylamino) cyclohexanecarboxylic acid (as the HBr salt) was the amine reactant, and the contents were heated to 85 ℃ as a solution in THF/water (10:1) for 18 h. The contents were cooled, concentrated in vacuo, and purified via reverse phase HPLC to give the desired compound, compound I-242 as a white solid (1mg, 3% yield).

¹H NMR (500MHz, methanol-d 4) delta ppm 8.75(d,1H),8.09(d,1H),7.38(s,1H),7.23-7.30(m,1H),7.06-7.11(m,1H),7.00-7.05(m,1H),6.89(d,1H),6.83(t,1H),5.94(s,2H),3.16-3.24(m,3H),2.79(br.s.,1H),2.08(d,1H),1.86-1.97(m,2H),1.81(d,2H),1.45-1.70(m,2H),1.34(dt, 1H).

Compound I-31

The title compound was prepared according to general procedure B, except 2-amino-1-morpholinoethanone (5 equivalents) was the amine reactant, 3 equivalents triethylamine was used and the contents were heated to 80 ℃ as a solution in THF for 1 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0 to 100% ethyl acetate/hexanes gradient to give the desired compound, compound I-31(4.7mg, 23% yield).

¹H NMR(500MHz,CDCl₃)δ8.44-8.52(m,1H),8.14-8.25(m,1H),7.19-7.27(m,1H),6.97-7.12(m,2H),6.83-6.91(m,1H),6.61-6.66(m,1H),6.00(s,2H),4.39-4.47(m,2H),3.71-3.82(m,7H),3.56-3.63(m,2H)。

Compound I-33

The title compound was prepared according to general procedure B except 3-methylmorpholine was the amine reactant, 5 equivalents of triethylamine were used, and the contents were heated as a solution in THF to 60 ℃ for 18h, followed by 80 ℃ for 18 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-5% methanol/dichloromethane gradient to give the desired compound, compound I-33(8mg, 41% yield).

¹H NMR(500MHz,CDCl₃)δ8.48(m,1H),8.22(m,1H),7.31(s,1H),7.1822(m,1H),6.99(s,2H),6.87(m,1H),6.61(d,1H),5.98(s,2H),4.69(m,1H),4.37(m,1H),4.05(m,1H),3.83(m,2H),3.69(m,1H),3.4752(m,1H),1.45(d,3H)。

Compound I-34

The title compound was prepared according to general procedure B except pyrrolidine-2-carboxylic acid methyl ester was the amine reactant, 2 equivalents of triethylamine were used, and the contents were heated as a solution in THF to 60 ℃ for 18 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-5% methanol/dichloromethane gradient to give the desired compound, compound I-34(10.6mg, 57% yield).

¹H NMR(500MHz,CDCl₃)δ8.47(m,1H),8.20(m,1H),8.17.29(s,1H),7.21(m,1H),7.04(m,1H),6.98(m,1H),6.87(m,1H),6.59(dm,1H),5.98(m,2H),4.76(m,1H),4.05(m,1H),3.94(m,1H),3.73(s,3H),2.35(m,1H),2.17(m,3H)。

Compound I-35

The title compound was prepared according to general procedure B, except that t-butyl pyrrolidin-3-ylcarbamate was the amine reactant (5 equivalents), 3 equivalents triethylamine was used and the contents were heated as a solution in THF to 80 ℃ for 1 h. The solvent was removed in vacuo, and the contents were purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-35(30mg, 68% yield).

¹H NMR(500MHz,CDCl₃)δ8.44-8.48(m,1H),8.14-8.19(m,1H),7.32(s,1H),7.17-7.24(m,1H),6.95-7.08(m,2H),6.82-6.89(m,1H),6.57-6.63(m,1H),5.99(s,2H),4.72-4.79(m,1H),4.32-4.43(m,1H),4.00-4.07(m,1H),3.86-3.95(m,2H),3.68-3.75(m,1H),2.23-2.33(m,1H),1.96-2.05(m,1H),1.48(s,9H)。

Compound I-41

The title compound was prepared according to general procedure B except pyrrolidine-2-carboxylic acid methyl ester was the amine reactant, 2 equivalents of triethylamine were used, and the contents were heated as a solution in THF to 60 ℃ for 18 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-5% methanol/dichloromethane gradient to give the desired compound, compound I-41(4mg, 22% yield).

¹H NMR(500MHz,CDCl₃)δ8.44-8.49(m,1H),8.19-8.26(m,1H),7.34-7.39(m,1H),7.18-7.25(m,1H),6.92-7.10(m,3H),6.74-6.80(m,1H),5.95-6.00(m,2H),4.45-4.51(m,2H),2.42-2.51(m,3H),2.16-2.23(m,4H)。

Compound I-46

The title compound was prepared by treating a solution of compound I-35 in dichloromethane with an equal volume of trifluoroacetic acid. After stirring at 23 ℃ for 1h, the solvent was removed under a stream of nitrogen and the contents were dried in vacuo for 18h to give the desired compound, compound I-46(29mg) as a solid.

¹H NMR(500MHz,CD₃OD)δ8.83-8.87(m,1H),8.37-8.42(m,1H),7.59-7.63(m,1H),7.29-7.37(m,1H),7.05-7.16(m,2H),6.94-7.02(m,2H),6.04(s,2H),4.13-4.33(m,5H),2.53-2.64(m,1H),2.27-2.39(m,1H)。

Compound I-48

The title compound was prepared according to general procedure B, except that piperidine-2-carboxylic acid methyl ester was the amine reactant, 2 equivalents of triethylamine was used, and the contents were heated as a solution in THF to 60 ℃ for 18 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-48(3.7mg, 18% yield).

¹H NMR(400MHz,CDCl₃)δ8.46-8.50(m,1H),8.37-8.44(m,1H),7.32-7.37(m,1H),7.17-7.23(m,1H),6.97-7.09(m,3H),6.59-6.62(m,1H),5.91(s,2H),5.46-5.57(m,1H),4.54-4.67(m,1H),3.75(s,3H),3.38-3.47(m,1H),2.34-2.45(m,1H),1.78-1.89(m,3H),1.61-1.72(m,1H),1.45-1.55(m,1H)。

Compound I-53

The title compound was prepared according to general procedure B, except azetidine-3-carboxylic acid was the amine reactant (5 equivalents), 3 equivalents triethylamine was used and the contents were heated as a solution in THF to 75 ℃ for 18 h. The solvent was removed under a stream of nitrogen. The product was isolated via reverse phase HPLC to give the desired compound, compound I-53(15.4mg, 88% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.81-8.85(m,1H),8.22-8.27(m,1H),7.55-7.59(m,1H),7.29-7.36(m,1H),7.05-7.16(m,2H),6.93-6.99(m,2H),5.99-6.05(m,2H),4.65-4.84(m,4H),3.75-3.84(m,1H)。

Compound I-54

The title compound was prepared according to general procedure B except 3-methylpiperazin-2-one was the amine reactant (5 equivalents), 3 equivalents triethylamine was used and the contents were heated to 75 ℃ as a solution in THF for 18 h. The solvent was removed under a stream of nitrogen. The product was isolated via reverse phase HPLC to give the desired compound, compound I-54(1.4mg, 8% yield).

¹H NMR(500MHz,CDCl₃)δ8.53-8.55(m,1H),8.49-8.53(m,1H),7.43-7.48(m,1H),7.31-7.37(m,1H),7.24-7.28(m,1H),7.09-7.14(m,1H),7.02-7.08(m,2H),6.67-6.70(m,1H),5.97(s,2H),5.34-5.47(m,1H),4.89-4.95(m,1H),3.62-3.78(m,2H),3.50-3.60(m,1H),1.70(d,3H).

Compound I-55

The title compound was prepared according to general procedure B except azetidine-2-carboxylic acid (5 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated to 75 ℃ as a solution in THF for 18 h. The solvent was removed in vacuo and the contents were purified via reverse phase HPLC to give the desired compound, compound I-55(1.3mg, 2% yield).

¹H NMR(500MHz,CD₃OD)δ8.82(s,1H),8.23-8.29(m,1H),7.40-7.52(m,1H),7.28-7.35(m,1H),7.04-7.16(m,2H),6.93(br.s.,2H),5.98-6.03(m,2H),5.23-5.36(m,1H),4.42-4.67(m,2H),2.92-3.07(m,1H),2.50-2.62(m,1H)。

Compound I-56

The title compound was prepared according to general procedure B except 3-fluoropiperidine (5 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated as a solution in THF to 75 ℃ for 18 h. The solvent was removed in vacuo, and the contents were purified via reverse phase HPLC to give the desired compound, compound I-56(1.3mg, 2% yield).

¹H NMR (500MHz, chloroform-d) Δ 8.52-8.56(m,1H),8.45-8.50(m,1H),7.49-7.54(m,1H),7.24-7.28(m,1H),7.13-7.20(m,1H),7.01-7.11(m,2H),6.68(s,1H),5.95(s,2H),4.85-5.03(m,1H),4.56-4.81(m,2H),3.71-3.89(m,1H),3.47-3.60(m,1H),1.75-2.26(m, 4H).

Compound I-57

The title compound was prepared according to general procedure B except 3, 3-difluoropiperidine (5 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated to 75 ℃ as a solution in THF for 18 h. The solvent was removed in vacuo, and the contents were purified via reverse phase HPLC to give the desired compound, compound I-57(4.5mg, 5% yield).

¹H NMR(500MHz,CDCl₃)δ8.52-8.55(m,1H),8.47-8.52(m,1H),7.40-7.45(m,1H),7.24-7.28(m,1H),7.11-7.17(m,1H),7.02-7.10(m,2H),6.65-6.68(m,1H),5.93-5.98(m,2H),4.20-4.30(m,2H),4.00-4.08(m,2H),2.16-2.27(m,2H),1.96-2.05(m,2H)。

Compound I-58

A solution of compound I-48 was dissolved in THF and aqueous lithium hydroxide (3 equivalents) was added. The solution was stirred at 25 ℃ for 18 h. The contents were concentrated and the remaining aqueous layer was acidified with 1N hydrochloric acid solution to give a white precipitate. The aqueous layer was extracted with ethyl acetate and washed with water and brine. The combined organic layers. The contents were dried over sodium sulfate, filtered and concentrated to give the desired compound, compound I-58(29mg, 100% yield).

¹H NMR(400MHz,CD₃OD)δ8.75(m,1H),8.20(m,1H),7.42(m,1H),7.26(m,1H),6.98-7.11(m,2H),6.84(m,2H),5.95(s,2H),5.47(m,1H),4.52(m,1H),3.44(m,1H),2.31-2.40(m,1H),1.93(m,1H),1.81(m,2H),1.68(m,1H),1.54(m,1H)。

Compound I-59

The title compound was prepared according to general procedure B except that piperazin-2-one was the amine reactant (5 equivalents), 5 equivalents triethylamine was used, and the contents were heated to 75 ℃ as a solution in THF for 18 h. The solvent was removed under a stream of nitrogen and the contents were purified via reverse phase HPLC to give the desired compound, compound I-59(1.6mg, 2% yield).

¹H NMR(500MHz,CDCl_3`)δ8.51-8.54(m,1H),8.45-8.49(m,1H),7.69-7.73(m,1H),7.23-7.27(m,1H),7.03-7.09(m,3H),6.69-6.73(m,2H),6.00-6.03(m,2H),4.70-4.73(m,2H),4.26-4.32(m,2H),3.64-3.69(m,2H)。

Compound I-60

The title compound was prepared according to general procedure B except triethylamine was the amine reactant (2 equivalents) and the contents were heated to 60 ℃ as a solution in THF for 18 h. The solvent was removed in vacuo and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-60(1.9mg, 11% yield).

¹H NMR(400MHz,CD₃OD)δ8.77-8.81(m,1H),8.17-8.22(m,1H),7.48-7.52(m,1H),7.23-7.32(m,1H),7.01-7.13(m,2H),6.89-6.98(m,2H),5.96-6.01(m,2H),3.81-3.90(m,4H),1.34(s,6H)。

Compound I-66

The title compound was prepared according to general procedure B except piperidine-3-carboxamide was the amine reactant (5 equivalents), 8 equivalents triethylamine was used, and the contents were heated to 75 ℃ as a solution in THF for 18 h. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-66(7mg, 36% yield).

¹H NMR(500MHz,CDCl₃)δ8.51-8.55(m,1H),8.25-8.31(m,1H),7.47-7.52(m,1H),7.22-7.27(m,1H),7.09-7.16(m,1H),7.00-7.09(m,2H),6.83-6.90(m,1H),6.67-6.72(m,1H),6.17-6.22(m,1H),5.90-5.95(m,2H),4.52-4.60(m,1H),4.30-4.43(m,1H),3.81-3.90(m,1H),3.60-3.69(m,1H),2.69-2.81(m,1H),2.05-2.13(m,2H),1.92-2.00(m,1H),1.69-1.81(m,1H)。

Compound I-75

The title compound was prepared according to general procedure B except that azepane-2-carboxylate was the amine reactant (1.5 equivalents), potassium carbonate (4 equivalents) was used instead of triethylamine, and the contents were heated to 150 ℃ in a microwave for 10min as a solution in NMP. The resulting mixture was filtered to remove solid potassium carbonate and concentrated in vacuo. The crude material was purified via reverse phase HPLC using a gradient of 20-70% acetonitrile/water (with 0.1% TFA) to afford the desired compound, compound I-75(1mg, 3% yield).

¹H NMR(500MHz,CDCl₃)δ8.83(m,1H),8.33(m,1H),7.48(m,1H),7.31(m,1H),7.10(m,2H),6.91(m,2H),6.01(s,2H),5.04(m,1H),4.18(m,1H),3.73(m,1H),2.58(m,1H),2.04(m,3H),1.92(m,1H),1.79(m,1H),1.53(m,2H)。

Compound I-82

The title compound was prepared according to general procedure B except that (1R,3S,5S) -8-azabicyclo [3.2.1] oct-3-ylcarbinol (as the HCl salt) was the amine reactant (3.5 equivalents), 5 equivalents triethylamine was used, and the contents were heated as a solution in NMP in a microwave to 120 ℃ for 30 min. The resulting mixture was purified via reverse phase HPLC to give the desired compound, compound I-82(10.8mg, 42% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.82-8.86(m,1H),8.25-8.29(m,1H),7.62-7.66(m,1H),7.30-7.36(m,1H),7.05-7.15(m,2H),6.92-7.02(m,2H),6.00-6.06(m,2H),3.66-3.72(m,2H),2.10-2.40(m,4H),1.78-2.07(m,5H)。

Compound I-83

The title compound was prepared according to general procedure B, except that morpholine-2-carboxylic acid (as the HCl salt) was the amine reactant (2 equivalents), Hunig's base (3 equivalents) was used instead of triethylamine, and the contents were heated to 120 ℃ for 30min in a microwave as a solution in NMP. The resulting mixture was purified via reverse phase HPLC using a 0-95% acetonitrile/water gradient (with 0.1% TFA) to afford the desired compound, compound I-83(10.8mg, 42% yield) as a clear glass.

¹H NMR (500MHz, methanol-d)₄)δ8.81-8.85(m,1H),8.35-8.44(m,1H),7.64(s,1H),7.26-7.35(m,1H),7.04-7.14(m,2H),6.97(d,2H),6.02(s,2H),4.73(m,1H),4.46(m,2H),4.14-4.20(m,1H),3.97(m,1H),3.89(d,2H)。

Compound I-87

The title compound was prepared according to general procedure B, except that (R) -piperidine-2-carboxylic acid (4 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-87(12mg, 48% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.79-8.83(m,1H),8.34-8.39(m,1H),7.60(s,1H),7.27-7.35(m,1H),7.03-7.15(m,2H),6.90-6.98(m,2H),6.02(s,2H),4.61-4.83(m,1H),3.43-3.58(m,1H),2.43-2.51(m,1H),1.69-2.02(m,5H),1.55-1.69(m,1H)。

Compound I-84

The title compound was prepared according to general procedure B, except that (S) -piperidine-2-carboxylic acid (4 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-84(9.6mg, 39% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.79-8.83(m,1H),8.31-8.36(m,1H),7.54-7.58(m,1H),7.27-7.34(m,1H),7.04-7.15(m,2H),6.89-6.97(m,2H),6.01(s,2H),5.65(br.s.,1H),4.58-4.80(m,1H),3.42-3.57(m,1H),2.41-2.50(m,1H),1.67-2.02(m,4H),1.55-1.66(m,1H)。

Compound I-95

The title compound was prepared according to general procedure B, except that (R) -morpholine-3-carboxylic acid (4 equivalents) was used as the amine reactant, Hunig's base (5 equivalents) was used instead of triethylamine, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-95(19mg, 76% yield).

¹H NMR(500MHz,CD₃OD)δ8.81(d,1H),8.39(d,1H),7.57(s,1H),7.26-7.34(m,1H),7.02-7.16(m,2H),6.93(d,2H),6.00(s,2H),5.26-5.59(m,1H),4.55(d,2H),4.04(s,1H),3.93(dd,1H),3.62-3.80(m,2H)。

Compound I-96

The title compound was prepared according to general procedure B, except that (S) -morpholine-3-carboxylic acid (4 equivalents) was used as the amine reactant, Hunig' S base (5 equivalents) was used instead of triethylamine, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-96(8mg, 31% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.81(s,1H),8.34-8.42(m,1H),7.51-7.59(m,1H),7.27-7.35(m,1H),7.02-7.15(m,2H),6.94(s,2H),6.01(s,2H),5.37-5.54(m,1H),4.56(d,2H),4.01-4.09(m,1H),3.89-3.96(m,1H),3.61-3.81(s,2H)。

Compound I-97

The title compound was prepared according to general procedure B, except 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (4 equivalents) was used as the amine reactant, Hunig's base (5 equivalents) was used instead of triethylamine, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-97 as a solid (3.4mg, 12% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.84-8.89(m,1H),8.42-8.49(m,1H),7.62-7.69(m,2H),7.30-7.40(m,4H),7.06-7.16(m,2H),6.97(m,2H),6.12-6.18(m,1H),6.05(s,2H),4.48-4.58(m,1H),4.14-4.23(m,2H),3.05-3.15(m,1H)。

Compound I-98

The title compound was prepared according to general procedure B except that 3-methyl-5- (piperidin-2-yl) -1,2, 4-oxadiazole (4 equivalents) was the amine reactant, Hunig's base (5 equivalents) was used instead of triethylamine, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 18 h. The solvent was removed under a stream of nitrogen and the contents were dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-98(5.3mg, 20% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.77-8.83(m,1H),8.37-8.45(m,1H),7.54(s,1H),7.26-7.36(m,1H),7.03-7.17(m,2H),6.93(s,2H),6.48-6.55(m,1H),6.00(s,2H),4.60-4.75(m,1H),3.45-3.55(m,1H),2.49-2.58(m,1H),2.38(s,3H),2.15-2.27(m,1H),1.74-1.94(m,3H),1.59-1.73(m,1H)。

Compound I-99

The title compound was prepared according to general procedure B, except that methyl morpholine-3-carboxylate (4 equivalents) was the amine reactant, Hunig's base (3 equivalents) was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in NMP for 2 h. After removal of the solvent and purification of the crude material via reverse phase HPLC to give the desired compound, compound I-99(7mg, 25% yield) as a solid.

¹H NMR(400MHz,CD₃OD)δ8.71-8.75(m,1H),8.21-8.26(m,1H),7.39-7.43(m,1H),7.19-7.29(m,1H),6.97-7.12(m,2H),6.85-6.88(m,1H),6.75-6.82(m,1H),5.90-5.95(m,2H),5.20-5.31(m,1H),4.45(s,1H),3.93-4.01(m,1H),3.82-3.93(m,2H),3.66-3.75(m,2H)。

Compound I-105

The title compound was prepared according to general procedure B except piperidine-2-carboxamide (4 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 60 ℃ as a solution in THF/water (9:1) for 48 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-105(12mg, 48% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.80-8.87(m,1H),8.35-8.41(m,1H),7.58-7.65(m,1H),7.28-7.36(m,1H),7.05-7.16(m,2H),6.91-7.02(m,2H),6.03(s,2H),5.53-5.61(m,1H),4.65-4.77(m,1H),3.56-3.69(m,1H),2.37-2.46(m,1H),1.62-2.07(m,6H)。

Compound I-106

The title compound was prepared according to general procedure B except 4-aminotetrahydro-2H-pyran-4-carboxylic acid (3.5 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated to 200 ℃ as a solution in NMP for 10 min. The reaction mixture was diluted with water and filtered. The filtrate was basified to pH 10 with 3N sodium hydroxide solution and extracted with dichloromethane. The filtrate was then acidified to pH1 with 1N hydrochloric acid solution and extracted with dichloromethane. The organic layer was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-106 as a solid (2.3mg, 9% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.81-8.87(m,1H),8.31-8.35(m,1H),7.38-7.41(m,1H),7.25-7.34(m,1H),7.04-7.15(m,2H),6.89-6.98(m,2H),6.01(s,2H),3.87-3.96(m,2H),3.76-3.87(m,2H),2.36-2.45(m,2H),2.23-2.33(m,2H)。

Compound I-110

The title compound was prepared according to general procedure B except that 4-amino-1- (tert-oxycarbonyl) piperidine-4-carboxylic acid (3 equivalents) was the amine reactant, 5 equivalents triethylamine was used, and the contents were heated as a solution in DMSO to 120 ℃ for 18 h. Without treatment, the crude material was purified via reverse phase HPLC to give the desired compound, compound I-110(8.2mg, 26% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.83(s,1H),8.31-8.36(m,1H),7.39(s,1H),7.26-7.36(m,1H),7.02-7.14(m,2H),6.91(s,2H),6.00(s,2H),3.75-3.88(m,2H),3.36-3.49(m,2H),2.29(br.s.,4H),1.50(s,9H)。

Compound I-111

The title compound was prepared according to general procedure B except 1,2,3, 4-tetrahydroisoquinoline (2.5 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated to 120 ℃ as a solution in THF for 18 h. The solvent was removed under a stream of nitrogen and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (with 0.1% TFA) gradient to give the desired compound, compound I-111(13.9mg, 55% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.82-8.86(m,1H),8.28-8.34(m,1H),7.68-7.73(m,1H),7.24-7.35(m,6H),6.93-7.15(m,5H),6.00-6.06(m,2H),5.24(s,2H),4.27-4.33(m,2H),3.10-3.16(m,2H)。

Compound I-122

In a 25mL flask, Compound I-110(0056g, 0.096mmol) was dissolved in DCM (vol.: 2mL) and TFA (2mL, 26.0 mmol). After stirring at room temperature for 3h, the reaction was complete. The solvent was removed in vacuo to give the pure product, compound I-122 as a white solid (13.9mg, 55% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.78-8.86(m,1H),8.30-8.38(m,1H),7.26-7.38(m,2H),7.01-7.15(m,2H),6.84-6.96(m,2H),5.97(s,2H),3.36-3.51(m,4H),2.50-2.67(m,4H)。

Compound I-126

The title compound was prepared according to general procedure B, except 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (3 equivalents) was used as the amine reactant, triethylamine was not used and the contents were heated to 120 ℃ as a solution in DMSO for 18 h. The reaction mixture was filtered and directly purified via reverse phase HPLC to give the desired compound, compound I-126(11mg, 38% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.82-8.85(m,1H),8.33-8.37(m,1H),7.53-7.59(m,2H),7.27-7.34(m,1H),7.10(m,2H),6.86-6.97(m,4H),5.01(s,2H),5.96(m,1H),4.35-4.45(m,1H),4.04-4.15(m,1H),3.84(s,3H),3.04(m,2H)。

Compound I-127

The title compound was prepared according to general procedure B, except 6-hydroxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (3 equivalents) was used as the amine reactant, triethylamine was not used and the contents were heated to 120 ℃ as a solution in DMSO for 18 h. The reaction mixture was filtered and directly purified via reverse phase HPLC to give the desired compound, compound I-127(5.2mg, 18% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.83-8.87(m,1H),8.37-8.42(m,1H),7.57-7.63(m,1H),7.42-7.48(m,1H),7.28-7.36(m,1H),7.05-7.16(m,2H),6.90-7.00(m,2H),6.71-6.80(m,2H),6.02(s,2H),5.94-5.99(m,1H),4.42-4.51(m,1H),3.99-4.13(m,1H),3.16-3.27(m,2H),2.94-3.02(m,1H)。

Compound I-128

The title compound was prepared according to general procedure B, except that 5-fluoro-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (3 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in DMSO to 60 ℃ for 18h, followed by heating to 120 ℃ for 1 h. The reaction mixture was filtered and directly purified via reverse phase HPLC to give the desired compound, compound I-128(5.7mg, 20% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δ8.83(m,1H),8.31(m,1H),7.68(m,1H),7.28(m,2H),7.03(m,6H),6.02(s,2H),5.21(s,2H),4.27(m,2H),3.08(m,2H)。

Compound I-130

A solution of compound I-122 (as TFA salt) in dichloromethane was treated with triethylamine (2 equivalents) and propionyl chloride (1.1 equivalents) at 25 ℃. The reaction was stirred at 25 ℃ for 18 h. The slurry was retained and the contents were therefore treated with 5 drops of NMP (contents clarified) and an additional 1 equivalent of propionyl chloride and triethylamine. The contents were then stirred at 25 ℃ for 18 h. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-130 as a solid (5.5mg, 47% yield).

¹H NMR (500MHz, methanol-d)₄)δ8.82-8.86(m,1H),8.33-8.38(m,1H),7.38-7.42(m,1H),7.28-7.36(m,1H),7.05-7.15(m,2H),6.89-6.99(m,2H),6.00(s,2H),4.04-4.13(m,1H),3.82-3.92(m,1H),3.55-3.64(m,1H),3.44-3.52(m,1H),2.21-2.52(m,7H),1.16(t,3H)。

Compound I-131

A solution of compound I-122 (as TFA salt) in dichloromethane was treated with triethylamine (2 equiv.) and methyl chloroformate (1.1 equiv.) at 25 deg.C. The reaction was stirred at 25 ℃ for 18 h. The slurry was retained and the contents were therefore treated with 5 drops of NMP (contents clarified) and an additional 1 equivalent of methyl chloroformate and triethylamine. The contents were then stirred at 25 ℃ for 18 h. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-131(3.8mg, 32% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.81-8.86(m,1H),8.30-8.37(m,1H),7.39(s,1H),7.26-7.34(m,1H),7.04-7.15(m,2H),6.93(m,2H),6.00(s,2H),3.88(m,2H),3.73(s,3H),3.42-3.52(m,2H),2.28-2.34(br.s.,4H)。

Compound I-132

A solution of compound I-122 (as TFA salt) in dichloromethane was treated with triethylamine (2 equiv.) and ethyl isocyanate (1.1 equiv.) at 25 deg.C. The reaction was stirred at 25 ℃ for 18 h. The slurry was retained and the contents were therefore treated with 5 drops of NMP (contents clear) and another 1 equivalent of ethyl isocyanate and triethylamine. The contents were then stirred at 25 ℃ for 18 h. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-132(5.9mg, 49% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.83-8.86(m,1H),8.32-8.37(m,1H),7.38-7.41(m,1H),7.28-7.34(m,1H),7.05-7.15(m,2H),6.89-6.99(m,2H),6.00(s,2H),3.74-3.83(m,2H),3.37-3.45(m,2H),3.19-3.26(m,2H),2.30(s,4H),1.14(s,3H)。

Compound I-153

The title compound was prepared according to general procedure B except 2- (methylamino) benzoic acid was the amine reactant, 5 equivalents of triethylamine were used, and the contents were heated as a solution in THF to 120 ℃ for 12 h. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-153(5.5mg, 40% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.80-8.85(m,1H),8.12-8.21(m,2H),7.71-7.78(m,1H),7.53-7.64(m,3H),7.28-7.36(m,1H),7.06-7.17(m,2H),6.91-7.02(m,2H),6.04(s,2H),3.72(s,3H)。

Compound I-161 and compound I-162

The title compound was prepared according to general procedure B, except 3-methylpiperidine-2-carboxylic acid was used as amine reactant, Hunig's base (5 equivalents) was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in THF/water (5:1) for 18 h. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-161 (cis, rac, 5.1mg, 20% yield) and compound I-162 (trans, rac, 1.3mg, 5% yield) as solids.

¹H NMR(400MHz,CD₃OD) Compound I-161. delta.8.77-8.80 (m,1H),8.30-8.34(m,1H),7.52-7.56(m,1H),7.23-7.32(m,1H),6.99-7.12(m,2H),6.87-6.94(m,2H),5.98(s,2H),5.24-5.30(m,1H),4.50-4.61(m,1H),3.72-3.83(m,1H),2.09-2.21(m,1H),1.91-2.00(m,1H),1.72-1.81(m,2H), 1.48-1H.62(m,1H),1.22(d,J＝7.43Hz,3H)。

¹H NMR(400MHz,CD₃OD) Compound I-162. delta.8.78-8.80 (m,1H),8.31-8.35(m,1H),7.55-7.58(m,1H),7.24-7.32(m,1H),7.01-7.12(m,2H),6.87-6.96(m,2H),5.99(s,2H),5.29-5.39(m,1H),3.44-3.57(m,1H),2.67-2.75(m,1H),1.78-2.03(m,3H),1.54-1.72(m,2H),1.19(d, 3H).

Compound I-197

The title compound was prepared according to general procedure B, except 2- (piperidin-4-yloxy) acetic acid was used as the amine reactant, Hunig's base (5 equivalents) was used in place of triethylamine, and the contents were heated to 100 ℃ as a solution in THF/water (10:1) for 18 h. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-197(3mg, 11% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.80-8.84(m,1H),8.24-8.30(m,1H),7.57-7.64(m,1H),7.29-7.35(m,1H),7.05-7.16(m,2H),6.92-7.01(m,2H),6.00-6.05(m,2H),4.28-4.36(m,2H),4.23(s,2H),3.97-4.05(m,2H),3.82-3.89(m,1H),2.05-2.16(m,2H),1.87-1.95(m,2H)。

Compound I-214

The title compound was prepared according to general procedure B, except 4-aminobutyric acid was the amine reactant, and the contents were stirred for 14 h. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-214(20mg, 57% yield) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.09(bs,1H),9.08(d,1H),8.21(d,1H),8.19(bs,1H),7.55(s,1H),7.33-7.27(m,1H),7.21-7.18(m,2H),7.08(ddd,1H),6.82(t,1H),5.88(s,2H),3.50(dd,2H),2.30(dd,2H),1.86-1.79(m,2H)。

Compound I-215

The title compound was prepared according to general procedure B, except that 4- (methylamino) butanoic acid was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-215(31mg, 81% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.10(d,1H),8.35(d,1H),7.67(s,1H),7.33-7.28(m,1H),7.22-7.18(m,2H),7.08(t,1H),6.86(t,1H),5.90(s,2H),1.88(t,2H),3.30(d,3H),2.30(t,2H),1.90-1.82(m,2H)。

Compound I-219

The title compound was prepared according to general procedure B, except that N-methyl-D-valine was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-219(17mg, 43% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.74(d,1H),8.17(d,1H),7.41(s,1H),7.27-7.22(m,1H),7.09-6.98(m,2H),6.87(d,1H),6.81(t,1H),5.93(s,2H),4.71(d,1H),3.31(s,3H),2.51-2.43(m,1H),1.14(d,3H),0.96(d,3H)。

Compound I-221

The title compound was prepared according to general procedure B, except that N-methyl-D-leucine was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-221 as a solid (31mg, 76% yield).

¹H-NMR(400MHz,DMSO-d₆)δ12.86(bs,1H),9.07(d,1H),8.29(d,1H),7.44(s,1H),7.32-7.27(m,1H),7.20-7.15(m,1H),7.16(d,1H),7.08-7.05(m,1H),6.85(t,1H),5.83(dd,2H),3.12(d,3H),3.05-3.00(m,1H),1.91-1.82(m,1H),1.76-1.68(m,1H),1.51-1.47(m,1H),0.89(d,3H),0.85(d,3H)。

Compound I-185

The title compound was prepared according to general procedure B, except 3- (trifluoromethyl) pyrrolidine-3-carboxylic acid was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-185(51mg, 87% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.05(d,1H),8.29(d,1H),7.53(s,1H),7.29(q,1H),7.24(d,1H),7.21-7.16(m,1H),7.07(t,1H),6.78(t,1H),5.88(s,2H),4.29(d,1H),3.98(d,1H),3.95-3.75(m,2H),2.64-2.37(m,2H)。

Compound I-180

The title compound was prepared according to general procedure B, except 2-amino-4, 4, 4-trifluorobutanoic acid was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-180(24mg, 58% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ13.29(bs,1H),9.07(d,1H),8.26(d,1H),8.15-8.12(m,1H),7.39(s,1H),7.28(q,1H),7.18(t,1H),7.15(s,1H),7.07(t,1H),6.83(t,1H),5.84(s,2H),4.95-4.92(m,1H),3.03-2.94(m,2H)。

Compound I-178

The title compound was prepared according to general procedure B, except 2-amino-4- (methylsulfonyl) butyric acid was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-178(6mg, 14% yield) as a solid.

H¹NMR(400MHz,CD₃OD)δ8.78(d,1H),8.29(d,1H),7.57(s,1H),7.29-7.23(m,1H),7.10-7.04(m,1H),7.03(t,1H),6.91(d,1H),6.89(t,1H),5.98(s,2H),5.24(dd,1H),3.38-3.25(m,1H),3.22-3.16(m,1H),2.29(s,3H),2.67-2.58(m,1H),2.47-2.38(m,1H)。

Compound I-72

This compound was prepared following the procedure described above for compound I-71, except that the reaction solvent was THF and treated with DCM and brine (22mg, 31%).

¹H-NMR(400MHz,DMSO-d₆)δ9.06(d,1H),8.23(d,1H),7.48(s,1H),7.33-7.27(m,1H),7.23-7.17(m,2H),7.08-7.03(m,1H),6.77-6.73(m,1H),5.86(s,2H),4.33-4.24(m,2H),4.11-4.03(m,2H),3.60-3.55(m,1H),3.14-3.07(m,2H),2.85-2.78(m,2H)。

Compound I-103

The title compound was prepared according to general procedure B, except D-leucine was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-103(18mg, 46% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.67(bs,1H),9.07(d,1H),8.23(d,1H),8.04(d,1H),7.39(s,1H),7.28(dd,1H),7.20-7.14(m,1H),7.14(d,1H),7.07(t,1H),6.84(t,1H),5.89-5.80(m,2H),4.74-4.64(m,1H),1.86-1.79(m,1H),1.70-1.58(m,2H),0.90(d,3H),0.67(d,3H)。

Compound I-148

The title compound was prepared according to general procedure B, except that (R) -2-amino-3, 3-dimethylbutyric acid was used as the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-148(33mg, 83% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.84(br.s,1H),9.09(d,1H),8.27(d,1H),7.43-7.27(m,2H),7.33-7.27(m,1H),7.18(t,1H),7.15(d,1H),7.08(t,1H),6.85(t,1H),5.85(s,2H),4.58(d,1H),0.96(s,9H)。

Compound I-151

The title compound was prepared according to general procedure B, except that (S) -2-amino-3, 3-dimethylbutyric acid was used as the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-151(22mg, 59% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.84(br.s,1H),9.09(d,1H),8.27(d,1H),7.43-7.27(m,2H),7.33-7.27(m,1H),7.18(t,1H),7.15(d,1H),7.08(t,1H),6.85(t,1H),5.85(s,2H),4.58(d,1H),0.96(s,9H)。

Compound I-137

The title compound was prepared according to general procedure B, except that N-methyl-L-leucine was the amine reactant. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-137(14mg, 36% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.79(d,1H),8.34(d,1H),7.52(s,1H),7.27(dd,1H),7.10-7.01(m,2H),6.95-6.90(m,2H),5.98(s,2H),5.57-5.47(m,1H),3.44(d,3H),2.03-1.98(m,2H),1.74-1.51(m,1H),1.00(d,3H),0.98(d,3H)。

Compound I-115

The title compound was prepared according to general procedure B except ethyl 5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine-3-carboxylate (4 equivalents) was the amine reactant and reacted in THF. The treatment was carried out in dichloromethane and brine. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-115(42mg, 37% yield) as a solid.

¹H-NMR(400MHz,CDCl3)δ8.47(d,1H),8.35(d,1H),7.40(s,1H),7.21-7.16(m,1H),7.01(t,1H),6.95(t,1H),6.84(t,1H),6.65(d,1H),5.98(s,2H),5.35(s,2H),4.59(t,2H),4.48(q,2H),4.30(t,2H),1.44(t,3H)。

Compound I-16

Intermediate 1(0.030g, 0.080mmol) was diluted with THF (2.0ml) and then charged with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazolo [4,3-a]Pyrazine (0.031g, 0.161 mmol). The reaction was heated to 50 ℃ and stirred for 1 hour. At this point, LC/MS did not show product formation, so TEA (0.056ml, 0.401mmol) was added at this point and the resulting reaction mixture was heated to 80 ℃ overnight. In the morning, the clear solution was checked by LC/MS. The crude reaction was concentrated and SiO was used₂Chromatography was performed using a gradient of 0-50% (7:1ACN/MeOH) in DCMPurification was performed to give the desired material as a white solid (32mg, 72%).

¹H-NMR(400MHz,DMSO-d₆)δ9.08(d,1H),8.43(d,1H),7.62(s,1H),7.30(dd,1H),7.23(d,1H),7.19(t,1H),7.07(t,1H),6.81(t,1H),5.89(s,2H),5.24(s,2H),4.33-4.25(m,4H)。

Compound I-112

The title compound was prepared according to general procedure B except D-serine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-112(4mg, 15% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.78(d,1H),8.27(dd,1H),7.51(s,1H),7.29-7.23(m,1H),7.07(t,1H),7.02(t,1H),6.92-6.91(m,1H),6.88(t,1H),5.97(s,2H),5.13(t,1H),4.09(d,2H)。

Compound I-86

The title compound was prepared according to general procedure B except D-valine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-86 as a solid (2mg, 7% yield).

¹H-NMR(400MHz,CD₃OD)δ8.80(d,1H),8.32(d,1H),7.57(s,1H),7.31-7.25(m,1H),7.10-7.02(m,2H),6.95(s,1H),6.95-6.91(m,1H),6.00(s,2H),4.85(d,1H),2.45-2.36(m,1H),1.11(d,3H),1.10(d,3H)。

Compound I-88

The title compound was prepared according to general procedure B, except that L-leucine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-88(3mg, 10% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.67(bs,1H),9.07(d,1H),8.23(d,1H),8.04(d,1H),7.39(s,1H),7.28(dd,1H),7.20-7.14(m,1H),7.14(d,1H),7.07(t,1H),6.84(t,1H),5.89-5.80(m,2H),4.74-4.64(m,1H),1.86-1.79(m,1H),1.70-1.58(m,2H),0.90(d,3H),0.67(d,3H)。

Compound I-67

The title compound was prepared according to general procedure B except glycine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-67(8mg, 33% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.72(bs,1H),9.07(d,1H),8.25(d,1H),8.14(bs,1H),7.45(s,1H),7.32-7.27(m,1H),7.21-7.16(m,1H),7.16(d,1H),7.07(t,1H),6.80(t,1H),5.86(s,2H),4.15(d,2H)。

Compound I-69

The title compound was prepared according to general procedure B except L-valine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-69(24mg, 66% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.80(d,1H),8.32(d,1H),7.57(s,1H),7.31-7.25(m,1H),7.10-7.02(m,2H),6.95(s,1H),6.95-6.91(m,1H),6.00(s,2H),4.85(d,1H),2.45-2.36(m,1H),1.11(d,3H),1.10(d,3H)。

Compound I-89

The title compound was prepared according to general procedure B except N-methyl-L-valine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-89(22mg, 76% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.74(d,1H),8.17(d,1H),7.41(s,1H),7.27-7.22(m,1H),7.09-6.98(m,2H),6.87(d,1H),6.81(t,1H),5.93(s,2H),4.71(d,1H),3.31(s,3H),2.51-2.43(m,1H),1.14(d,3H),0.96(d,3H)。

Compound I-79

The title compound was prepared according to general procedure B except thiomorpholine 1, 1-dioxide was the amine reactant and the reaction was carried out in THF/water. The treatment was carried out in dichloromethane and brine. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-79(4mg, 16% yield).

¹H-NMR(400MHz,CDCl3)δ8.47-8.45(m,1H),8.33(d,1H),7.24(s,1H),7.19(dd,1H),7.02(t,1H),6.96(t,1H),6.84(t,1H),6.57(d,1H),5.94(s,2H),4.36(dd,2H),3.19(dd,2H)。

Compound I-68

The title compound was prepared according to general procedure B, except that L-serine was the amine reactant and the reaction was carried out in THF/water. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-68(12mg, 48% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.78(d,1H),8.27(dd,1H),7.51(s,1H),7.29-7.23(m,1H),7.07(t,1H),7.02(t,1H),6.92-6.91(m,1H),6.88(t,1H),5.97(s,2H),5.13(t,1H),4.09(d,2H)。

Compound I-65

The title compound was prepared according to general procedure B except that tert-butylamine (50 equivalents) was the amine reactant and the reaction was heated as a solution in THF to 60 ℃ for 48 h. The reaction was concentrated in vacuo and the crude material was purified via silica gel chromatography with a 0-30% (7:1 acetonitrile/methanol) gradient in dichloromethane to give the desired compound, compound I-65(19mg, 96% yield) as a solid.¹H-NMR(400MHz,CDCl3)δ8.45(d,1H),8.14(d,1H),7.40(bs,1H),7.21-7.16(m,1H),7.03-6.91(m,3H),6.61(d,1H),5.93(s,2H),1.58(s,9H)。

Compound I-113

By using LiOH. H in a 2:1:1 solvent mixture of THF, MeOH and water₂O treatment of Compound I-115 to prepare this compound. Once the decarboxylation was complete, the reaction was acidified using 1N HCl and then extracted with dichloromethane (3 times). The organic fractions were combined and dried (Na)₂SO₄) Filtering andand then concentrated. The crude material was purified via silica gel chromatography using a 0-10% MeOH in dichloromethane gradient to give the title compound, compound I-113 as a white solid (5mg, 5%).

¹H-NMR(400MHz,DMSO-d₆)δ9.07(d,1H),8.50(s,1H),8.41(d,1H),7.61(s,1H),7.32-7.28(m,1H),7.24(d,1H),7.19(t,1H),7.07(t,1H),6.81(t,1H),5.89(s,2H),5.14(s,2H),4.28-4.16(m,4H)。

Compound I-174

The title compound was prepared according to general procedure B except 3-aminopropionic acid was the amine reactant and the contents were heated as a solution in THF/water (10:1) at 110 ℃ for 14 h. The crude material was purified via reverse phase preparative HPLC to give the desired compound, compound I-174(17mg, 56%) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.80(br.s.,1H),8.17(br.s.,1H),7.55(s,1H),7.29(d,1H),7.01-7.15(m,2H),6.95(br.s.,1H),6.91(d,1H),6.00(br.s.,2H),3.96(t,2H),2.77(t,2H)。

Compound I-169

The title compound was prepared according to general procedure B except 3- (methylamino) propionic acid was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 4 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-169(14mg, 56% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.71(d,1H),8.17(d,1H),7.48(s,1H),7.19(d,1H),6.89-7.05(m,2H),6.84(d,2H),5.90(s,2H),4.05(t,2H),3.42(d,3H),2.71(t,2H)。

Compound I-170

The title compound was prepared according to general procedure B except 2-methyl-3- (methylamino) propionic acid was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-170(13mg, 51% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.68(d,1H),8.09(d,1H),7.38(s,1H),7.14-7.21(m,1H),6.90-7.02(m,2H),6.76-6.83(m,2H),5.87(s,2H),4.01(dd,1H),3.77(dd,1H),3.34(d,3H),2.92(m,1H),1.14(d,3H)。

Compound I-171

The title compound was prepared according to general procedure B, except that (R) -2- (aminomethyl) -3-methylbutyric acid was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo, methanol was added and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-171(15mg, 57% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.86(d,1H),8.29(d,1H),7.60(s,1H),7.33(d,1H),7.06-7.17(m,2H),6.99-7.05(m,1H),6.95(d,1H),6.04(s,2H),3.93-4.08(m,2H),2.71(ddd,1H),2.10(dq,1H),1.07-1.20(m,6H).

Compound I-173

The title compound was prepared according to general procedure B, except that (S) -2- (aminomethyl) -3-methylbutyric acid was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-173(18mg, 68% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.84(d,1H),8.25(d,1H),7.56(s,1H),7.31(d,1H),7.04-7.15(m,2H),6.96-7.01(m,1H),6.93(d,1H),6.01(s,2H),3.91-4.04(m,2H),2.71(dt,1H),2.04-2.14(m,1H),1.14(d,3H),1.10(d,3H)。

Compound I-181

The title compound was prepared according to general procedure B, except that (R) -3-amino-4-methylpentanoic acid was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-181(7mg, 21% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.85(d,1H),8.29(d,1H),7.65(s,1H),7.30-7.37(m,1H),7.07-7.16(m,2H),6.98-7.03(m,2H),6.05(s,2H),4.91-4.96(m,1H),2.71-2.86(m,2H),2.05-2.13(m,1H),1.08(dd,6H)。

Compound I-182

The title compound was prepared according to general procedure B, except that (S) -3-amino-4-methylpentanoic acid was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-182(7mg, 24% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.79-8.85(m,1H),8.23-8.28(m,1H),7.63(d,1H),7.30(br.s.,1H),7.03-7.15(m,2H),6.94-7.02(m,2H),6.03(br.s.,2H),2.66-2.85(m,2H),2.01-2.13(m,2H),1.00-1.10(m,6H)。

Compound I-195 and compound I-196

The title compound was prepared according to general procedure B except 4-methyl-3- (methylamino) pentanoic acid was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/water (10:1) for 18 h. The reaction was concentrated in vacuo and the crude material was purified via reverse phase HPLC to give two compounds, compound I-195(5mg, 16% yield) and compound I-196(12mg, 41% yield).

Of Compound I-195¹H NMR(500MHz,CD₃OD)δppm 8.82(d,1H),8.28(d,1H),7.57(s,1H),7.29-7.34(m,1H),7.05-7.15(m,2H),6.93-6.98(m,2H),6.02(s,2H),2.92(m,2H),2.75-2.82(m,3H),2.10-2.19(m,2H),1.13(d,3H)1.00(d,3H)。

Of Compound I-196¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),8.21(d,1H),7.64(s,1H),7.29-7.35(m,1H),7.05-7.14(m,2H),6.95-7.01(m,2H),6.03(s,2H),3.27(s,3H)。

Compound I-202

The title compound was prepared in 3 steps:

step 1: synthesis of methyl (R) -3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -4-methylpentanoate

TMS-diazomethane (2 equiv.) is slowly added to a stirred solution of compound I-181 in ether/methanol (3:1) at 23 ℃. The mixture was stirred for 30min and the solvent was removed in vacuo. The crude material was purified via silica gel chromatography to give the desired intermediate, methyl (R) -3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -4-methylpentanoate (58mg, 56% yield).

Step 2: synthesis of (R) -methyl 3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) (methyl) amino) -4-methylpentanoate

To a solution of methyl (R) -3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -4-methylpentanoate in DMF at 0 ℃ was added sodium hydride (1.2 eq) followed by methyl iodide (1.1 eq). The mixture was stirred and warmed to 23 ℃. The reaction was quenched with water and the layers were separated. The aqueous layer was extracted with dichloromethane and the organic layer was dried, filtered and concentrated. The residue was taken to the next step without further purification.

And step 3: synthesis of Compound I-202

To a solution of methyl (R) -3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) (methyl) amino) -4-methylpentanoate in THF/water/methanol (3:1:1) was added solid sodium hydroxide (3 equivalents). The contents were stirred at 23 ℃ for 18 h. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give compound I-202(0.5mg, 12% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),8.29(d,1H),7.58(s,1H),7.32(dd,2H),7.06-7.15(m,1H),6.93-6.99(m,2H),6.02(s,2H),2.90(dd,2H),2.75-2.82(m,3H),2.14(m,2H),1.13(d,3H),1.00(d,3H)。

Compound I-206

The title compound was prepared according to general procedure B except 3-amino-2, 2-difluoropropionic acid was the amine reactant and the contents were heated to 110 ℃ as a solution in dioxane/water (10:1) for 18 h. The reaction was concentrated in vacuo, methanol was added and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-206(20mg, 22% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.78(d,1H),8.22(d,1H),7.61(s,1H),7.25-7.31(m,1H),7.07-7.12(m,1H),7.05(t,1H),6.96(d,1H),6.89(t,1H),6.00(s,2H),4.35(t,2H)。

Compound I-251

The title compound was prepared according to general procedure B, except that (S) -3-amino-4, 4-dimethylpentanoic acid was the amine reactant and the contents were heated to 110 ℃ as a solution in dioxane/water (10:1) for 18 h. The reaction was concentrated in vacuo, methanol was added and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-251(15mg, 44% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),8.26(d,1H),7.63(s,1H),7.29-7.35(m,1H),7.06-7.16(m,2H),7.02(d,1H),6.95-7.00(m,1H),6.04(s,2H),2.82-2.88(m,1H),2.72(dd,2H),1.08(s,9H)。

Compound I-266

Following general procedure B, a solution of 5, 5-difluoropiperidine-2-carboxylic acid (2.5-3.0 equivalents), triethylamine (8.0-10 equivalents), and intermediate 1 was stirred in dioxane/water (2:1 ratio) at 100 ℃ until LC/MS indicated complete consumption of the starting material. The solution was poured into 1N HCl and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (3-8% methanol/dichloromethane gradient) afforded the desired compound, compound I-266 as an off-white solid (29mg, combined yield of 2 experiments).

¹H-NMR(400MHz,CDCl₃)δ8.46(d,1H),8.25(d,1H),7.36(s,1H),7.20(app.q,1H),7.03(app.t,1H),6.96(app.t,1H),6.69(app.t,1H),6.58(d,1H),6.22(d,1H),6.08(d,1H),5.95(m,1H),4.59(m,1H),3.53(dd,1H),2.37(br.d,1H),2.08(m,2H),1.57(m,1H)。

Compound I-263

The title compound was prepared in 4 steps:

step 1: synthesis of tert-butyl 4, 4-difluoropiperidine-1-carboxylate

A suspension of 4, 4-difluoropiperidine hydrochloride and triethylamine (2.2 equivalents) in dichloromethane was slowly added via pipette to a solution of di-tert-butyl dicarbonate (1.1 equivalents) in dichloromethane (note: gas evolution was observed). The reaction was stirred at ambient temperature until NMR indicated complete consumption of the starting material. The reaction mixture was diluted with dichloromethane and washed with half-saturated ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and the solvent was concentrated in vacuo. Purification by silica gel chromatography (2% ethyl acetate/hexanes) afforded tert-butyl 4, 4-difluoropiperidine-1-carboxylate (73%).

Step 2: synthesis of 1- (tert-butoxycarbonyl) -4, 4-difluoropiperidine-2-carboxylic acid

A0.5M solution of tert-butyl 4, 4-difluoropiperidine-1-carboxylate, tetramethylethylenediamine (TMEDA, 1.0 eq.) in anhydrous ether at-78 deg.C was treated dropwise with sec-butyllithium (1.2 eq.) and stirred for 2 hours. Then, carbon dioxide gas was introduced via bubbling for 2 min. The reaction was stirred at-78 ℃ for 10min, warmed to ambient temperature and stirred for an additional 1 h. The resulting mixture was then quenched with water, acidified to pH 2 with 1N HCl, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (20-50% ethyl acetate/hexanes gradient) afforded 1- (tert-butoxycarbonyl) -4, 4-difluoropiperidine-2-carboxylic acid (87%).

And step 3: synthesis of 2-carboxy-4, 4-difluoropiperidinium trifluoroacetate

A solution of trifluoroacetic acid (20 equivalents) and 1- (tert-butoxycarbonyl) -4, 4-difluoropiperidine-2-carboxylic acid was stirred in dichloromethane at ambient temperature until LC/MS indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo to give 2-carboxy-4, 4-difluoropiperidinium trifluoroacetate (intermediate WW) (> 99%) as a viscous pale orange solid, which was used without further manipulation.

And 4, step 4: synthesis of Compound I-263

The title compound was prepared according to general procedure B except 2-carboxy-4, 4-difluoropiperidinium trifluoroacetate (2.4 equivalents) was the amine reactant and the contents were heated to 100 ℃. The crude material was purified via silica gel chromatography with a gradient of 2-7% methanol in dichloromethane to give the desired compound, compound I-263 as an off-white solid (26mg, 56% yield).

¹H-NMR (400MHz, acetone-d)₆)δ8.88(s,1H),8.30(d,1H),7.50(s,1H),7.31(app.q,1H),7.14(app.t,1H),7.08(app.t,1H),7.01(s,1H),6.90(app.t,1H),5.96(s,2H),5.70(br.d,1H),4.69(br.d,1H),3.68(app.t,1H),2.84(m,1H),2.52(m,1H),2.23(m,2H)。

Compound I-247

A mixture of intermediate-1 (26.0mg), (2S) -3-methyl-2- (methylamino) pentanoic acid (0.030g, 3 equivalents) and triethylamine (0.096ml, 10 equivalents) in a 10:1 mixture of THF/water was heated at 85 deg.C for 16 hours according to procedure B. The reaction was cooled, the solvent removed and the resulting crude material was purified via preparative reverse phase HPLC to give the desired product, compound I-247(2.4mg, 7.2% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δ8.80(d,1H),8.32(d,1H),7.51(s,1H),7.26-7.32(m,1H),7.02-7.13(m,2H),6.92-6.95(m,1H),6.91(d,1H),5.99(s,2H),5.49(s,1H),3.44(d,3H),2.03(s,1H),1.03(t,3H),0.98(dd,2H),0.85-0.92(m,3H)。

Compound I-255

Following general procedure B, a mixture of intermediate-1 (36.0mg), 4-isopropylpiperidine-4-carboxylic acid (3 equivalents) and TEA (10 equivalents) in a 10:1 mixture of THF/water was heated at 90 ℃ for 3 h. The reaction was cooled, the solvent removed and the resulting crude material purified to give the desired product, compound I-255 as a white solid (22mg, 49% yield).

¹H NMR (500MHz, chloroform-d) delta ppm 8.49(d,1H),8.35(d,1H),7.64(s,1H),7.48(s,1H),7.20-7.25(m,1H),7.05(s,1H),7.01-7.05(m,3H),6.67(d,1H),5.98(s,2H),4.80(d,2H),3.72-3.79(m,1H),3.23(t,2H),2.35(d,3H),1.80-1.92(m,2H),1.62(td,2H),1.41(t,1H),0.97(d, 6H).

Compound I-254

A mixture of intermediate-1 (35.0mg), 42- (piperidin-4-yl) benzoic acid (3 equiv.), and TEA (10 equiv.) in a 10:1 mixture of THF/water was heated at 90 deg.C for 2 h. The reaction mixture was cooled, the solvent was removed and the mixture was treated with 1N HCl and the resulting crude material was purified via preparative reverse phase HPLC to give the desired product, compound I-254(1mg, 2% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.45(d,1H),8.22(d,1H),7.99(dd,1H),7.51-7.56(m,1H),7.39-7.44(m,2H),7.32(t,1H),7.17-7.24(m,1H),6.95-7.09(m,2H),6.86-6.93(m,1H),6.61(s,1H),5.98(s,2H),4.90(br.s.,2H),3.94(br.s.,1H),3.21(t,2H),2.03-2.09(m,2H),1.80-1.90(m,2H)。

Compound I-256

A mixture of intermediate 1(20.0mg), 4- (tert-amyl) piperidine-4-carboxylic acid (3 equivalents as TFA salt), and TEA (10 equivalents) in a 10:1 mixture of THF/water was heated at 90 deg.C for 2 h. The reaction was cooled, the organic solvent was removed, 1n hcl was added, and the resulting precipitate was filtered to give the desired product, compound I-256(13.4mg, 47% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm:8.45(d,1H),8.17(d,1H),7.29(s,1H),7.15-7.22(m,1H),6.99-7.07(m,1H),6.96(t,1H),6.85(t,1H),6.58(d,1H),5.97(s,2H),4.69(d,2H),3.04(t,2H),2.25(d,2H),1.71(td,2H),1.35-1.45(m,2H),0.90-0.95(m,6H),0.87(t,3H)。

Compound I-258

To a solution of (S) -2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -3-methylbutanoic acid (compound I-69, 0.040g, 0.088mmol) in DCM (1.8ml) was added CDI (0.043g, 0.264 mmol). The reaction was stirred at 45 ℃ for 60 minutes. Thereafter, DBU (0.013ml, 0.088mmol) and cyclopropanesulfonamide (0.053g, 0.440mmol) were added. The reaction was continued at the same temperature for an additional 40 minutes until deemed complete. At this time, the reaction was quenched with 1N HCl. The layers were separated and the aqueous portion was extracted twice with DCM. The organic fractions were combined and dried (Na)₂SO4), filtered and then concentrated. The crude material was purified using silica chromatography (0-10% MeOH in DCM gradient) to give the desired compound, compound I-258 as a white solid (10.8mg, 80% yield).

¹H NMR (500MHz, chloroform-d) delta ppm 9.93(br.s.,1H),8.46(d,1H),8.21(d,1H),7.32(s,1H),7.21-7.25(m,1H),6.99-7.09(m,2H),6.91-6.97(m,1H),6.61(d,1H),6.03-6.08(m,1H),5.93-5.99(m,1H),5.45(d,1H),4.35(t,1H),2.77-2.88(m,1H),2.52-2.62(m,1H),1.12-1.15(m,6H),1.05-1.07(m,2H),0.88-0.90(m, 2H).

Compound I-259

To a solution of compound I-88 in dichloromethane was added CDI (3 equivalents). The reaction was heated to 45 ℃ for 30min, after which DBU (1 equivalent) and methanesulfonamide (5 equivalents) were added. The reaction was heated for an additional 40min until the reaction was complete. At this time, the reaction was quenched with 1N hydrochloric acid solution. The layers were separated and the aqueous portion was extracted with dichloromethane (2 ×). The organic fractions were combined and dried (Na)₂SO₄) Filtered and concentrated. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-259(15.8mg, 44% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 10.14(br.s.,1H),8.47(d,1H),8.22(d,1H),7.33(s,1H),7.21-7.26(m,1H),6.99-7.08(m,2H),6.91-6.96(m,1H),6.63(d,1H),5.96-6.09(m,2H),5.3(br.s.,1H)4.51-4.60(m,1H),3.06-3.11(m,3H),1.90-2.00(m,1H),1.71-1.87(m,2H),1.05(d,3H),0.96-0.99(m,3H)。

Compound I-261

To a solution of compound I-103 in dichloromethane was added CDI (3 equivalents). The reaction was heated to 45 ℃ for 1.5h, after which DBU (1 equivalent) and cyclopropanesulfonamide (5 equivalents) were added. The reaction was heated for an additional 40 minutes until the reaction was complete. Quench the reaction with 1N hydrochloric acid solution, separate the layers and extract the aqueous portion with dichloromethane (2 ×). The organic fractions were combined and dried (Na)₂SO₄) Filtered and concentrated. The crude material was purified using silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-261(40mg, 80% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δppm:10.20(br.s.,1H),8.47(s,1H),8.22(br.s.,1H),7.35(s,1H),7.17-7.26(m,1H),6.91-7.09(m,3H),6.64(s,1H),5.92-6.09(m,2H),5.39(br.s.,1H),4.59-4.70(m,1H),2.76-2.89(m,1H),2.50-2.65(m,1H),1.95(dt,1H),1.69-1.86(m,2H),1.04(d,2H),0.98(d,3H),0.85-0.95(m,3H),0.74-0.83(m,1H)。

Compound I-264

Following general procedure B, a mixture of intermediate-1 (38.8mg), 2-dimethylthiomorpholine 1, 1-dioxide (3 equivalents) and TEA (10 equivalents) in a 10:1 mixture of THF/water was heated at 90 ℃ for 3 h. The reaction was cooled, poured into a 1:1 mixture of 1N HCl and DCM, the organics extracted (three times), combined, dried, and purified by silica chromatography using a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-264 as a white solid (40mg, 77% yield).

¹H NMR(500MHz,,CDCl₃)δppm 8.48(d,1H),8.31(d,1H),7.26(s,1H),7.22(q,1H),7.02-7.07(m,1H),6.99(t,1H),6.86-6.91(m,1H),6.59(d,1H),5.97(s,2H),4.41(br.s.,2H),4.09(br.s.,2H),3.26(t,2H),1.43(s,6H)。

Compound I-270

Following general procedure B, a mixture of intermediate-1 (313mg), (S) -4-methyl-3- (methylamino) pentanoic acid (3 equivalents) and TEA (10 equivalents) in a 10:1 mixture of THF/water was heated at 85 ℃ for 3 h. The reaction was cooled, poured into a 1:1 mixture of 1N HCl and DCM, the organics extracted (three times), combined, dried, and purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-270 as a white solid (56mg, 14% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.48-8.53(m,1H),8.31(br.s.,1H),7.39(s,1H),7.20-7.26(m,1H),7.13(t,1H),6.99-7.05(m,2H),6.66(br.s.,1H),5.86-5.94(m,2H),3.19(d,3H),2.85(dd,1H),2.60-2.73(m,1H),1.93-2.05(m,1H),1.26(s,1H),0.93(d,3H),1.08(d,3H)。

Compound I-271

Following general procedure B, a mixture of intermediate 1(313mg), (1R,5S,6R) -3-azabicyclo [3.1.0] hexane-6-carboxylic acid (3 equivalents) and TEA (10 equivalents) in a 10:1 mixture of THF/water was heated at 85 ℃ for 3 h. The reaction was cooled, poured into a 1:1 mixture of 1N HCl and DCM, the organics extracted (three times), combined, dried, and purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-271 as a white solid (22mg, 33% yield).

¹H NMR(500MHz,CDCl₃)δppm:8.49(d,1H),8.35(d,1H),7.45(br.s.,1H),7.23(td,1H),7.05(d,1H),7.01(d,2H),6.63(d,1H),5.97(s,2H),4.32(d,2H),3.95(d,2H),2.40(br.s.,2H,1.65(t,1H),0.97(d,1H)。

Compound I-268

The title compound was prepared in 2 steps:

step 1: synthesis of 2-carboxy-5, 5-dimethylpiperidinium trifluoroacetate

2-carboxy-5, 5-dimethylpiperidinium trifluoroacetate was prepared as a white solid following the procedure for the synthesis of 2-carboxy-4, 4-difluoropiperidinium trifluoroacetate as described in preparation of compound I-263, except that 3, 3-dimethylpiperidinium hydrochloride was used in step 1.

Step 2: synthesis of Compound I-268

The title compound was prepared according to general procedure B except 2-carboxy-5, 5-dimethylpiperidinium trifluoroacetate was the amine reactant and the contents were heated to 100 ℃. The resulting solution was poured into water and acidified to pH 3 with 1N aqueous hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with HCl solution (pH 3) and diethyl ether to give the desired compound, compound I-268(38mg, 62% yield) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ13.0(br.s,1H),9.10(d,1H),8.33(d,1H),7.50(s,1H),7.33(app.q,1H),7.22(m,2H),7.10(app.t,1H),6.85(app.t,1H),5.89(s,2H),5.38(m,1H),3.99(m,1H),3.03(m,1H),2.11(m,1H),2.01(m,1H),1.44(br.d,1H),1.32(td,1H),0.97(s,3H),0.95(s,3H)。

Compound I-245

Following general procedure B, a solution of methyl 2- (4-aminotetrahydro-2H-pyran-4-yl) acetate hydrochloride (3.0 equivalents), triethylamine (10 equivalents) and intermediate 1 was stirred in dioxane/water (2:1 ratio) at 100 ℃ until LC/MS indicated complete consumption of the starting material. The solution was poured into water and acidified to pH 3 with 1N HCl and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC (20-65% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) gave compound I-245 as a white solid (8.8mg, 13%).

¹H-NMR(400MHz,CD₃OD)δ8.82(d,1H),8.31(d,1H),7.53(s,1H),7.30(app.q,1H),7.09(m,1H),7.05(app.t,1H),7.01(d,1H),6.97(app.t,1H),6.00(s,2H),3.82(dt,2H),3.74(td,2H),3.20(s,2H),2.65(br.d,2H),2.06(m,2H)。

Compound I-155

The title compound was prepared according to general procedure B, except that (R) -pyrrolidin-2-ylmethanol was the amine reactant and the contents were heated to 40 ℃ as a solution in THF for 18 min. The reaction was diluted with ethyl acetate and washed with water and brine. Through Na₂SO₄The organic phase was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 20-60% ethyl acetate/hexanes gradient to give the desired compound, compound I-155(11mg, 44% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δ8.43(d,1H),8.14(d,1H),7.27(s,1H),7.19(m,1H),7.01(app.t,1H),6.97(app.t,1H),6.89(app.t,1H),6.57(d,1H),5.94(s,2H),5.29(br.s,1H),4.52(m,1H),3.88(m,2H),3.78(m,2H),2.13(m,1H),2.07-1.92(m,2H),1.79(m,1H)。

Compound I-160

The title compound was prepared according to general procedure B, except that piperidin-2-ylmethanol was the amine reactant and the contents were heated to 55 ℃ as a solution in THF/DMSO (2:1) for 4 days. The reaction was diluted with ethyl acetate and washed with water and brine. Through Na₂SO₄The organic phase was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 30-60% ethyl acetate/hexanes gradient to give the desired compound, compound I-160 as a clear oil (9.6mg, 70% yield).

¹H-NMR(400MHz,CDCl₃)δ8.44(d,1H),8.17(d,1H),7.26(s,1H),7.19(m,1H),7.02(app.t,1H),6.97(app.t,1H),6.86(app.t,1H),6.58(d,1H),5.97(d,1H),5.93(d,1H),4.81(m,1H),4.25(m,1H),4.14(m,1H),3.83(br.s,1H),3.79(m,1H),3.28(m,1H),1.85-1.65(m,6H)。

Compound I-183

The title compound was prepared according to general procedure B, except that t-butyl pyrazolidine-1-carboxylate (1.1 equivalents) was the amine reactant and the contents were heated to 70 ℃ as a solution in THF/DMSO (4:1) for 5 days. The reaction was poured into water and extracted with ethyl acetate. Through Na₂SO₄The organic phase was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 20% ethyl acetate/hexanes gradient to give the desired compound, compound I-183(53mg, 75% yield).

¹H-NMR(400MHz,CDCl₃) δ 8.44(d,1H),8.26(d,1H),7.30(s,1H),7.18(m,1H),7.01(app.t,1H),6.95(app.t,1H),6.84(app.t,1H),6.56(d,1H),5.96(s,2H),4.40-3.60(br.m,4H),2.13 (app.quintet, 2H),1.45(s, 9H).

Compound I-193

A solution of trifluoroacetic acid (20 equivalents) and compound I-183 was stirred in dichloromethane at ambient temperature until LC/MS indicated complete consumption of the starting material. The solution was carefully poured into saturated sodium bicarbonate and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to give compound I-193 as a white solid (35mg, 85%).

¹H-NMR(400MHz,CDCl3)δ8.43(d,1H),8.17(d,1H),7.31(s,1H),7.18(m,1H),7.01(app.t,1H),6.95(app.t,1H),6.82(app.t,1H),6.57(d,1H),5.96(s,2H),4.58(br.s,1H),3.87(m,2H),3.19(app.t,2H),2.19(app. quintet, 2H).

Compound I-213

A solution of ethyl bromoacetate (1.0 eq), N-diisopropylethylamine (1.5 eq), and compound I-193 was stirred in dimethylformamide at ambient temperature until the LC/MS indicated complete consumption of the starting material. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (50% ethyl acetate/hexanes) gave compound I-213 as a clear oil (20mg, 59%).

¹H-NMR(400MHz,CDCl₃) δ 8.44(d,1H),8.21(d,1H),7.32(s,1H),7.17(m,1H),7.01(app.t,1H),6.95(app.t,1H),6.83(app.t,1H),6.57(d,1H),5.96(s,2H),4.22(q,2H),3.98(app.t,2H),3.70(s,2H),3.28(app.t,2H),2.25(app. quintet, 2H),1.28(t, 3H).

Compound I-216

A solution of sodium hydroxide (3.0N in water, 8.0 equivalents) and compound I-213 was stirred in methanol at ambient temperature until LC/MS indicated complete consumption of the starting material. The reaction mixture was concentrated, diluted with water and neutralized to pH 6-7 by addition of 1N HCl. The crude product was collected by vacuum filtration and purified by reverse phase HPLC (5-95% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give compound I-216(13mg, 72%) as an off white solid.

¹H-NMR(400MHz,CD₃OD) δ 9.09(d,1H),8.29(d,1H),7.53(s,1H),7.33(m,1H),7.22(m,2H),7.10(app.t,1H),6.84(app.t,1H),5.90(s,2H),3.84(m,2H),3.57(s,2H),3.12(m,2H),2.17(app. quintet, 2H).

Compound I-222

Following general procedure B, a solution of 2- (pyrrolidin-2-yl) acetic acid hydrochloride (2.3 equivalents), triethylamine (10 equivalents) and intermediate 1 was stirred in dioxane/water (2:1 ratio) at 100 ℃ until LC/MS indicated complete consumption of the starting material. The solution was diluted with water and neutralized to pH 3 by addition of 1N HCl. The resulting solid was collected by filtration and dried in vacuo to give compound I-222(63mg, 94%).

¹H-NMR(400MHz,DMSO-d₆)δ12.3(s,1H),9.11(d,1H),8.24(d,1H),7.48(s,1H),7.33(m,1H),7.21(m,1H),7.11(m,2H),6.90(m,1H),5.87(s,2H),4.62(m,1H),3.80(m,1H),3.65(m,1H),2.82(m,1H),2.39(m,1H),2.12-1.90(m,3H),1.84(m,1H)。

Compound I-184

The compound was obtained by general procedure B starting from intermediate 1. Purification by silica gel chromatography (20-50% ethyl acetate/hexanes gradient) afforded compound I-184(62mg, 81%) as a clear oil.

¹H-NMR(400MHz,CDCl3)δ8.45(d,1H),8.22(d,1H),7.27(s,1H),7.19(m,1H),7.02(app.t,1H),6.97(app.t,1H),6.87(app.t,1H),6.59(d,1H),5.97(d,1H),5.93(d,1H),4.76(br.m,1H),4.34-3.96(br.m,3H),3.96-3.74(br.m,2H),3.50-3.10(br.m,4H),1.49(s,9H)。

Compound I-211 and compound I-212

A solution of trifluoroacetic acid (20 equivalents) and compound I-184 was stirred in dichloromethane at ambient temperature until LC/MS indicated complete consumption of the starting material. The solution was carefully poured into saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) afforded two products:

compound I-211(17mg, 28% as TFA salt) as a clear oil.¹H-NMR(400MHz,CD₃OD)δ8.79(m,1H),8.35(m,1H),7.52(s,1H),7.28(m,1H),7.10(m,1H),7.04(m,1H),6.90(m,1H),6.85(m,1H),5.97(s,2H),5.08(m,1H),4.91(m,1H),4.09(m,1H),4.01(m,1H),3.85(app.t,1H),3.71(app.d,1H),3.52(app.d,1H),3.45(m,1H),3.40(m,1H)。

Compound in transparent oilSubstance I-212(19mg, 32%).¹H-NMR(400MHz,CD₃OD) δ 8.80(s,1H),8.34(d,1H),7.61(d,1H),7.29(m,1H),7.10(app.t,1H),7.05(app.t,1H),6.94(m,1H),6.91(app.t,1H),6.00(s,2H),5.12-4.98(m, 1H), 4.82(m,1H),4.59-4.32(m, 1H), 4.17(m, 1H), 3.93-3.58(m, 4H), 3.65-3.33(m, 1H). Multiple sets of rotamer peaks (about 0.5H each) were visible for the selected protons labeled with x.

Compound I-150

The title compound was prepared in 3 steps:

step 1: synthesis of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -6-hydroxypyrimidin-4 (3H) -one (the preparation of this compound is described in published patent application WO 2013/101830).

A mixture of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine, diethyl 2-fluoromalonate (1 eq) and DBU (1 eq) in ethanol was heated to 70 ℃ for 24H. The mixture was concentrated in vacuo to give an oil. The oil was purified by column chromatography (0 to 20% dichloromethane in methanol) to give 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -6-hydroxypyrimidin-4 (3H) -one as a white solid (145mg, 100% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.81(d,1H),7.42(s,1H),7.26-7.36(m,1H)7.05-7.18(m,2H),6.97(t,1H),6.92(d,1H),5.97(s,2H)。

Step 2: synthesis of 3- (3- (4, 6-dichloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole

5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -6-hydroxypyrimidin-4 (3H) -one (1 eq) was reacted with POCl₃(40 equivalents) the mixture was heated to 70 ℃ for 24 h. The mixture was concentrated in vacuo to give a white solid. It was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give 3- (3- (4, 6-dichloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole as a white solid (61mg, 38% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.40(s,1H)7.37(s,1H)7.10-7.18(m,1H)6.88-7.00(m,2H)6.76(t,1H)6.53(d,1H)5.96(s,2H)。

And step 3: synthesis of Compound I-150

A mixture of 3- (3- (4, 6-dichloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (1 eq), morpholine [ 1M in THF ] (1 eq) and Hunig's base (1 eq) in THF was stirred at 23 ℃ for 24H. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give a white solid. The solid was purified by column chromatography (0 to-100% ethyl acetate in hexanes) to give the desired compound, compound I-150 as a white solid (32mg, 47% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.47(d,1H),7.31-7.34(m,1H),7.19-7.26(m,1H),7.02-7.09(m,1H),6.99(t,1H),6.84(t,1H),6.59(d,1H),6.00(s,2H),3.89-3.96(m,4H),3.81-3.89(m,4H)。

Compound I-172

This compound was prepared in two steps.

Step 1: synthesis of 3- (3- (4-chloro-5-fluoro-6-methoxypyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole

To a suspension of 3- (3- (4, 6-dichloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (1 equivalent) in methanol was added sodium methoxide [ 0.5M in methanol ] (1 equivalent). The mixture was stirred at 23 ℃ for 4 h. The mixture was treated with HCl (4.0M in dioxane, 1 eq). The mixture was concentrated in vacuo. The resulting solid was dissolved in ethyl acetate and washed with brine. The organic layer was dried, filtered and evaporated to give 3- (3- (4-chloro-5-fluoro-6-methoxypyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole as a white solid (42mg, 85% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.67(d,1H),7.45(s,1H),7.16-7.21(m,1H),6.97-7.04(m,1H),6.94(t,1H),6.83(d,1H),6.74(t,1H),5.88(s,2H),4.12(s,3H)。

Step 2: synthesis of Compound I-172

A mixture of 3- (3- (4-chloro-5-fluoro-6-methoxypyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (1 eq), triethylamine (2 eq) and morpholine (2 eq) in THF was stirred at 100 ℃ for 24H. The mixture was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography (0-100% ethyl acetate in hexanes) to give a light brown solid. The solid was washed with methanol to give the desired compound, compound I-172 as a white solid (19mg, 41% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.08(d,1H),7.56(s,1H),7.29-7.36(m,1H),7.18-7.26(m,2H),7.09(t,1H),6.72(t,1H),5.92(s,2H),4.01(s,3H),3.72(s,8H)。

Compound I-23

A suspension of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-4 (3H) -one, this intermediate being described in published patent application WO2012/3405 a1, in phosphorus oxychloride (75 equivalents) was heated to 70 ℃ for 1H. The phosphorus oxychloride was removed under a stream of nitrogen and the resulting crude intermediate was dissolved in tetrahydrofuran. Morpholine (30 equivalents) was added and the solution was stirred at room temperature until the LC/MS indicated completion of the reaction. The solution was poured into saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was suspended in diethyl ether and the resulting solid was then filtered off to give the desired compound, compound I-23 as a white solid (6.5mg, 69% yield).

¹H-NMR(400MHz,CD₃OD)δ8.77(m,1H),8.66(s,1H),7.57(s,1H),7.31-7.26(m,1H),7.12-7.02(m,2H),6.94(m,1H),6.84(t,1H),5.99(s,2H),3.85-3.81(m,8H)。

Compound I-24

The title compound was synthesized according to the procedure described for compound I-23, except that 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4 (3H) -one (this intermediate is described in the previous patent application publication WO2012/3405 a 1) was used as the starting pyrimidinone. The final residue was suspended in diethyl ether and the resulting solid was then filtered off to give the desired compound, compound I-24(42mg, quantitative yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.74(m,1H),8.21(d,1H),7.46(s,1H),7.27-7.22(m,1H),7.10-6.99(m,2H),6.89(m,1H),6.79(t,1H),6.70(d,1H),5.95(s,2H),3.77(br s,8H)。

Compound I-28

The title compound was synthesized according to the procedure described for compound I-23, except that 5-chloro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4 (3H) -one (this intermediate is described in published patent application WO2012/3405 a 1) was used as the starting pyrimidinone. The final residue was suspended in diethyl ether and the resulting solid was then filtered off to give the desired compound, compound I-28(7.5mg, 32% yield) as a solid.

¹H-NMR(400MHz,CDCl3)δ8.44(m,1H),8.38(s,1H),7.30(s,1H),7.21-7.15(m,1H),7.03-6.98(s,1H),6.95(t,1H),6.82(t,1H),6.57(m,1H),5.95(s,2H),3.85-3.81(m,8H)。

Compound I-29

The title compound was synthesized according to the procedure described for compound I-23, except that 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (this intermediate is described in the previous patent application publication WO2012/3405 a 1) was used as the starting pyrimidinone. The final residue was suspended in diethyl ether and the resulting solid was then filtered off to give the desired compound, compound I-29 as a white solid (18mg, 84% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.11(m,1H),8.78(s,1H),7.71(s,1H),7.36-7.31(m,1H),7.27-7.20(m,2H),7.11(t,1H),6.83(t,1H),5.93(s,2H),4.02-4.00(m,4H),3.76-3.74(m,4H)。

Compound I-73

The title compound was prepared in 2 steps:

step 1Synthesis of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-methoxypyrimidin-4 (3H) -one

A solution of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine (1 eq), methyl 3- (dimethylamino) -2-methoxyacrylate (3.1 eq) and 1, 8-diazabicycloundec-7-ene (2 eq) was stirred at 100 ℃ for 6H. The reaction solution was diluted with dichloromethane and saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2 ×). The organics were washed with saturated sodium chloride and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification of the crude material via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-methoxypyrimidin-4-ol (49mg, 35% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.77(d,1H),7.58(s,1H),7.38(s,1H),7.29-7.24(m,1H),7.10-7.02(m,2H),6.92-6.85(m,2H),5.96(s,2H),3.87(s,3H)。

Step 2: synthesis of Compound I-73

The title compound was synthesized according to the procedure described for compound I-23, except 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) methoxypyrimidin-4 (3H) -one was used as the starting pyrimidinone. The final residue was suspended in diethyl ether and the resulting solid was then filtered off to give the desired compound, compound I-73(50mg, 86% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.08(m,1H),8.11(s,1H),7.51(s,1H),7.35-7.29(m,1H),7.24-7.20(m,2H),7.10(t,1H),6.79(t,1H),5.89(s,2H),3.88(s,3H),3.75-3.71(m,8H)。

Compound I-77

Following general procedure B, a solution of piperidine-4-carboxylic acid (3 equiv.), triethylamine (10 equiv.), and intermediate 1 was stirred in tetrahydrofuran and water (1:1 ratio) at 100 ℃ until LC/MS indicated complete consumption of the starting material. The solution was diluted with 1N aqueous hydrochloric acid and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and 5:1 dichloromethane/isopropanol. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) afforded compound I-77(11mg, 44% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.79(m,1H),8.23(d,1H),7.57(m,1H),7.31-7.26(m,1H),7.12-7.03(m,2H),6.96(m,1H),6.90(t,1H),5.99(s,2H),4.70(d,2H),3.51-3.45(m,2H),2.79-2.74(m,1H),2.15-2.11(m,2H),1.90-1.80(m,2H)。

Compound I-78

The title compound was prepared according to general procedure B except piperidine-3-carboxylic acid was the amine reactant and the contents were heated as a solution in THF/water (1:1) at 90 ℃ for 1.5 h. The solution was diluted with 1N hydrochloric acid solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and 5:1 dichloromethane/isopropanol. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-78 as a white solid (7mg, 28% yield).

¹H-NMR(400MHz,CD₃OD)δ8.81(m,1H),8.28(d,1H),7.60(m,1H),7.33-7.27(m,1H),7.13-7.04(m,2H),6.97-6.92(m,2H),6.01(s,2H),4.52(d,1H),4.31-4.26(m,1H),4.00(dd,1H),3.93-3.84(m,1H),2.84-2.78(m,1H),2.23-2.12(m,1H),2.04-1.88(m,2H),1.82-1.73(m,1H)。

Compound I-76

The title compound was prepared according to general procedure B except pyrrolidine-3-carboxylic acid was the amine reactant and the contents were heated as a solution in THF/water (1:1) at 60 ℃ for 2.5 h. The solution was diluted with 1N hydrochloric acid solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and 5:1 dichloromethane/isopropanol. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-76 as a white solid (11mg, 45% yield).

¹H-NMR(400MHz,CD₃OD)δ8.83(m,1H),8.29-8.27(m,1H),7.63(s,1H),7.33-7.29(m,1H),7.13-7.05(m,2H),6.99-6.96(m,2H),6.03(s,2H),4.23-4.03(m,5H),2.34(br s,2H)。

Compound I-92

The title compound was prepared according to general procedure B except 2-azabicyclo [2.2.1] heptane-3-carboxylic acid was the amine reactant and the contents were heated as a solution in THF/water (10:1) at 90 ℃ for 16 h. After the reaction was complete, 3N hydrochloric acid solution was added and the solvent was removed in vacuo. The crude residue was dissolved in water, and the solid was filtered and washed with water to give the desired compound, compound I-92(12mg, 47% yield) as a brown solid.

¹H-NMR(400MHz,CD₃OD) as>The 3 diastereomers exist as Δ 8.80(m,1H),8.25-8.16(m,1H),7.32-7.28(m,2H),7.12-7.03(m,2H),6.97-6.83(m,2H),6.00-5.96(m,2H),4.51-4.36(m,1H),2.99-2.90(m,1H),2.25(d,1H),1.94-1.57(m, 6H).

Compound I-100

Sodium hydride (1.0 eq) and ethyl 1H-pyrrole-2-carboxylate (1 eq) were dissolved in tetrahydrofuran. After stirring for 15 minutes, 0.5 equivalents of pyrrolidine anion was added to a solution of intermediate 1(1.0 equivalents) in tetrahydrofuran at room temperature. After 5 minutes, a further 0.5 equivalent of anion is added. The solution was stirred at room temperature for 45 minutes, at 45 ℃ for 2 hours, and then at 65 ℃ for 15 hours. 1 equivalent of pyrrole anion was added and after 1.5 hours at 65 ℃, the solution was diluted with saturated aqueous ammonium chloride and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate in hexanes) afforded compound I-100(16mg, 42% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δ8.71(m,1H),8.45(m,1H),7.40(s,1H),7.33-7.32(m,1H),7.22-7.14(m,2H),7.04-6.95(m,2H),6.84(t,1H),6.57(m,1H),6.43-6.41(m,1H),6.00(s,2H),4.23(q,2H),1.25(t,3H)。

Compound I-104

A solution of compound I-100(1 eq) in tetrahydrofuran, methanol and water (3:1:1 ratio) was treated with lithium hydroxide hydrate (1.5 eq). The solution was stirred at room temperature for 45 minutes and at 45 ℃ for 3 hours. The solution was diluted with ethyl acetate, 1N aqueous sodium hydroxide and water. The layers were separated and the aqueous layer was acidified to about pH1 with 1N aqueous hydrochloric acid. The acidified aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) gave compound I-104 as a white solid (1mg, 6% yield).

¹H-NMR(400MHz,CD₃OD)δ8.83(m,1H),8.77(m,1H),7.59(s,1H),7.47(m,1H),7.31-7.25(m,1H),7.16-7.03(m,3H),6.94(m,1H),6.87(t,1H),6.48-6.46(m,1H),6.00(s,2H)。

Compound I-119

The title compound was prepared according to general procedure B except 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid (as the HCl salt) was the amine reactant and the reaction was heated as a solution in THF/water (10:1) for 16 h. The solvent was removed in vacuo and the residue was dissolved in water. The solid was filtered off and the filtrate was purified by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-119(20mg, 48% yield) as a white solid.

1H-NMR(400MHz,CD₃OD)δ8.80(m,1H),8.33(d,1H),7.55(brs,1H),7.30-7.27(m,5H),7.12-7.03(m,2H),6.93(s,1H),6.89(t,1H),5.99(s,2H),5.58(br s,1H),5.21(d,1H),5.10(d,1H),3.42-3.40(m,2H)。

Compound I-140

This compound was synthesized according to general procedure B using 1,2,3, 4-tetrahydroquinoline-2-carboxylic acid and tetrahydrofuran: water in a 10:1 ratio as solvents. After consumption of the starting material, the solvent was removed in vacuo and the resulting residue was purified by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 20min gradient) to give compound I-140 as an orange solid (9mg, 22% yield).

¹H-NMR(400MHz,CD₃OD)δ8.79(m,1H),8.35(d,1H),7.47(s,1H),7.30-7.19(m,3H),7.16-7.02(m,4H),6.90-6.85(m,2H),5.97(s,2H),5.04(t,1H),2.85-2.81(m,1H),2.75-2.69(m,2H),1.88-1.80(m,1H)。

Compound I-120

The title compound was prepared according to general procedure B, except that (S) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid was used as the amine reactant and the reaction was heated to 80 ℃ as a solution in THF/water (10:1) for 2 h. After consumption of the starting material, the solvent was removed in vacuo and the resulting residue was dissolved in methanol, the solid was filtered off and the filtrate was purified by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 20min gradient) to give the desired compound, compound I-120 as a white solid (27mg, 65% yield).

¹H-NMR(400MHz,CD₃OD)δ8.80(m,1H),8.34(d,1H),7.67-7.64(m,1H),7.55(s,1H),7.34-7.26(m,4H),7.12-7.03(m,2H),6.91(t,1H),6.87(s,1H),6.02(s,1H),5.98(s,2H),4.45-3.37(m,1H),4.13-4.04(m,1H),3.26-3.20(m,1H),3.05(dt,1H)。

Compound I-121

The title compound was prepared according to general procedure B, except that (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid was used as the amine reactant and the reaction was heated to 80 ℃ as a solution in THF/water (10:1) for 2 h. After consumption of the starting material, the solvent was removed in vacuo and the resulting residue was dissolved in methanol, the solid was filtered off and the filtrate was purified by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 20min gradient) to give the desired compound, compound I-121 as a white solid (17mg, 62% yield).

¹H-NMR(400MHz,CD₃OD)δ8.80(m,1H),8.34(d,1H),7.67-7.64(m,1H),7.55(s,1H),7.34-7.26(m,4H),7.12-7.03(m,2H),6.91(t,1H),6.87(s,1H),6.02(s,1H),5.98(s,2H),4.45-3.37(m,1H),4.13-4.04(m,1H),3.26-3.20(m,1H),3.05(dt,1H)。

Compound I-123

The title compound was prepared according to general procedure B except piperidine-4-carbonitrile was the amine reactant and the reaction was heated as a solution in THF/water (10:1) to 80 ℃ for 2 h. After consumption of the starting material, the reaction solution was diluted with dichloromethane and the solvent was dried over magnesium sulfate. After filtration and removal of the solvent in vacuo, the crude material was purified by silica gel chromatography (0-70% ethyl acetate in hexanes) to give the desired compound, compound I-123 as a white solid (28mg, 94% yield).

¹H-NMR(400MHz,CD₃OD)δ8.75(m,1H),8.16(d,1H),7.42(s,1H),7.29-7.24(m,1H),7.11-7.06(m,1H),7.02(t,1H),6.90(m,1H),6.80(t,1H),5.95(s,2H),4.24-4.18(m,2H),3.76-3.70(m,2H),3.13(tt,1H),2.08(ddd,2H),1.96-1.87(m,2H)。

Compound I-141

The title compound was prepared according to general procedure B except 2-aminoacetonitrile (as the HCl salt) was the amine reactant and the reaction was heated to 90 ℃ as a solution in THF/water (10: 1). After stirring for 15h, a further 2 equivalents of 2-aminoacetonitrile (as the HCl salt) were added and the solution was stirred for a further 24h, at which time the solution was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with water. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Methanol was added and the resulting desired solid product was filtered off. The methanol filtrate contained the dissolved product and it was purified by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give additional product, which was combined with the filtered solid to give the desired compound, compound I-141 as a tan solid (11mg, 35% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.11(m,1H),8.43(t,1H),8.36(d,1H),7.61(s,1H),7.36-7.30(m,1H),7.25-7.20(m,2H),7.11(t,1H),6.86(t,1H),5.90(s,2H),4.55(d,2H)。

Compound I-145

A suspension of sodium azide (1 equivalent), ammonium chloride (1 equivalent) and compound I-141(1 equivalent) in N, N-dimethylformamide was heated to 80 ℃ for 1 hour, and then to 110 ℃ for 16 hours. Additional ammonium chloride and sodium azide were added and after 20 hours, the solution was diluted with methanol and water. Purification by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) gave compound I-145(6mg, 43%) as a yellow solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.10(m,1H),8.37(d,1H),7.59(s,1H),7.35-7.30(m,1H),7.25-7.20(m,2H),7.10(t,1H),6.81(t,1H),5.90(s,2H),3.93-3.91(m,4H),3.28-3.26(m,4H),2.91(br s,2H)。

Compound I-139

To a 0 ℃ solution of 2-methylpropan-2-ol (165 equiv) in dichloromethane was added chlorosulfonyl isocyanate (150 equiv). The solution was maintained at 0 ℃ for 20 minutes and then 3 equivalents of the resulting sulfonyl chloride were added to a room temperature solution of compound I-4(1 equivalent) and triethylamine (3 equivalents) in dichloromethane. The solution was maintained at room temperature for 30 minutes, at which time the solution was diluted with saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography (hexanes in ethyl acetate) gave compound I-139 as a tan solid (8mg, quantitative yield).

¹H-NMR(400MHz,CD₃OD)δ8.76(m,1H),8.21(d,1H),7.46(s,1H),7.29-7.24(m,1H),7.12-7.07(m,1H),7.02(t,1H),6.91(m,1H),6.80(t,1H),5.96(s,2H),4.02-3.99(m,4H),3.49-3.47(m,2H),1.46-1.43(m,9H)。

Compound I-125

To a solution of compound I-4(1 equivalent) in dichloromethane was added triethylamine (2 equivalents) followed by methanesulfonyl chloride (1.5 equivalents). The solution was stirred at room temperature for 15 minutes, and then diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with water. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give compound I-125(8.5mg, quantitative yield) as a tan solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.06(m,1H),8.34(d,1H),7.56(s,1H),7.32-7.27(m,1H),7.22-7.17(m,2H),7.07(t,1H),6.78(t,1H),5.87(s,2H),3.90-3.88(m,4H),3.25-3.22(m,4H),2.88(s,3H)。

Compound I-146

The title compound was prepared according to general procedure B, (1H-tetrazol-5-yl) methylamine (as the HCl salt) as the amine reactant and the reaction was heated to 90 ℃ as a solution in dioxane/water (3:1) for 3H. After treatment, the organics were washed with water, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the desired compound, compound I-146 as a white solid (21mg, 60% yield).

¹H-NMR(400MHz,CD₃OD)δ8.81(m,1H),8.34(d,1H),7.45(s,1H),7.32-7.26(m,1H),7.12-7.03(m,2H),6.94-6.90(m,2H),6.00(s,2H),5.23(s,2H)。

Compound I-147

A solution of compound I-139(1 eq) in dichloromethane and trifluoroacetic acid (200 eq) was stirred at 23 ℃ for 2h, at which time the solvent was removed in vacuo and the residue dissolved in methanol. The solid product was filtered off. Purification of the filtrate by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) and combination with the previously filtered product gave the desired compound, compound I-147(2.4mg, 41% yield) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.10(m,1H),8.37(d,1H),7.59(s,1H),7.36-7.30(m,1H),7.24-7.20(m,2H),7.10(t,1H),6.88(s,2H),6.81(t,1H),5.90(s,2H),3.91-3.89(m,4H),3.11-3.09(m,4H)。

Compound I-149

The title compound was prepared according to general procedure B, isoindoline-1-carboxylic acid as the amine reactant, and the reaction was heated to 80 ℃ as a solution in THF/water (10:1) for 1.5 h. After completion of the LC/MS indication, the solvent was removed under a stream of nitrogen and the resulting solid was dissolved in methanol and water (5: 1). The resulting solid was filtered off and the filtrate was purified by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-149 as a tan solid (14.5mg, 54% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.13(br s,1H),8.39(br s,1H),7.51(br s,2H),7.45-7.39(m,2H),7.36-7.31(m,1H),7.27-7.21(m,1H),7.14-7.05(m,2H),6.96-6.75(m,2H),6.03-5.82(m,3H),5.23-5.07(m,2H)。

Compound I-158

To a solution of compound I-139(1 equivalent) in methanol was added (diazomethyl) trimethylsilane (about 15 equivalents) until the yellow color persisted. The solvent was removed under a stream of nitrogen to give an intermediate which was not isolated. Dichloromethane and trifluoroacetic acid (200 equivalents) were added and after stirring at room temperature for 2 hours, the solvent was removed under a stream of nitrogen. Purification by silica gel chromatography (0-5% methanol in dichloromethane) gave compound I-158 as a white solid (2.1mg, 31% yield).

¹H-NMR(400MHz,CD₃OD)δ8.74(m,1H),8.19(d,1H),7.44(s,1H),7.28-7.22(m,1H),7.10-7.05(m,1H),7.01(t,1H),6.90(m,1H),6.78(t,1H),5.94(s,2H),4.01-3.98(m,4H),2.66(s,3H)。

Compound I-177

To a 0 ℃ solution of compound I-147(1 eq) and pyridine (100 eq) in dichloromethane was added acetyl chloride (5 eq). After 5 minutes, the solution was allowed to warm to room temperature and maintained at that temperature for 1 hour. Additional acetyl chloride (5 equivalents) was added and stirred at room temperature for 2.5 hours. Then, the solution was poured into a saturated aqueous ammonium chloride solution and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) gave compound I-177 as a yellow solid (7.9mg, 29% yield).

¹H-NMR(400MHz,CD₃OD)δ8.83(m,1H),8.36(d,1H),7.67(s,1H),7.33-7.28(m,1H),7.13-7.04(m,2H),6.97-6.92(m,2H),6.02(s,2H),4.22-4.20(m,4H),3.60-3.58(m,4H),2.03(s,3H)。

Compound I-175

The title compound was prepared according to general procedure B, 4- (methylsulfonyl) piperidine as the amine reactant, and the reaction was heated to 80 ℃ as a solution in THF for 1.5 h. After completion of the LC/MS indication, the solution was diluted with ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with additional ammonium chloride solution, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the desired compound, compound I-175(25mg, 93% yield) as a yellow solid.

¹H-NMR(400MHz,CDCl₃)δ8.44(m,1H),8.21(d,1H),7.26(s,1H),7.20-7.15(m,1H),7.03-6.96(m,1H),6.95(t,1H),6.82(t,1H),6.57(m,1H),5.95(s,2H),4.83(d,2H),3.18-3.05(m,3H),3.07(s,3H),2.26(d,2H),1.93(qd,2H)。

Compound I-192

The title compound was prepared according to general procedure B, N-methyl-1- (1H-tetrazol-5-yl) methylamine (as the HCl salt) as the amine reactant and the reaction heated to 90 ℃ as a solution in dioxane/water (3:1) for 1.5H. After completion of the reaction, the solution was diluted with 1N hydrochloric acid solution and ethyl acetate as judged by LC/MS. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were washed with water, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the desired compound, compound I-192(30mg, 83%) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ9.11(m,1H),8.34(d,1H),7.44(s,1H),7.35-7.30(m,1H),7.23-7.17(m,2H),7.10(t,1H),6.84(t,1H),5.88(s,2H),5.21(s,2H),3.35(m,3H)。

Compound I-201

The title compound was prepared according to general procedure B, ethyl 2- ((cyclopropylmethyl) amino) acetate as the amine reactant, and the reaction was heated to 90 ℃ as a solution in dioxane for 16 h. The crude material was purified by silica gel chromatography (0-70% ethyl acetate in hexanes) to give the desired compound, compound I-201 as a clear oil (32mg, 81% yield).

¹H-NMR(400MHz,CDCl₃)δ8.43(m,1H),8.17(d,1H),7.21(s,1H),7.19-7.13(m,1H),7.01-6.92(m,2H),6.81(t,1H),6.54(m,1H),5.92(s,2H),4.37(s,2H),4.17(q,2H),3.63(d,2H),1.21(t,3H),1.15-1.09(m,1H),0.59-0.54(m,2H),0.31-0.26(m,2H)。

Compound I-203

A solution of compound I-201(1 eq) in tetrahydrofuran, ethanol and water (ratio 3:1:1) was treated with lithium hydroxide monohydrate (1.5 eq) and stirred at room temperature for 4 hours, at which time the solution was diluted with water and dichloromethane. The layers were separated and the aqueous layer was acidified to about pH 1. The acidified aqueous layer was extracted with dichloromethane, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give compound I-203 as a white solid (18.5mg, 65% yield).

¹H-NMR(400MHz,CD₃OD)δ8.76(d,1H),8.15(d,1H),7.36(s,1H),7.29-7.24(m,1H),7.10-7.01(m,2H),6.86-6.82(m,2H),5.94(s,2H),4.47(s,2H),3.96(d,2H),1.22-1.15(m,1H),0.59-0.55(m,2H),0.38-0.34(m,2H)。

Compound I-204

The title compound was prepared according to general procedure B, 2- (isopropylamino) acetic acid as the amine reactant, and the reaction was heated to 100 ℃ as a solution in dioxane/water (3:1) for 16 h. The crude material was purified via silica gel chromatography (0-10% methanol in dichloromethane) to give the desired compound, compound I-204 as a white solid (8mg, 33% yield).

¹H-NMR(400MHz,CDCl₃)δ8.40(br s,1H),8.11(br s,1H),7.22(s,1H),7.20-7.15(m,1H),7.20-6.92(m,2H),6.83(br s,1H),6.60(br s,1H),5.91(br s,2H),4.75(br s,1H),4.14(br s,2H),1.29(d,6H)。

Compound I-205

The title compound was prepared according to general procedure B, ethyl 2- (isobutylamino) acetate as the amine reactant and the reaction was heated to 90 ℃ for 44h as a solution in dioxane. After completion of the reaction, the solution was diluted with water and dichloromethane as judged by LC/MS. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography (0-50% ethyl acetate in hexanes) to give the desired compound, compound I-205 as a yellow solid (19mg, 57% yield).

¹H-NMR(400MHz,CDCl₃)δ8.43(m,1H),8.16(d,1H),7.20-7.14(m,2H),7.02-6.98(m,1H),6.94(t,1H),6.81(t,1H),6.54(m,1H),6.54(m,1H),5.93(s,2H),4.26(s,2H),4.16(q,2H),3.54(d,2H),2.09-2.03(m,1H),1.19(t,3H),0.97(d,6H)。

Compound I-209

A solution of compound I-205(1 eq) in tetrahydrofuran, ethanol and water (ratio 3:1:1) was treated with lithium hydroxide monohydrate (2 eq) and stirred at room temperature until complete consumption of the starting material as judged by LC/MS. The solution was diluted with water and ether. The layers were separated and the aqueous layer was acidified to about pH 1. The acidified aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give compound I-209(13mg, 86% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.76(m,1H),8.15(d,1H),7.36(s,1H),7.29-7.24(m,1H),7.10-7.01(m,2H),6.86-6.82(m,2H),5.92(s,2H),4.38(s,2H),3.61(d,2H),2.15-2.08(m,1H),1.00(d,6H)。

Compound I-257

The title compound was prepared in 4 steps:

step 1: synthesis of (S) -2- (4-methylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid

A suspension of (S) -2-amino-3- (pyridin-2-yl) propionic acid, p-toluenesulfonyl chloride (1.2 equiv.) in water was treated with sodium hydroxide (1N solution, 3 equiv.). The reaction was stirred at 90 ℃ for 18 h. The resulting mixture was cooled to room temperature and neutralized to pH 6 with 1n hcl solution. Sodium chloride was added to saturate the solution, then the solution was extracted with dichloromethane/isopropanol (4:1 v/v). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo to give (S) -2- (4-methylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid as an off white solid (35% yield).

Step 2: synthesis of (S) -2- (N, 4-dimethylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid

A suspension of (S) -2- (4-methylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid and methyl iodide (3.2 equiv.) in 1N aqueous sodium hydroxide (4.0 equiv.) was heated at 100 ℃ for 6 h. The resulting mixture was cooled to room temperature, neutralized to pH 6 with 1n hcl solution, and extracted with dichloromethane/isopropanol (4:1 v/v). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (20-50% acetonitrile/methanol in dichloromethane (7:1) gradient) afforded (S) -2- (N, 4-dimethylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid as a yellow foam solid (39% yield).

And step 3: synthesis of (S) -2- (methylamino) -3- (pyridin-2-yl) propionic acid (as HBr salt)

To (S) -2- (N, 4-dimethylphenylsulfonylamino) -3- (pyridin-2-yl) propionic acid was added HBr (33 wt% in glacial acetic acid, 25 equivalents). The reaction was stirred at 85 ℃ for 6h and then at 60 ℃ for 3 days. An additional amount of HBr solution (3.3 equiv) was added and the resulting mixture was stirred at 85 ℃ for 6 h. The reaction was cooled to room temperature, diluted with water and washed with diethyl ether. The aqueous phase was concentrated in vacuo to give crude (S) -2- (methylamino) -3- (pyridin-2-yl) propionic acid dihydride (> 99% yield) as a thick red oil, which was used in the next step without further manipulation.

And 4, step 4: synthesis of Compound I-257

The title compound was prepared according to general procedure B, except that (S) -2- (methylamino) -3- (pyridin-2-yl) propionic acid (as the HBr salt) was the amine reactant, 1.1 equivalents of intermediate 1 were used, and the contents were heated to 100 ℃. The crude material was purified via reverse phase HPLC (20-75% acetonitrile in water with 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-257(123mg, 73% yield) as a tan solid.

¹H-NMR(400MHz,CD₃OD)d 8.81(d,1H),8.49(d,1H),8.24(d,1H),8.13(app.t,1H),7.88(d,1H),7.58(app.t,1H),7.42(s,1H),7.29(app.q,1H),7.11(m,1H),7.06(app.t,1H),6.90(d,1H),6.89(m,1H),6.01(d,1H),5.97(d,1H),5.65(br.m,1H),3.88(dd,1H),3.67(dd,1H),3.35(d,3H)。

¹H-NMR(400MHz,CD₃OD)δ8.81(d,1H),8.49(d,1H),8.24(d,1H),8.13(app.t,1H),7.88(d,1H),7.58(app.t,1H),7.42(s,1H),7.29(app.q,1H),7.11(m,1H),7.06(app.t,1H),6.90(d,1H),6.89(m,1H),6.01(d,1H),5.97(d,1H),5.65(br.m,1H),3.88(dd,1H),3.67(dd,1H),3.35(d,3H)。

Compound I-200

The title compound was synthesized in 8 steps:

step 1: synthesis of 3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylic acid ethyl ester

A suspension of isoxazole-3-carbohydrazide (1 eq), ethyl 2-amino-2-thioacetate (1 eq) and ammonium chloride (10 eq) in dry ethanol in a sealed vial was heated at 110 ℃ for 7 days. The crude mixture was concentrated in vacuo. Water was added, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification via silica gel chromatography (10-20% acetonitrile/methanol in dichloromethane (7:1) gradient) afforded ethyl 3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylate (24% yield) as an orange solid.

Step 2: synthesis of ethyl 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxylate and ethyl 1- (2-fluorobenzyl) -3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylate

To 3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylic acid ethyl ester in DMF was added sodium hydride (60 wt% in mineral oil, 1.2 equivalents). After 10min, 2-fluorobenzyl bromide (1.2 eq) was added and the reaction was stirred for 2 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (10-40% ethyl acetate/hexanes gradient) afforded ethyl 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxylate and ethyl 1- (2-fluorobenzyl) -3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylate (63% yield, 42:58 ratio).

And step 3: synthesis of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxylic acid and 1- (2-fluorobenzyl) -3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylic acid

To a solution of ethyl 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxylate and ethyl 1- (2-fluorobenzyl) -3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylate in tetrahydrofuran/methanol/water (3:1:1 ratio) was added lithium hydroxide hydrate (1.5 equivalents). After 1h, water and 1N HCl solution (50:8 ratio) were added and the resulting mixture was extracted with ethyl acetate. Note that: the product was not completely soluble and was collected by vacuum filtration. The aqueous layer was extracted with dichloromethane/isopropanol (4:1 v/v). The combined organic phases were concentrated in vacuo and triturated with ether to give additional product. The combined solids (88%, mixture of regioisomers) were used in the next step without further work-up.

And 4, step 4: synthesis of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carbonitrile

To a suspension of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxylic acid and 1- (2-fluorobenzyl) -3- (isoxazol-3-yl) -1H-1,2, 4-triazole-5-carboxylic acid, 2-methylpropan-2-amine (2 eq) and triethylamine (2 eq) in ethyl acetate was added n-propylphosphonic anhydride (T3P, 50 wt% solution in ethyl acetate, 3 eq). The resulting yellow solution was heated at 65 ℃ for 2.5 h. The solvent was removed in vacuo. Phosphorus oxychloride (18 equivalents) was added and the resulting mixture was stirred at 70 ℃ for 50 min. The reaction was quenched by careful pouring into a mixture of water and ice, neutralized to pH 7 by addition of saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (10-60% ethyl acetate/hexanes gradient) afforded 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carbonitrile (39% yield). Note that: one regioisomer is decarboxylated to form 3- (1- (2-fluorobenzyl) -1H-1,2, 4-triazol-3-yl) isoxazole. The structural assignment was consistent with that observed for nOe. This side reaction may occur in the saponification step (step 3).

And 5: synthesis of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxamidine

A solution of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carbonitrile in methanol was treated with sodium methoxide (25 wt% solution in methanol, 5 equivalents) and stirred for 1H. Ammonium chloride (10 equivalents) was added. After 18h, the reaction mixture was concentrated in vacuo and partitioned between half-saturated sodium bicarbonate/1N sodium hydroxide solution (10:1 ratio) and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo to give 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxamidine (> 99% yield), which was used without further purification.

Step 6: synthesis of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazol-3-yl) pyrimidin-4 (3H) -one

The suspension of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazole-3-carboxamidine was treated with sodium (Z) -3-ethoxy-2-fluoro-3-oxoprop-1-en-1-ol (3.0 equiv) and heated at 90 ℃ for 1H. After cooling to ambient temperature, the reaction mixture was neutralized by adding HCl (1.25M solution in ethanol). The resulting pale yellow suspension was stirred for 5min and then concentrated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous layer was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (5-20% acetonitrile/methanol in dichloromethane (7:1) gradient) afforded 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazol-3-yl) -pyrimidin-4 (3H) -one (61mg, 74% yield) as a light yellow solid.

¹H-NMR(400MHz,CD₃OD)δ8.95(d,1H),8.09(d,1H),7.35(app.q,1H),7.23(app.t,1H),7.17(d,1H),7.15(m,2H),6.07(s,2H)。

And 7: synthesis of 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-1,2, 4-triazol-5-yl) isoxazole

A suspension of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-1,2, 4-triazol-3-yl) pyrimidin-4 (3H) -one in phosphorus oxychloride (77 equivalents) was heated to 65 ℃ for 2H. The reaction mixture was carefully poured into ice and stirred for 20 min. The resulting mixture was basified to pH 8 by addition of saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo to give 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-1,2, 4-triazol-5-yl) isoxazole as an off-white solid (> 99% yield).

And 8: synthesis of Compound I-200

The title compound was prepared according to general procedure B, except that (S) -3-methyl-2- (methylamino) butanoic acid was the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-1,2, 4-triazol-5-yl) isoxazole was used instead of intermediate 1, and the contents were heated to 100 ℃. The crude material was purified via silica gel chromatography (20-50% (acetonitrile/methanol ═ 7:1) gradient in dichloromethane) to afford an impure product. The sample was then purified by reverse phase HPLC (5-95% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) to give the desired compound, compound I-200 as a white solid (23mg, 66%, over two steps).

¹H-NMR(400MHz,CDCl₃)δ8.56(d,1H),8.34(d,1H),7.27(app.q,1H),7.21(app.t,1H),7.15(d,1H),7.06(m,2H),6.09(d,1H),6.02(d,1H),4.27(d,1H),3.07(d,3H),2.55(m,1H),1.10(d,3H),0.95(d,3H)。

Compound I-249

The title compound was prepared according to general procedure B except that 4-methylpiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-1,2, 4-triazol-5-yl) isoxazole (the synthesis is described in the procedure for compound I-200) was used in place of intermediate 1, and the contents were heated to 100 ℃ for 19H. The reaction was cooled and diluted with water and neutralized with 1N aqueous HCl. The resulting solid was collected via vacuum filtration, washed with water, and dried in vacuo to give the desired compound, compound I-249 as an off-white solid (29mg, 85% yield).

¹H-NMR(400MHz,CDCl3)δ8.54(d,1H),8.22(d,1H),7.24(m,1H),7.17(d,1H),7.07-7.00(m,3H),6.08(s,2H),4.41(br.d,2H),3.38(app.t,2H),2.28(br.d,2H),1.59(m,2H),1.31(s,3H)。

Compound I-1

The title compound was prepared according to general procedure B except that pyrrolidone (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-1(23mg, 76% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.08(d,1H),8.20(d,1H),7.52(s,1H),7.30-7.40(m,1H),7.18-7.28(m,2H),7.10(t,1H),6.82(t,1H),5.89(s,2H),3.65-3.70(m,4H),1.92(d,4H)。

Compound I-2

The title compound was prepared according to general procedure B except piperidine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-2(25mg, 80% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(s,1H),8.26(d,1H),7.54(s,1H),7.32(s,2H),7.20-7.27(m,2H),7.10(t,1H),6.81(t,1H),5.90(s,2H),3.74-3.80(m,4H),1.58-1.62(m,6H)。

Compound I-3

The title compound was prepared according to general procedure B except morpholine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-3(24mg, 76% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.08(s,1H),8.33(d,1H),7.57(s,1H),7.32(d,2H),7.20-7.27(m,2H),7.10(t,2H),6.81(t,1H),5.90(s,2H),3.79(d,4H),3.74(d,4H)。

Compound I-4

The title compound was prepared according to general procedure B except piperazine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-4(20mg, 64% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(s,1H),8.33(d,1H),7.56(s,1H),7.32(s,1H),7.20-7.28(m,2H),7.10(t,1H),6.81(t,1H),5.90(s,2H),3.78-3.84(m,4H),2.90-3.00(m,3H)。

Compound I-5

The title compound was prepared according to general procedure B except that N-methylpiperazine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min and then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-5(23mg, 71% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(s,1H),8.31(d,1H),7.56(s,1H),7.32(s,1H),7.18-7.27(m,2H),7.10(t,1H),6.80(s,1H),5.90(s,2H),3.74-3.81(m,4H),3.25-3.35(s,3H),2.20-2.30(m,4H)。

Compound I-6

The title compound was prepared according to general procedure B except 2-morpholinoethylamine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-6(25mg, 72% yield) as a gum.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.17(d,1H),7.59(s,1H),7.48(s,1H),7.28-7.38(m,1H),7.17-7.26(m,2H),7.10(t,1H),6.86(t,1H),5.88(s,2H),3.56-3.62(m,4H),3.48(t,4H),2.44(m,2H),2.29-2.40(m,2H)。

Compound I-7

The title compound was prepared according to general procedure B except N, N-dimethylethane-1, 2-diamine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-7(24mg, 76% yield) as a gum.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.17(d,1H),7.54(s,1H),7.48(s,1H),7.29-7.38(m,1H),7.18-7.27(m,2H),7.11(t,1H),6.88(t,1H),5.89(s,2H),3.57(q,2H),2.43-2.49(m,2H),2.19(s,6H)。

Compound I-9

The title compound was prepared according to general procedure B except cyclohexylamine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-9(20mg, 62% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.14(d,1H),7.51(d,1H),7.45(s,1H),7.33(d,1H),7.18-7.28(m,2H),7.10(t,1H),6.85(t,1H),5.88(s,2H),4.03-4.08(m,1H),1.89-1.92(m,2H),1.72-1.76(m,2H),1.63(d,2H),1.32-1.43(m,4H)。

Compound I-8

The title compound was prepared according to general procedure B except dimethylamine (7 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-8(19mg, 67% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(s,1H),8.18(d,1H),7.52(s,1H),7.39-7.45(m,1H),7.18-7.27(m,2H),7.10(t,1H),6.82-6.88(m,1H),5.90(s,2H),3.24(d,6H)。

Compound I-11

The title compound was prepared according to general procedure B except 2-methylpyrrolidine was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-11(16mg, 51% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.21(d,1H),7.49(s,1H),7.29-7.38(m,1H),7.17-7.27(m,2H),7.10(t,1H),6.84(t 1H),5.92(s,2H),4.40-4.48(m,1H),3.75-3.90(m,1H),3.56-3.69(m,1H),2.00-2.07(m,2H),1.93(d,1H),1.65-1.73(m,1H),1.23(d,3H)。

Compound I-10

The title compound was prepared according to general procedure B except that piperidin-4-ol was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min and then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-10(19mg, 58% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.08(d,1H),8.27(d,1H),7.54(s,1H),7.21-7.39(m,3H),7.10(t,1H),6.81(t,1H),5.90(s,2H),4.78-4.84(m,1H),4.18(d,2H),3.74-3.79(m,1H),3.37-3.47(m,2H),1.81-8.89(m,2H),1.40-1.54(m,2H)。

Compound I-12

The title compound was prepared according to general procedure B except that tert-butyl 4-aminopiperidine-1-carboxylate (1.5 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min and then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-12(36mg, 90% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.04-9.15(m,1H),8.18(d,1H),7.53-7.65(m,1H),7.47(s,1H),7.30-7.39(m,1H),7.19-7.27(m,2H),7.07-7.16(m,1H),6.85(t,1H),5.83-5.91(m,2H),4.25(d,1H),3.96(d,2H),2.87-2.91(m,2H),1.87(d,2H),1.44-1.51(m,2H),1.41(s,9H)。

Compound I-13

The title compound was prepared according to general procedure B, except that (S) -pyrrolidin-2-ylmethanol was the amine reactant, triethylamine was not used, and the contents were heated as a solution in THF to 40 ℃ for 10min, then at 23 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-13(18mg, 55% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.21(d,1H),7.49(s,1H),7.28-7.37(m,1H),7.18-7.26(m,2H),7.10(t,1H),6.83(t,1H),5.85-5.93(m,2H),4.86(t,1H),4.32-4.39(m,1H),3.74-3.79(m,1H),3.62-3.69(m,1H),3.52-3.59(m,1H),3.44-3.50(m,1H),1.98-2.04(m,2H),1.91(d,2H)。

Compound I-17

The title compound was prepared according to general procedure B except 3-methoxypyrrolidine (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated as a solution in THF to 40 ℃ for 1 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-17(12mg, 61% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.23(d,1H),7.53(s,1H),7.29-7.40(m,1H),7.18-7.28(m,2H),7.10(t,1H),6.82(t,1H),5.90(s,2H),4.03-4.12(m,1H),3.70-3.87(m,3H),3.66(d,1H),3.28(s,3H),1.96-2.15(m,2H)。

Compound I-18

The title compound was prepared according to general procedure B except that piperidin-3-ol (4 equivalents) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 1 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-18(14mg, 72% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.09(d,1H),8.25(d,1H),7.53(s,1H),7.28-7.39(m,1H),7.17-7.27(m,2H),7.10(t,1H),6.81(t,1H),5.90(s,2H),4.97(d,1H),4.18(d,1H),3.56-3.68(m,1H),3.37-3.48(m,2H),3.21(dd,1H),1.73-1.96(m,2H),1.43-1.58(m,2H)。

Compound I-25

The title compound was prepared according to general procedure B except that tert-butyl piperidin-3-ylcarbamate (4 equivalents) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 1 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-25(25mg, 66% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.75(d,1H),8.16(d,1H),7.58(s,1H),7.23-7.38(m,1H),7.08-7.17(m,1H),7.05(t,1H),6.95(s,1H),6.84(t,1H),6.78(d,1H),5.98(s,2H),4.40(d,1H),4.13-4.24(m,1H),3.69(br.s.,1H),3.56(d,1H),3.35-3.42(m,1H),2.00-2.09(m,1H),1.91(dd,1H),1.59-1.72(m,2H),1.45(s,9H)。

Compound I-26

The title compound was prepared according to general procedure B except that tert-butyl 3-aminoazetidine-1-carboxylate (4 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated as a solution in THF to 40 ℃ for 1h, followed by heating to 75 ℃ until complete consumption of the starting material was observed on LC/MS. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-26, as a solid (24mg, 67% yield).

¹H NMR(400MHz,DMSO-d₆)δppm 9.10(d,1H),8.31(d,1H),8.25(d,1H),7.48-7.57(m,1H),7.29-7.38(m,1H),7.15-7.28(m,2H),7.11(t,1H),6.85(t,1H),5.89(s,2H),4.76-4.93(m,1H),4.15-4.25(m,2H),3.91(dd,2H),1.39(s,9H)。

Compound I-27

The title compound was prepared according to general procedure B except that tert-butyl 3-aminopiperidine-1-carboxylate (4 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated as a solution in THF to 40 ℃ for 1h, followed by heating to 75 ℃ until complete consumption of the starting material was observed on LC/MS. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-27(24mg, 57% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.78(d,1H),8.15(d,1H),7.58(s,1H),7.25-7.33(m,1H),7.08-7.17(m,1H),7.05(t,1H),6.95(s,1H),6.84(t,1H),6.78(d,1H),5.98(s,2H),4.40(d,1H),4.18(d,1H),3.69(m,1H),3.56(d,1H),3.39(d,1H),1.99-2.08(m,1H),1.91(dd,1H),1.57-1.76(m,2H),1.45(s,9H)。

Compound I-19

The title compound was prepared according to general procedure B except 3-methoxypiperidine (4 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated as a solution in THF to 40 ℃ for 1h, then to 75 ℃ until complete consumption of the starting material was observed on LC/MS. The reaction was cooled and filtered, and the solid was washed with ethyl acetate. The filtrate was collected and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-19(15mg, 74% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.06(d,1H),8.23(d,1H),7.49(s,1H),7.25-7.35(m,1H),7.13-7.24(m,2H),7.07(t,1H),6.78-6.87(m,1H),5.86(s,2H),3.91(d,1H),3.62-3.81(m,3H),3.34(dd,1H),3.23(s,3H),1.83-1.94(m,1H),1.72-1.81(m,1H),1.56-1.65(m,1H),1.44-1.54(m,1H)。

Compound I-20

The title compound was prepared according to general procedure B except that pyrrolidin-3-ol (4 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated to 40 ℃ as a solution in THF for 1 h. The reaction was cooled and filtered, and the solid was washed with ethyl acetate. The filtrate was collected and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-20(10mg, 53% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.08(d,1H),8.21(d,1H),7.52(s,1H),7.29-7.37(m,1H),7.18-7.28(m,2H),7.10(t,1H),6.82(t,1H),5.90(s,2H),5.04(d,1H),4.32-4.39(m,1H),3.81(d,1H),3.69-3.77(m,1H),3.60-3.68(m,1H),1.96-2.05(m,1H),1.88-1.95(m,1H)。

Compound I-21

The title compound was prepared according to general procedure B except that t-butyl azetidin-3-ylcarbamate (4 equivalents) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 1 h. The reaction was cooled and filtered, and the solid was collected and dried in vacuo to give the desired compound, compound I-21(30mg, 79% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.08(s,1H),8.25(m,1H),7.62-7.66(m,2H),7.51(s,1H),7.29-7.34(m,1H),7.15-7.27(m,2H),7.07-7.14(m,1H),6.79-6.84(m,1H),5.90(s,2H),4.35-4.44(m,2H),4.01-4.12(m,2H),3.84-3.90(m,1H),1.39(s,9H)。

Compound I-22

The title compound was prepared according to general procedure B except 4-methoxypiperidine (4 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated to 40 ℃ as a solution in THF for 1 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo to give the desired compound, compound I-22(15mg, 74% yield) as a solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.05(d,1H),8.25(d,1H),7.51(s,1H),7.26-7.31(m,1H),7.14-7.25(m,2H),7.07(t,1H),6.74-6.82(m,1H),5.87(s,2H),4.06-4.11(m,2H),3.42-3.50(m,2H),3.25(s,3H),1.89-1.95(m,2H),1.46-1.51(m,3H)。

Compound I-64

The title compound was prepared according to general procedure B except that 4-methyltetrahydro-2H-pyran-4-amine (as the HCl salt) (5 equivalents) was the amine reactant, 10 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 175 ℃ for 1H in a microwave as a solution in THF/DMF (1: 1). The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the crude material was purified via silica gel chromatography using a gradient of 5-90% ethyl acetate in hexanes to give the desired compound, compound I-64(4mg, 20% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.74(s,1H),8.05(d,1H),7.19-7.33(m,2H),6.97-7.12(m,2H),6.79-6.93(m,2H),5.92(s,2H),3.67-3.81(m,4H),2.49(d,2H),1.77-1.91(m,2H),1.63(s,3H)。

Compound I-101

The title compound was prepared according to general procedure B except that 4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid hydrate (4 equivalents) was the amine reactant, 5 equivalents of triethylamine were used, and the contents were heated to 90 ℃ as a solution in THF/water (9:1) for 5 h. Instead of dichloromethane, treatment was performed with ethyl acetate. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-101(12mg, 26% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.39(d,1H),7.54(s,1H),7.28-7.39(m,1H),7.15-7.25(m,2H),7.11(t,1H),6.85(t,1H),5.85-5.97(m,2H),5.17(br.s.,1H),4.45(d,1H),4.33(br.s.,1H),3.91-4.02(m,1H),3.33-3.39(m,2H),3.05-3.17(m,1H),1.41(s,9H)。

Compound I-163

The title compound was prepared according to general procedure B except 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-4-carboxylic acid (4 equivalents) was the amine reactant, 3 equivalents triethylamine was used and the contents were heated to 175 ℃ as a solution in NMP for 10 min. The contents were diluted with ether and the resulting precipitate was filtered and collected. The crude material was further purified via reverse phase HPLC to give the desired compound, compound I-163(5mg, 15% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δppm 9.03(d,1H),8.82-8.89(m,1H),8.58(s,1H),7.58(s,1H),7.28-7.37(m,1H),7.11-7.18(m,1H),7.02-7.10(m,1H),6.94(s,1H),6.83-6.92(m,1H),6.01(s,2H),5.12(d,1H),5.00(d,1H),4.55-4.64(m,1H),3.43(dd,1H),3.20(d,1H)。

Compound I-189

The title compound was prepared according to general procedure B except 4-ethylpiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 18 h. The reaction was incomplete, so additional amine reactant (3 equivalents), triethylamine (4 equivalents) and DMF (equal volume to THF) were introduced into the vessel and the resulting mixture was heated to 85 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-189 as a solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.79(d,1H),8.20(d,1H),7.54(s,1H),7.21-7.35(m,1H),7.07-7.13(m,1H),7.05(t,1H),6.95(d,1H),6.89(t,1H),5.99(s,2H),4.65(d,2H),3.33-3.43(m,2H),2.32(d,2H),1.63-1.68(m,2H),1.55-1.63(m,2H),0.91(t,3H)。

Compound I-190

The title compound was prepared according to general procedure B except 3-methylpiperidine-4-carboxylic acid was used as amine reactant, 4 equivalents of triethylamine were used, and the contents were heated to 40 ℃ as a solution in THF for 18 h. The reaction was incomplete, so additional amine reactant (3 equivalents), triethylamine (4 equivalents) and DMF (equal volume to THF) were introduced into the vessel and the resulting mixture was heated to 85 ℃ for 18 h. The reaction was cooled and diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-190 as a solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.79(d,1H),8.22-8.29(m,1H),7.59(s,1H),7.24-7.34(m,1H),7.02-7.15(m,2H),6.96-7.00(m,1H),6.93(t,1H),6.01(m,2H),4.76(d,1H),4.58(d,1H),3.70(dd,1H),3.52-3.58(m,1H),2.87-2.94(m,1H),2.45-2.54(m,1H),2.00-2.11(m,1H),1.90-1.99(m,1H),1.02(d,3H)。

Compound I-235

The title compound was prepared in 3 steps:

step 1: synthesis of 2- (1- (2, 3-difluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-fluoropyrimidin-4 (3H) -one

The above compound was prepared following general procedure a using 1- (isoxazol-3-yl) ethanone in step 1 and 2, 3-difluorobenzylhydrazine in step 2.

Step 2: preparation of 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2, 3-difluorobenzyl) -1H-pyrazol-5-yl) isoxazole

A suspension of 2- (1- (2, 3-difluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-fluoropyrimidin-4 (3H) -one in phosphorus oxychloride (47 equivalents) was heated at 65 ℃ for 2 hours. The reaction mixture was carefully poured into ice and stirred for 20 min. The resulting mixture was basified to pH 8 by addition of saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo to give 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2, 3-difluorobenzyl) -1H-pyrazol-5-yl) isoxazole as a light yellow solid, which was used in the next step without further manipulation.

And step 3: synthesis of Compound I-235

Following general procedure B, a solution of (S) -3-methyl-2- (methylamino) butanoic acid (3.0 equivalents), triethylamine (10 equivalents), and 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2, 3-difluorobenzyl) -1H-pyrazol-5-yl) isoxazole in dioxane/water (2:1 ratio) was stirred at 100 ℃ for 23H. The solution was diluted with water, neutralized to pH 3 by addition of 1N HCl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (0-10% acetonitrile/methanol in dichloromethane (7:1) gradient) afforded compound I-235(38mg, 61% over 2 steps) as an off-white solid.

¹H-NMR(400MHz,CDCl₃)δ8.46(d,1H),8.22(d,1H),7.23(s,1H),7.04(dd,1H),6.92(dd 1H),6.77(app.t,1H),6.58(d,1H),5.99(d,1H),5.94(d,1H),4.27(d,1H),3.24(d,3H),2.52(m,1H),1.11(d,3H),0.94(d,3H)。

Compound I-236

The title compound was prepared in 3 steps:

step 1: synthesis of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (oxazol-2-yl) -1H-pyrazol-3-yl) pyrimidin-4 (3H) -one

The above compound was prepared following general procedure a using 1- (oxazol-2-yl) ethanone in step 1 and 2-fluorobenzylhydrazine in step 2.

Step 2: synthesis of 2- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) oxazole

The above compound was prepared according to a procedure analogous to step 2 of the synthesis of compound I-235, using 5-fluoro-2- (1- (2-fluorobenzyl) -5- (oxazol-2-yl) -1H-pyrazol-3-yl) -pyrimidin-4 (3H) -one as the starting pyrimidinone.

And step 3: synthesis of Compound I-236

The title compound was prepared according to general procedure B, except that (S) -3-methyl-2- (methylamino) butanoic acid was the amine reactant, 2- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) oxazole was used instead of intermediate 1, and the contents were heated to 100 ℃ for 41H. The crude material was purified by silica gel chromatography (0-20% (acetonitrile/methanol ═ 7:1) gradient in dichloromethane) to afford the desired compound, compound I-236 as an off white solid (8.9mg, 49% over two steps).

¹H-NMR(400MHz,CDCl₃)δ8.25(d,1H),7.70(s,1H),7.46(s,1H),7.24(s,1H),7.21(m 1H),7.07-6.95(m,3H),6.11(d,1H),6.04(d,1H),4.27(d,1H),3.23(d,3H),2.52(m,1H),1.11(d,3H),0.94(d,3H)。

Compound I-36

To a stirred solution of compound I-12 in dichloromethane was added an equal volume of trifluoroacetic acid at 23 ℃. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, water and brine. Subjecting the organic layer to Na₂SO₄Drying, filtration and concentration in vacuo afforded the desired compound, compound I-36(19.5mg, 75% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δ8.46(s,1H),8.15(d,1H),7.27-7.30(m,1H),7.13-7.23(m,1H),7.00-7.09(m,1H),6.91-7.00(m,1H),6.81-6.90(m,1H),6.54-6.62(m,1H),5.95(s,2H),5.19(d,1H),4.26-4.40(m,1H),3.23-3.35(m,2H),3.03(br.s,1H),2.92(td,2H),2.10-2.20(m,2H),1.59-1.77(m,2H)。

Compound I-37

To a stirred solution of compound I-25 in dichloromethane was added an equal volume of trifluoroacetic acid at 23 ℃. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, water and brine. Subjecting the organic layer to Na₂SO₄Drying, filtration and concentration in vacuo afforded the desired compound, compound I-37(14mg, 79% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δ8.45(d,1H),8.16(d,1H),7.30(s,1H),7.14-7.23(m,1H),7.00-7.07(m,1H),6.96(td,1H),6.78-6.89(m,1H),6.60(d,1H),5.96(s,2H),4.39-4.51(m,1H),4.22-4.36(m,1H),3.25(ddd,1H),2.93-3.08(m,2H),1.99-2.11(m,1H),1.83-1.92(m,1H),1.59-1.72(m,1H),1.37-1.50(m,1H)。

Compound I-38

To a stirred solution of compound I-26 in dichloromethane was added an equal volume of trifluoroacetic acid at 23 ℃. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, water and brine. Subjecting the organic layer to Na₂SO₄Drying, filtration and concentration in vacuo afforded the desired compound, compound I-38(11mg, 55% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δ8.46(d,1H),8.16-8.22(m,1H),7.30(m,1H),7.17-7.25(m,2H),7.00-7.09(m,1H),6.91-6.98(m,1H),6.85(d,1H),6.56-6.68(m,1H),5.96-6.03(m,1H),5.95(s,2H),4.94-5.01(m,1H),4.39(t,2H),3.99(dd,2H)。

Compound I-39

To a stirred solution of compound I-27 in dichloromethane was added an equal volume of trifluoroacetic acid at 23 ℃. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, water and brine. Subjecting the organic layer to Na₂SO₄Drying, filtration and concentration in vacuo afforded the desired compound, compound I-39(12.2mg, 69% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δ8.45(d,1H),8.13(d,1H),7.35(s,1H),7.14-7.24(m,1H),6.99-7.08(m,1H),6.92-6.99(m,1H),6.79-6.89(m,1H),6.64(d,1H),5.97(s,2H),5.55(br.s.,1H),4.34-4.49(m,1H),3.29(dd,1H),2.88-3.01(m,1H),2.79-2.87(m,1H),2.75(dd,1H),1.90-2.02(m,1H),1.77-1.88(m,1H),1.58-1.76(m,2H)。

Compound I-40

To a stirred solution of compound I-21 in dichloromethane was added an equal volume of trifluoroacetic acid at 23 ℃. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, water and brine. Subjecting the organic layer to Na₂SO₄Drying, filtration and concentration in vacuo afforded the desired compound, compound I-40(22mg, 90% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δ8.73(d,1H),8.06(d,1H),7.37(s,1H),7.19-7.30(m,1H),7.04-7.11(m,1H),7.00(t,1H),6.86(d,1H),6.77(t,1H),5.93(s,2H),4.58(t,2H),4.13(dd,2H),3.98-4.09(m,1H)。

Compound I-133

To a stirred solution of compound I-101 in dichloromethane at 23 ℃ was added an equal volume of trifluoroacetic acid. The contents were stirred until complete consumption of the starting material was observed via LC/MS. The mixture was concentrated in vacuo and the resulting gum was triturated with ether, filtered, and the solid was washed with ether. The solid was collected and dried in vacuo to give the desired compound, compound I-133 (as a TFA salt, 100mg, 83% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δ9.11(s,1H),8.87(s,1H),8.47(d,1H),7.58(s,1H),7.29-7.40(m,1H),7.17-7.27(m,2H),7.11(t,1H),6.83(t,1H),5.89(s,2H),5.44-5.49(m,1H),4.59-4.64(m,1H),3.79(d,1H),3.41-3.46(m,1H),3.11-3.18(m,1H),3.01-3.12(m,1H)。

Compound I-30

The title compound was prepared according to general procedure B except 2, 8-diazaspiro [4.5] decan-3-one (2 equiv.) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 2 days. The reaction was cooled, the solvent removed in vacuo and the resulting solid washed with 1N HCl solution to give the desired compound, compound I-30 as a white solid (57.8mg, 83% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.86(s,1H)8.36(d,1H)7.71(s,1H)7.31-7.37(m,1H)7.13(dd,2H)6.99-7.04(m,2H)6.06(s,2H)4.32(br.s.,2H)4.13(br.s.,2H)3.37(br.s.,2H)2.42(s,2H)1.95(t,4H)。

Compound I-42

The title compound was prepared according to general procedure B except 2-oxa-7-azaspiro [3.5] nonane oxalate (2 equivalents) was the amine reactant, 8 equivalents of triethylamine were used, and the contents were heated as a solution in NMP to 40 ℃ for 24 h. The reaction was cooled, diluted with ethyl acetate, and the mixture was washed with water. The contents were dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-80% ethyl acetate/hexanes gradient to give the desired compound, compound I-42(42mg, 52% yield) as a white solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.75(s,1H)8.13(d,1H)7.41(s,1H)7.20-7.32(m,1H)6.97-7.14(m,2H)6.90(s,1H)6.81(t,1H)5.95(s,2H)4.52(s,4H)3.80-3.88(m,4H)1.90-2.05(m,4H)。

Compound I-43

The title compound was prepared according to general procedure B except 8-oxa-2-azaspiro [4.5] decane (2 equivalents) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 24 h. The reaction was cooled and concentrated to give a solid, which was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous HCl, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-42 as a white solid (6.4mg, 17% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.77(s,1H)8.09(d,1H)7.44(s,1H)7.25-7.33(m,1H)7.11(t,1H)7.05(s,1H)6.93(s,1H)6.82(s,1H)5.98(s,2H)3.92(br.s.,2H)3.71-3.84(m,6H)2.00(t,2H)1.64-1.75(m,4H)。

Compound I-32

The title compound was prepared according to general procedure B except 2-oxa-6-azaspiro [3.3] heptane oxalate (2 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 40 ℃ as a solution in NMP for 2 h. The reaction was cooled and concentrated to give a solid, which was dissolved in ethyl acetate. The organic layer was washed with 1N HCl solution, dried, filtered and concentrated in vacuo to give the desired compound, compound I-32 as a white solid (19mg, 33% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.83(s,1H)8.24(br.s,1H)7.57(br.s.,1H)7.29-7.33(m,1H)7.03-7.16(m,2H)6.91-7.01(m,2H)5.99-6.05(m,2H)4.28-4.61(m,4H)3.99(s,2H)3.88(s,2H)。

Compound I-47

The title compound was prepared according to general procedure B except 2-oxa-6-azaspiro [3.5] nonane oxalate (2 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated as a solution in NMP to 40 ℃ for 2 h. The reaction was cooled and concentrated to give a solid, which was dissolved in ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-47 as a white solid (42.3mg, 66% yield).

¹H NMR (400MHz, methanol-d)₄)δppm 8.67-8.76(m,1H)8.12(d,1H)7.40(s,1H)7.19-7.28(m,1H)7.02-7.10(m,1H)6.99(t,1H)6.88(d,1H)6.79(t,1H)5.89-5.95(m,2H)4.38-4.49(m,4H)4.05-4.10(m,2H)3.71-3.79(m,2H)1.92-1.98(m,2H)1.58-1.68(m,2H)。

Compound I-44

The title compound was prepared according to general procedure B except that tert-butyl 2, 8-diazaspiro [4.5] decane-2-carboxylate (2 equivalents) was the amine reactant, no triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 2 days. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-44 as a white solid (51.6mg, 67% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.77(s,1H)8.15(d,1H)7.43(s,1H)7.23-7.33(m,1H)7.11(t,1H)7.05(t,1H)6.92(s,1H)6.83(t,1H)5.97(s,2H)3.79-4.09(m,4H)3.43-3.52(m,2H)3.30(s,2H)1.89(t,2H)1.72(br.s.,4H)1.49(s,9H)。

Compound I-45

The title compound was prepared according to general procedure B except that tert-butyl 2, 7-diazaspiro [4.4] nonane-2-carboxylate (2 equivalents) was the amine reactant, 1 equivalent triethylamine was used, and the contents were heated to 40 ℃ as a solution in THF for 2 days. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-45 as a white solid (48.3mg, 64% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.75(s,1H)8.04-8.13(m,1H)7.40(s,1H)7.24-7.32(m,1H)7.10(t,1H)7.03(t,1H)6.89(s,1H)6.82(t,1H)5.96(s,2H)3.85-3.98(m,2H)3.69-3.82(m,2H)3.49(br.s.,2H)3.30-3.43(m,4H)1.48(d,9H)。

Compound I-61

The title compound was prepared according to general procedure B except 3, 3-difluoroazetidine (1 equivalent as the HCl salt) was the amine reactant, 2 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 40 ℃ as a solution in NMP for 3 h. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-30% ethyl acetate/hexanes gradient to give the desired compound, compound I-61 as a white solid (37mg, 71% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.44(d,1H)8.22(d,1H)7.30(s,1H)7.14-7.21(m,1H)6.91-7.04(m,2H)6.81(t,1H)6.54-6.59(m,1H)5.95(s,2H)4.60-4.71(m,4H)。

Compound I-62

The title compound was prepared according to general procedure B except 4, 4-difluoropiperidine (as the HCl salt, 1 equivalent) was the amine reactant, 2 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 40 ℃ as a solution in NMP for 3 h. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-30% ethyl acetate/hexanes gradient to give the desired compound, compound I-62 as a white solid (40.4mg, 71% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.43(d,1H)8.22(d,1H)7.24-7.25(m,1H)7.12-7.21(m,1H)6.91-7.04(m,2H)6.82(t,1H)6.56(d,1H)5.94(s,2H)3.94-4.02(m,4H)2.04-2.17(m,4H)。

Compound I-63

The title compound was prepared according to general procedure B except 3, 3-difluoro-pyrrolidine (1 equivalent as the HCl salt) was the amine reactant, 2 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 40 ℃ as a solution in NMP for 3 h. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-30% ethyl acetate/hexanes gradient to give the desired compound, compound I-63 as a white solid (41.5mg, 71% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.43(d,1H)8.19(d,1H)7.29(s,1H)7.11-7.22(m,1H)6.90-7.04(m,2H)6.78-6.87(m,1H)6.56(d,1H)5.94(s,2H)3.98-4.18(m,4H)2.40-2.54(m,2H)。

Compound I-166

The title compound was prepared according to general procedure B except that ethyl N-benzylglycine (1 equivalent) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in THF/water (10:1) for 24 h. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography to give the desired compound, compound I-166 as a white solid (33mg, 47% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.42(d,1H)8.23(d,1H)7.28-7.39(m,5H)7.23(d,1H)7.12-7.21(m,1H)6.91-7.05(m,2H)6.83(t,1H)6.53(d,1H)5.94(s,2H)5.00(s,2H)4.20-4.24(m,2H)4.14-4.20(m,2H)1.21(t,3H)。

Compound I-167

The title compound was prepared according to general procedure B except that ethyl N-methylaminoacetate (1 equivalent as the HCl salt) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF for 24 h. The reaction was cooled and diluted with ethyl acetate and water. The layers were separated and the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-167(77mg, 79% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.46(d,1H)8.22(d,1H)7.28(d,1H)7.15-7.25(m,1H)6.95-7.06(m,2H)6.81-6.89(m,1H)6.58(d,1H)5.95-6.00(m,2H)4.35(s,2H)4.23(q,2H)3.43(d,3H)1.25(t,3H)。

Compound I-176

A mixture of compound I-167(70mg, 1 eq) and sodium hydroxide [1.0N aq ] (770 μ l, 5 eq) in THF (385 μ l) and MeOH (385 μ l) was stirred at rt for 24 h. The mixture was quenched with 1N HCl (5 equivalents). The white precipitate formed was collected by filtration, washed with a minimal amount of diethyl ether, and dried to give compound I-176(52mg, 79% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H)8.34(d,1H)7.54(s,1H)7.30-7.37(m,1H)7.19-7.25(m,2H)7.11(t,1H)6.86(t,1H)5.90(s,2H)4.41-4.45(m,2H)3.32(d,3H)。

Compound I-168

A mixture of compound I-167(30mg, 1 eq) and sodium hydroxide [1.0N aq ] (57 μ l, 1 eq) in THF (141 μ l) and MeOH (141 μ l) was stirred at rt for 24 h. It was treated with 1N HCl (1 eq.). The mixture was diluted in dichloromethane (100ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography (0 to 10% methanol in dichloromethane) to give compound I-168 as a white solid (10mg, 36% yield).

¹H NMR (400MHz, methanol-d)₄)δppm 8.74(d,1H)8.20(d,1H)7.33-7.43(m,5H)7.22-7.32(m,3H)6.99-7.13(m,3H)6.84(d,2H)5.95(s,2H)5.05(s,2H)。

Compound I-218

A mixture of compound I-176(48mg, 1 equivalent), O-methylhydroxylamine hydrochloride (14mg, 1.5 equivalents), EDC (32mg, 1.5 equivalents) and DMAP (21mg, 1.5 equivalents) in DMF (563. mu.l) was stirred at rt for 2 h. The mixture was diluted in ethyl acetate (100ml) and washed with water (50ml × 3). The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography to give compound I-218(26mg, 51% yield) as a white solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.63-8.68(m,1H)8.08(d,1H)7.30(s,1H)7.13-7.20(m,1H)6.96-7.02(m,1H)6.92(t,1H)6.77(s,1H)6.71(t,1H)5.85(s,2H)4.17(s,2H)3.55(s,3H)3.30-3.34(m,3H)。

Compound I-223

The title compound was prepared according to general procedure B except that N-methyl-1- (3-methyl-1, 2, 4-oxadiazol-5-yl) methylamine (1 equivalent as the HCl salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 85 ℃ as a solution in dioxane for 24 h. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with 1N HCl solution, dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-223 as a white solid (16.3mg, 21% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.46(d,1H)8.25(d,1H)7.15-7.22(m,2H)6.96(t,1H)6.84(t,1H)6.61(d,1H)5.95(s,2H)5.03(s,2H)3.52(d,3H)2.38(s,3H)。

Compound I-14

2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-nitropyrimidin-4-ol (1 equivalent) (this intermediate was in the previous patent WO2012/3405A 1) (25mg, 1 equivalent) was treated with POCl₃(457. mu.l, 75 equivalents) and washed at reflux for 1.5 h. The contents were concentrated in vacuo and the residue azeotroped with toluene (× 2). The residue was redissolved in THF (0.7mL) and usedMorpholine (171 μ l, 30 equivalents). The contents were heated to 40 ℃ and the reaction was stirred for 1.5 h. The residue was transferred to a 1:1 mixture of ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (× 3). The organic portions were combined and washed with brine. The mixture was passed over MgSO₄Drying, filtration and concentration in vacuo afforded desired compound I-14(30mg, 97%) as a pale yellow solid.

¹H-NMR(400MHz,CDCl₃)δ8.47(d,1H),8.36(d,1H),8.09-8.16(m,1H),7.69(dd,1H),7.41(d,1H),7.20(t,1H),6.66-6.70(m,1H),6.45(d,1H),6.06(s,2H),3.79-3.86(m,4H),3.74(m,4H)。

Compound I-15

A solution of compound I-14(30mg, 1 equivalent) in methanol was treated with palladium on charcoal (7mg, 10% wt palladium, 0.1 equivalent) and placed under a hydrogen atmosphere. The contents were stirred at 23 ℃ for 2 h. The contents were filtered through celite and eluted with methanol. The contents were concentrated in vacuo and the crude material was purified via silica gel chromatography with a 0-70% (acetonitrile: methanol: 7: 1)/dichloromethane gradient to give the desired compound I-15 as a white solid (11.5mg, 39%).

¹H-NMR(400MHz,CDCl₃)δ8.43(d,1H),8.36(d,1H),7.35(d,1H),6.80(t,1H),6.59-6.53(m,1H),6.49-6.40(m,2H),6.11(dd,1H),5.93-5.82(m,2H),3.87-3.76(m,4H),3.72(d,4H)。

Compound I-70

A solution of compound I-37 in toluene was treated with ethyl isocyanate (3 equivalents) and heated to 90 ℃ for 20 min. The resulting precipitate was filtered and washed with toluene. The solid was collected and dried in vacuo to give the desired compound, compound I-70(7mg, 36% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δ9.09(d,1H),8.27(d,1H),7.77(s,1H),7.30-7.36(m,1H),7.14-7.27(m,2H),7.07-7.12(m,1H),6.83(t,1H),5.94(d,1H),5.91(s,2H),5.76(t,1H),4.17(d,1H),3.94(d,1H),3.69(dt,1H),3.52(t,1H)3.22(dd,1H),3.02 (quintuple, 2H),1.85(d,1H),1.71-1.81(m,1H),1.43-1.62(m,2H),0.97(t, 3H).

Compound I-71

A solution of compound I-40 in toluene was treated with ethyl isocyanate (3 equivalents) and heated to 90 ℃ for 20 min. The resulting precipitate was filtered and washed with toluene. The solid was collected and dried in vacuo to give the desired compound, compound I-71(3mg, 16% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δ9.10(d,1H),8.25(d,1H),7.49-7.55(m,1H)7.29-7.37(m,1H),7.19-7.27(m,2H),7.10(t,1H),6.81(t,1H),6.52-6.61(m,1H),6.02(t,1H),5.90(s,2H),4.51-4.59(m,1H),4.47(m,2H),4.06(d,2H),2.94-3.07(m,2H),0.99(t,3H)。

Compound I-136

A solution of compound I-133 in dichloromethane was treated with ethyl isocyanate (1.1 equiv.) and triethylamine (2 equiv.) and stirred at 23 ℃ for 1 h. The solvent was removed in vacuo and the residue was resuspended in diethyl ether. The resulting precipitate was filtered and washed with diethyl ether. The solid was collected and dried in vacuo to give the desired compound, compound I-136(2.9mg, 28% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δ9.09(s,1H),8.26-8.39(m,1H),7.52(s,1H)7.32(m,1H),7.17-7.27(m,2H),7.10(t,1H),6.78-6.88(m,1H),6.63(br.s.,1H),5.90(m,2H),4.90-5.19(m,1H)4.43(d,1H),4.30(br.s.,1H),3.91(d,1H),3.48(d,1H),3.22(d,1H),2.99-3.05(m,3H),1.01(t,3H)。

Compound I-134

A solution of compound I-133 in dichloromethane was treated with propionyl chloride (1.1 equiv.) and triethylamine (2 equiv.) and stirred at 23 ℃ for 1 h. The solvent was removed in vacuo and the residue was resuspended in diethyl ether. The resulting precipitate was filtered and washed with diethyl ether. The solid was collected and dried in vacuo to give the desired compound, compound I-134(3.5mg, 35% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δ9.10(s,1H),8.40(d,1H),7.49-7.64(m,1H),7.28-7.39(m,1H),7.15-7.26(m,2H),7.11(t,1H),6.84(br.s.,1H),5.89(s,2H),4.79(d,1H),4.24-4.45(m,2H),3.91(d,1H),3.67(br.s.,1H),3.58(d,1H),2.87-3.00(m,1H),2.31-2.40(m,2H),0.93-1.04(m,3H)。

Compound I-135

A solution of compound I-133 in dichloromethane was treated with methyl chloroformate (1.1 equiv.) and triethylamine (2 equiv.) and stirred at 23 deg.C for 1 h. The solvent was removed in vacuo and the residue was resuspended in diethyl ether. The resulting precipitate was filtered and washed with diethyl ether. The solid was collected and purified via reverse phase HPLC to give the desired compound, compound I-135 as a solid (3.5mg, 37% yield).

¹H NMR(500MHz,CD₃OD)δ8.82(s,1H),8.41(d,1H),7.58(s,1H),7.26-7.35(m,1H),7.12(t,1H),7.07(t,1H),6.88-6.97(m,2H),6.01(s,2H),5.51(br.s.,1H),4.68(d,1H),4.58(br.s.,1H),4.09(d,1H),3.79-3.95(m,1H),3.76(s,3H),3.52-3.62(m,1H),3.35-3.45(m,1H)。

Compound I-49 and Compound I-50

A solution of 1-methylcyclopropanecarboxylic acid (141mg, 10 equivalents) in dichloromethane (1mL) was treated with oxalyl chloride (0.11mL, 9 equivalents) and the contents stirred until no more bubbling was observed. The resulting solution was then added portionwise over 5 minutes to a cooled (0 ℃) solution of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (1 eq, 50mg, this intermediate is described in the previous patent application publication WO2012/3405a 1) in dichloromethane (0.35mL) and pyridine (0.35 mL). The mixture was heated to 60 ℃ and stirred for 24 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (× 3) and dichloromethane (× 1). The organic portions were combined and washed with brine. Over MgSO₄The mixture was dried, filtered and concentrated in vacuo. Chromatography on silica gel with a 0-60% ethyl acetate/hexane gradientThe crude material was purified to give the desired compound I-49 as a white solid (18.5mg, 30%) and I-50 as a clear oil (16.2mg, 22%).

Compound I-49H¹NMR(400MHz,CDCl₃)δ8.57(d,1H),8.43(d,1H),8.01(s,1H),7.38(s,1H),7.22-7.13(m,1H),7.00(t,1H),6.98-6.90(m,1H),6.78(t,1H),6.57(d,1H),5.99(s,2H),1.48(s,3H),1.38-1.32(m,2H),0.79-0.73(m,2H)。

Compound I-50H¹NMR(400MHz,CDCl₃)δ8.64(d,1H),8.47-8.44(m,1H),7.28(s,1H),7.22-7.15(m,1H),7.02(d,1H),6.97(t,1H),6.93-6.87(m,1H),6.55-6.53(m,1H),5.95(s,2H),1.53-1.48(m,4H),1.22(s,6H),0.85-0.79(m,4H)。

Compound I-51 and Compound I-52

A solution of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (1 equivalent, this intermediate was in prior patent application publication WO2012/3405a 1) (see above) (50mg, 1 equivalent) in THF (0.7mL) was cooled to 0 ℃ and treated with LiHMDS (0.16mL, 1.1 equivalents, 1M solution) and stirred for 20 minutes. The reaction was then treated with methyl chloroformate (44 μ L, 4 equivalents). The reaction mixture was stirred at 0 ℃ for 20 minutes and then warmed to 23 ℃ over 1 h. The reaction was diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate (twice) and dichloromethane (three times). The organic portions were combined and washed with brine. Over MgSO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound I-51 as an off-white solid (5.3mg, 9%) and compound I-52 as a white solid (13.1mg, 20%).

Compound I-51¹H-NMR(500MHz,CDCl₃)δ8.56(s,1H),8.45(s,1H),7.41(s,1H),7.38(s,1H),7.19(m,1H),7.02(t,1H),6.95(m,1H),6.81(m,1H),6.61(s,1H),6.00(s,2H),3.87(s,3H)。

Compound I-52¹H-NMR(500MHz,CDCl₃)δ8.77(s.,1H),8.47(s,1H),7.40(s,1H),7.21(m,1H),7.07-6.93(m,2H),6.84(m,1H),6.59(s,1H),6.02(s,2H),3.83(s,6H)。

Compound I-144

In a vial, compound I-58(0.022g, 0.047mmol) was diluted with DCM (vol: 2.0ml) and then charged with CDI (28mg, 0.173 mmol). The reaction mixture was then heated to 45 ℃ until complete consumption of the starting acid was noted by LC/MS. At this point cyclopropanesulfonamide (22.86mg, 0.189mmol) and DBU (7.11. mu.l, 0.047mmol) were added and the reaction was heated for an additional 30 minutes. At this time, the reaction was quenched with 1N HCl and then diluted with DCM. The layers were separated and the aqueous portion was extracted two additional times with DCM. The organic fractions were combined and dried (Na)₂SO4), filtered and then concentrated. Using SiO₂The crude material was purified by chromatography using a gradient of 0-10% MeOH in DCM to afford the desired acylsulfonamide, Compound I-144(16mg, 54% yield).

¹H-NMR(400MHz,CDCl₃)δ10.62(bs,1H),8.43(d,1H),8.23(d,1H),7.45(s,1H),7.19(dd,1H),7.03-6.95(m,2H),6.85(t,1H),6.69(s,1H),5.96(dd,2H),4.20-4.12(m,1H),2.87-2.79(m,1H),2.30-2.24(m,1H),2.02-1.92(m,1H),1.86-1.70(m,4H),1.30-0.86(m,6H)。

Compound I-157

The title compound was prepared using the same procedure as described for compound I-144, except that compound I-88 was used as the starting carboxylic acid. Purification via silica gel chromatography afforded the desired compound, compound I-157(10mg, 55% yield) as a solid.

¹H-NMR(400MHz,CD₃OD)δ8.76(d,1H),8.18(d,1H),7.55(s,1H),7.25(dd,1H),7.07(t,1H),7.00(t,1H),6.92(d,1H),6.81(t,1H),5.96(dd,2H),4.66-4.62(m,1H),2.88-2.83(m,1H),1.93-1.83(m,2H),1.31-1.27(m,2H),1.16-1.10(m,1H),1.04(d,3H),0.97(d,3H),0.92-0.78(m,2H)。

Compound I-187

The title compound was prepared using the same procedure as described for compound I-144, except that compound I-89 was used as the starting carboxylic acid. Purification via silica gel chromatography gave the desired compound, compound I-187(33mg, 80% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ11.92(s,1H),9.09(d,1H),8.33(d,1H),7.55(s,1H),7.29(dd,1H),7.18(t,1H),7.12(d,1H),7.07(t,1H),6.84(t,1H),5.87(s,2H),4.50(d,1H),3.19(d,3H),2.95-2.87(m,1H),2.42-2.35(m,1H),1.05(d,3H),1.02-0.94(m,2H),0.89(d,3H),0.87-0.83(m,2H)。

Compound I-272

The title compound was prepared according to general procedure B, except (S) -3-methyl-2- (methylamino) butanoic acid was the amine reactant, 3- (3- (4-chloropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (the synthesis described in the procedure for compound I-24) was used in place of intermediate 1, and the contents were heated to 110 ℃ for 72H. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-272(4mg, 8% yield) as a solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.98(bs,1H),9.07(s,1H),8.24(bs,2H),7.48(bs,1H),7.30(dd,1H),7.19(t,1H),7.07(t,1H),6.84(bs,1H),6.60(bs,1H),5.86(s,2H),5.24(bs,1H),2.94(bs,3H),2.30(bs,1H),1.02(d,3H),0.77(d,3H)。

Compound I-74

Intermediate 1 was dissolved in THF and cooled to 0 ℃. In a separate vial, 1H-pyrazole (1 equivalent) was diluted with THF and then charged with sodium hydride (60% in dispersed oil, 1 equivalent) to give the sodium salt. The contents were allowed to stir for 15 min. At this point, the sodium salt was added portionwise to the solution of intermediate 1. After consumption of the starting material, the reaction was quenched with 1N aqueous HCl and the mixture was extracted with dichloromethane (three times) as observed on LC/MS. The organic fractions were combined, dried, filtered and concentrated. The crude material was then purified using a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-74(41mg, 72% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.10(t,1H),9.03(dd,1H),8.80-8.79(m,1H),8.02-8.00(m,1H),7.81(d,1H),7.34-7.28(m,1H),7.24(t,1H),7.23-7.18(m,1H),7.09(t,1H),6.88(t,1H),6.72-6.70(m,1H),5.93(s,2H)。

Compound I-273

This compound was synthesized according to general procedure B using 2- ((2,2, 2-trifluoroethyl) amino) acetic acid hydrochloride. After complete consumption of the starting material, the solution was diluted with 1N aqueous sodium hydroxide solution until pH about 10. Diethyl ether was added and the layers were separated. The aqueous layer was acidified with 1N aqueous hydrochloric acid until pH about 2. Ethyl acetate was added and the layers were separated again. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography (0-15% methanol in dichloromethane) gave compound I-273(6mg, 23%) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.73(m,1H),8.27(d,1H),7.40(s,1H),7.27-7.22(m,1H),7.09-6.99(m,2H),6.87-6.86(m,1H),6.80(t,1H),5.94(s,2H),4.61-4.55(m,2H),4.45(s,2H)。

Compound I-274

The title compound was prepared according to general procedure B except that 3- ((methylamino) methyl) benzoic acid (as the HCl salt) was the amine reactant and the contents were heated to 90 ℃ as a solution in dioxane for 2 h. During the work-up, ethyl acetate was used as extraction solvent. Compound I-274 was isolated as a white solid (20mg, 68% yield), which required no additional purification.

¹H-NMR(400MHz,CD₃OD)δ8.76(m,1H),8.29(d,1H),8.08(s,1H),7.97(d,1H),7.65-7.63(m,1H),7.54(s,1H),7.48(t,1H),7.30-7.24(m,1H),7.10-7.01(m,2H),6.94-6.88(m,2H),5.99(s,2H),5.16(s,2H),3.48(d,3H)。

Compound I-275

The title compound was prepared according to general procedure B except that 4- ((methylamino) methyl) benzoic acid (as the HCl salt) was the amine reactant. During the work-up, ethyl acetate was used as extraction solvent. Compound I-275 was isolated as a white solid (17mg, 63% yield), which required no additional purification.

¹H-NMR(400MHz,DMSO-d₆)δ12.88(br s,1H),9.05(m,1H),8.25(d,1H),7.87(d,2H),7.48(s,1H),7.44(d,2H),7.32-7.27(m,1H),7.21-7.19(m,2H),7.07(t,1H),6.83(t,1H),5.86(s,2H),4.95(s,2H),3.24(d,3H)。

Compound I-276

This compound was synthesized according to general procedure B, using 1H-tetrazol-5-amine and dioxane as solvents. The crude residue was suspended in dichloromethane and filtered. The filtrate was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give compound I-276 as a white film (0.4mg, 2% yield).

¹H-NMR(400MHz,CD₃OD)δ8.75(m,1H),8.42(d,1H),7.48(s,1H),7.29-7.24(m,1H),7.11-7.06(m,1H),7.05-7.01(m,1H),6.89-6.83(m,2H),5.97(s,2H)。

Compound I-277

This compound was synthesized according to general procedure B using 3-amino-3-methylbutyric acid and the contents were heated to 80 ℃ for 68 h. Purification by silica gel chromatography (0-10% methanol in dichloromethane) gave compound I-277(1.3mg, 5% yield) as a white film.

¹H-NMR(400MHz,CD₃OD)δ8.74(m,1H),8.02(d,1H),7.34(d,1H),7.27-7.22(m,1H),7.09-7.00(m,2H),6.89-6.83(m,2H),5.93(s,2H),3.03(s,2H),1.66(s,6H)。

Compound I-278

This compound was synthesized according to general procedure B using 5- (aminomethyl) pyridin-2 (1H) -one, and the contents were stirred at 90 ℃ for 40H. The crude reaction mixture was diluted with 1N aqueous hydrochloric acid and ethyl acetate. The layers were separated and the aqueous layer was concentrated in vacuo. Purification by reverse phase HPLC (20-50% acetonitrile in water with 0.1% TFA, 20min gradient) afforded compound I-278(13mg, 35% yield) as a tan solid.

¹H-NMR(400MHz,CD₃OD)δ8.82(s,1H),8.28(d,1H),7.73-7.64(m,3H),7.32-7.26(m,1H),7.11-7.03(m,2H),6.99-6.95(m,2H),6.54(d,1H),6.01(s,2H),4.73(s,2H)。

Compound I-279

This compound was synthesized according to general procedure B using the trifluoroacetate salt of 2- ((methylamino) methyl) benzoic acid, and dioxane as solvent, and the contents were heated at 90 ℃ for 2 days. The crude reaction mixture was purified by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 20min gradient) to give compound I-279 as a white solid (15mg, 37% yield).

¹H-NMR(400MHz,DMSO-d₆)δ13.17(br s,1H),9.10(m,1H),8.25(d,1H),7.94(d,1H),7.56-7.52(m,1H),7.44(s,1H),7.41-7.29(m,3H),7.24-7.19(m,2H),7.12-7.08(m,1H),6.85-6.81(m,1H),5.89(s,2H),5.24(s,2H),3.30(s,3H)。

Compound I-280

This compound was synthesized according to general procedure B using 4- (aminomethyl) benzoic acid and ethyl acetate as the extraction solvent. Purification of the crude reaction mixture by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 20min gradient) gave compound I-280 as a white solid (3.4mg, 9% yield).

¹H-NMR(400MHz,CD₃OD)δ8.81(s,1H),8.26(d,1H),8.02(d,2H),7.58(d,2H),7.53(s,1H),7.33-7.27(m,1H),7.13-7.04(m,2H),6.95-6.91(m,2H),6.01(s,2H),5.01(s,2H)。

Compound I-281

This compound was synthesized according to general procedure B using 6-methylpiperidine-2-carboxylic acid. The crude reaction mixture was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give compound I-181 as a white solid (3.4mg, 9% yield).

¹H-NMR(400MHz,CD₃OD)δ8.75(d,1H),8.15(d,1H),7.40(s,1H),7.29-7.23(m,1H),7.11-7.06(m,1H),7.02(td,1H),6.88(d,1H),6.82-6.78(m,1H),5.95(s,2H),5.46(br s,1H),2.46-2.43(m,1H),1.91-1.72(m,4H),1.63-1.60(m,2H),1.35(d,3H)。

Compounds I-282 and I-283

These compounds were synthesized according to general procedure B using a mixture of (1R,4S) -4-methylpiperidine-2-carboxylic acid and (1S,4S) -4-methylpiperidine-2-carboxylic acid. The crude reaction mixture was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give compound I-282 as a white solid (15mg, 39% yield). The combined fractions were purified again by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA) to afford compound I-283(4mg, 10% yield).

Compound I-282:¹H-NMR(400MHz,CD₃OD)δ8.74(m,1H),8.22(d,1H),7.41(s,1H),7.26-7.21(m,1H),7.08-7.04(m,1H),7.01-6.98(m,1H),6.84(m,1H),6.81-6.78(m,1H),5.93(s,2H),4.44(dd,1H),4.04-3.98(m,1H),3.65-3.60(m,1H),2.19(dt,1H),1.93-1.70(m,3H),1.46-1.38(m,1H),1.04(d,3H)。

compound I-283:¹H-NMR(400MHz,CD₃OD)δ8.77(d,1H),8.28(d,1H),7.52(s,1H),7.29-7.23(m,1H),7.10-7.00(m,2H),6.92(d,1H),6.88-6.85(m,1H),5.97(s,2H),5.68(brs,1H),4.74(br s,1H),3.41(br s,1H),2.44-2.39(m,1H),1.87-1.82(m,1H),1.74-1.65(m,1H),1.58-1.50(m,1H),1.38-1.28(dq,1H),1.00(d,3H)。

compound I-237

This compound was synthesized according to general procedure B using (R) -N, 2-dimethyl-1- (1H-tetrazol-5-yl) propan-1-amine (2 equivalents). The crude reaction mixture was purified by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA) to afford compound I-237 as a clear oil (4mg, 23% yield).

¹H-NMR(400MHz,CD₃OD)δ8.80(m,1H),8.31(d,1H),7.53(s,1H),7.28-7.25(m,1H),7.09-7.01(m,3H),6.96(m,1H),6.05(d,1H),5.98(d,1H),5.76(br s,1H),3.35(d,3H),2.86-2.80(m,1H),1.07(d,3H),0.90(d,3H)。

Compound I-284

This compound was synthesized according to general procedure B using (R) -2-methyl-1- (1H-tetrazol-5-yl) propan-1-amine. The crude reaction mixture was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give compound I-284(16mg, 37% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.75(m,1H),8.12(d,1H),7.27-7.21(m,2H),7.06-7.03(m,1H),7.01-6.98(m,1H),6.88(d,1H),6.82-6.78(m,1H),5.96(d,1H),5.91(d,1H),5.50(d,1H),2.61-2.52(m,1H),1.14(d,3H),0.93(d,3H)。

Compound I-285

To a solution of compound I-147 (previously described, 1 equivalent) and pyridine (50 equivalents) in dichloromethane at 0 ℃ was added cyclopropanecarbonyl chloride (1.2 equivalents) over 30 seconds. The solution was immediately warmed to room temperature and stirred for a further 2.5 hours. After dilution with saturated aqueous ammonium chloride and dichloromethane, the layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography (0-5% methanol in dichloromethane) gave compound I-285 as a white solid (11mg, 34% yield).

¹H-NMR(400MHz,CD₃OD)δ8.73(m,1H),8.18(d,1H),7.43(s,1H),7.27-7.22(m,1H),7.09-7.04(m,1H),7.00(t,1H),6.90(m,1H),6.77(t,1H),5.95(s,2H),3.98-3.95(m,4H),3.46-3.44(m,4H),1.65-1.59(m,1H),0.92-0.84(m,4H)。

Compound I-229

The title compound was prepared according to general procedure B, except 2- (piperidin-3-yl) acetic acid was the amine reactant, 6 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in THF/water (10:1) for 18 h. The solvent was removed under a stream of nitrogen and the resulting crude material was purified via reverse phase HPLC to give the desired compound, compound I-229(8.1mg, 32% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.84(m,1H),8.28(m,1H),7.73(m,1H),7.32(m,1H),7.12(m,2H),6.98(m,2H),6.04(s,2H),4.96(m,1H),4.67(m,1H),3.54(m,1H),3.27(m,1H),2.42(m,2H),2.25(m,1H),2.00(m,2H),1.79(m,1H),1.54(m,1H)。

Compound I-230 and Compound I-231

The title compound was prepared according to general procedure B except that the mixture of 2- (piperidin-4-yl) acetic acid and methyl 2- (piperidin-4-yl) acetate was the amine reactant, 6 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in THF/water (10:1) for 18 h. The solvent was removed under a stream of nitrogen and the resulting crude material was purified via reverse phase HPLC to give the desired compound, compound I-230 as a solid (6.5mg, 25% yield) and compound I-231 as a solid (16.2mg, 61% yield).

Process for preparation of compound I-230¹H NMR (500MHz, methanol-d)₄)δppm 8.83(m,1H),8.26(m,1H),7.63(m,1H),7.30(m,1H),7.10(m,2H),6.97(m,2H),6.03(s,2H),4.98(m,2H),3.40(m,1H),2.35(m,2H),2.25(m,1H),2.04(m,2H),1.50(m,2H)。

Of Compound I-231¹H NMR (500MHz, methanol-d)₄)δppm 8.84(m,1H),8.30(m,1H),7.66(m,1H),7.28-7.37(m,1H),7.05-7.17(m,2H),7.00(d,2H),6.04(s,2H),4.93-5.02(m,2H),3.70(s,3H),3.35-3.45(m,2H),2.358(d,2H),2.22-2.34(m,1H),1.99-2.08(m,2H),1.50(br.s.,2H)。

Compound I-232

The title compound was prepared according to general procedure B, except 2-amino-4-methoxybutanoic acid was used as the amine reactant, 6 equivalents of Hunig's base was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in THF/water (10:1) for 18 h. The solvent was removed under a stream of nitrogen and the resulting crude material was purified via reverse phase HPLC to give the desired compound, compound I-232(10mg, 40% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.80(m,1H),8.32(m,1H),7.55(s,1H),7.29(m,1H),7.08(m,2H),6.96(m,2H),6.01(s,2H),5.11(m,1H),3.61(m,2H),3.35(s,3H),2.43(m,1H),2.21(m,1H)。

Compound I-234

The title compound was prepared according to general procedure B, except that 3- (piperidin-4-yl) propionic acid was the amine reactant. The solvent was removed under a stream of nitrogen and the resulting crude material was purified via reverse phase HPLC to give the desired compound, compound I-234(13mg, 49% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.81-8.86(m,1H),8.25-8.31(m,1H),7.61-7.67(m,1H),7.29-7.36(m,1H),7.05-7.16(m,2H),6.95-7.02(m,2H),6.04(s,2H),4.93-5.02(m,2H),3.37(s,2H),2.36-2.45(m,2H),1.96-2.06(m,2H),1.76-1.88(m,1H),1.61-1.70(m,2H),1.35-1.48(m,2H)。

Compound I-286

The title compound was prepared according to general procedure B except 4- (aminomethyl) phenol was the amine reactant (1.1 equivalents), 4 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (10:1) for 12 h. The crude material was purified via silica gel chromatography with a gradient of 1-5% methanol in dichloromethane over 40min to give the desired compound, compound I-286 as a white solid (17.7mg, 48% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.45(d,1H),8.16(d,1H),7.34(s,1H),7.16-7.24(m,3H),6.99-7.04(m,1H),6.94-6.99(m,1H),6.85-6.90(m,1H),6.79-6.83(m,2H),6.58(d,1H),5.97(s,2H),5.67(br.s,1H),5.28-5.30(m,1H),4.72(d,2H)。

Compound I-287

The title compound was prepared according to general procedure B, except that (4- (methylsulfonyl) phenyl) methylamine was the amine reactant (1 equivalent), 4 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (10:1) for 12 h. The crude material was purified via silica gel chromatography with a 1-5% methanol/dichloromethane gradient over 40min to give the desired compound, compound I-287 as a white solid (23.3mg, 56% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(d,1H),8.22(m,1H),7.90-7.96(m,2H),7.64-7.68(m,2H),7.20-7.25(m,2H),6.98-7.08(m,2H),6.88-6.93(m,1H),6.57(d,1H),5.98(s,2H),5.52-5.63(br.d,1H),4.93-4.97(m,2H),3.06(s,3H)。

Compound I-288

The title compound was prepared according to general procedure B except 2- (aminomethyl) phenol was the amine reactant (1.1 equivalents), 4 equivalents of triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (10:1) for 12 h. The crude material was purified via silica gel chromatography with a gradient of 1-5% methanol in dichloromethane over 40min to give the desired compound, compound I-288 as a white solid (4.5mg, 12% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):9.52(s,1H),8.49(d,1H),8.15(d,1H),7.42(s,1H),7.21-7.27(m,3H),7.02-7.11(m,3H),6.89-6.95(m,2H),6.64(d,1H),6.03(s,2H),5.80-5.85(m,1H),4.75(d,2H)。

Compound I-289

The title compound was prepared according to general procedure B except 2- (4-methylpiperidin-4-yl) acetic acid (1.15 equivalents as the HCl salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (3:1) for 12 h. A dichloromethane/isopropanol mixture (5:1) was used as the extraction solvent. The crude material was purified via silica gel chromatography with a 1-5% methanol/dichloromethane gradient over 40min to give the desired compound, compound I-289 as a white foam solid (37.4mg, 70% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.45(s,1H),8.12(d,1H),7.30(s,1H),7.16-7.22(m,1H),7.00-7.06(m,1H),6.94-6.98(m,1H),6.82-6.88(m,1H),6.59(d,1H),5.97(s,2H),3.83-3.96(m,2H),3.59(s,2H),2.42-2.49(m,2H),1.76-1.86(m,4H),1.15(s,3H)。

Compound I-290

The title compound was prepared according to general procedure B except that 4-cyclohexylpiperidine-4-carboxylic acid (1.2 equivalents as TFA salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (3:1) for 12 h. A dichloromethane/isopropanol mixture (5:1) was used as the extraction solvent. The crude material was purified via silica gel chromatography with a gradient of 1-5% methanol in dichloromethane over 40min to give the desired compound, compound I-290(44.6mg, 76% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(s,1H),8.17(d,1H),7.31(s,1H),7.16-7.24(m,1H),7.01-7.08(m,1H),6.95-7.00(m,1H),6.83-6.88(m,1H),6.60(d,1H),5.99(s,2H),4.58-4.65(m,2H),3.07-3.18(m,2H),2.24-2.32(m,2H),1.77-1.86(m,4H),1.45-1.70(m,3H),1.13-1.26(m,3H),1.03-1.13(m,3H)。

Compound I-291

The title compound was prepared according to general procedure B except that methyl 2-phenylpiperidine-2-carboxylate was the amine reactant, 4 equivalents of sodium bicarbonate were used instead of triethylamine, and the contents were heated to 110 ℃ for 48 h. Ethyl acetate was used as the extraction solvent. The first purification was achieved by silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to give the product with a purity of 80%. Further purification was achieved by reverse phase HPLC using a gradient of 5 to 95% acetonitrile in water over 30 minutes to afford the desired compound in analytical purity, compound I-291 as a white solid (2mg, 3% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.41(s,1H),8.35(br.s,1H),7.24-7.27(m,2H),7.09-7.18(m,3H),7.02-7.09(m,1H),6.90-7.00(m,2H),6.79-6.87(m,1H),6.67-6.74(m,1H),6.44-6.51(m,1H),5.86(d,1H),5.74(d,1H),3.72-3.85(m,1H),3.36-3.51(m,1H),2.47-2.56(m,1H),1.70-1.99(m,5H)。

Compound I-292

The title compound was prepared according to general procedure B except 4-amino-2-phenylbutyric acid (as the HCl salt) was the amine reactant, 4 equivalents of triethylamine were used, and the contents were heated to 95 ℃ for 12 h. Ethyl acetate was used as the extraction solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-292 as a white solid (37.9mg, 50% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(d,1H),8.13(d,1H),7.29-7.36(m,6H),7.15-7.23(m,1H),6.99-7.04(m,1H),6.92-6.97(m,1H),6.86-6.91(m,1H),6.60(d,1H),6.01(d,1H),5.94(d,1H),5.21-5.28(m,1H),3.85-3.94(m,1H),3.62-3.80(m,2H),2.51-2.61(m,1H),2.11-2.19(m,1H)。

Compound I-293

The title compound was prepared according to general procedure B except that 4-methoxypiperidine-4-carboxylic acid (as TFA salt) was the amine reactant (2 eq), 4 eq triethylamine was used, and the contents were heated to 105 ℃ as a solution in dioxane/water (3:1) for 12 h. Ethyl acetate was used as the extraction solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-293 as a white solid (52.7mg, 56% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(s,1H),8.22(d,1H),7.31(s,1H),7.16-7.25(m,1H),7.01-7.09(m,1H),6.95-7.01(m,1H),6.84-6.89(m,1H),6.60(d,1H),5.98(s,2H),4.33-4.41(m,2H),3.53-3.62(m,2H),3.41(s,3H),2.05-2.20(m,4H)。

Compound I-294

The title compound was prepared according to general procedure B except 2- (piperidin-4-yl) propionic acid was the amine reactant (2 equivalents), 4 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in dioxane/water (3:1) for 12 h. A dichloromethane/isopropanol mixture (5:1) was used as the extraction solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to afford the desired compound, compound I-294, as an off-white solid (42.8mg, 68% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(s,1H),8.20(d,1H),7.31(s,1H),7.17-7.23(m,1H),7.00-7.07(m,1H),6.94-7.02(m,1H),6.81-6.89(m,1H),6.60(d,1H),5.98(s,2H),4.70-4.84(m,2H),3.01-3.06(t,2H),2.39-2.44(m,1H),1.93-2.01(m,1H),1.82-1.93(m,2H),1.37-1.54(m,2H),1.24(d,3H)。

Compound I-295

The title compound was prepared according to general procedure B except 4-phenylpiperidine-2-carboxylic acid (as TFA salt) was the amine reactant (2 eq), 4 eq triethylamine was used, and the contents were heated to 110 ℃ for 64 h. Ethyl acetate was used as the extraction solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to afford the desired compound, compound I-295(12.0mg, 18% yield) as a racemic mixture (off-white solid) with the relative cis configuration.

¹H NMR(500MHz,CD₃OD)δ(ppm):8.76(s,1H),8.21(d,1H),7.45(s,1H),7.25-7.36(m,5H),7.19-7.25(m,1H),7.08-7.14(m,1H),7.02-7.07(m,1H),6.91(d,1H),6.80-6.86(m,1H),5.97(s,2H),5.62-5.77(m,1H),2.77-2.89(m,1H),2.55-2.62(m,1H),2.03-2.12(m,1H),1.96-2.02(m,1H),1.83-1.96(m,1H),1.25-1.35(m,1H),0.84-0.98(m,1H)。

Compound I-296

The title compound was prepared according to general procedure B except that 4- (4-methoxyphenyl) piperidine-4-carboxylic acid (as TFA salt) was the amine reactant (2 equivalents), 4 equivalents triethylamine was used, and the contents were heated to 110 ℃ as a solution in dioxane/water (3:1) for 17 h. Ethyl acetate was used as the extraction solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-296(41.1mg, 66% yield) as a white solid.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.43(s,1H),8.12(d,1H),7.34(d,2H),7.28(s,1H),7.12-7.16(m,1H),6.94-7.02(m,1H),6.88-6.93(m,1H),6.86(d,2H),6.75-6.80(m,1H),6.56(d,1H),5.94(s,2H),4.44-4.52(m,2H),3.78(s,3H),3.36-3.41(m,2H),2.63-2.72(m,2H),1.96-2.08(m,2H)。

Compound I-298

The title compound was prepared according to general procedure B, except that 4-aminopiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant (2 equivalents) and the contents were heated to 100 ℃ as a solution in THF/DMF/triethylamine (1:1:1) for 18 h. After complete consumption of the starting material, the reaction was cooled to 0 ℃ and an excess of 2M trimethylsilyl diazomethane solution was added and stirred at 23 ℃ for 3 days until complete conversion to the amino ester. The contents were diluted with 1N NaOH solution and extracted with dichloromethane. The organic layer was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 20 to 100% ethyl acetate gradient in hexanes to give the desired compound, compound I-298 as a solid (22mg, 63% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.08(d,1H),8.28(d,1H),7.54(s,1H),7.29-7.39(m,1H),7.18-7.27(m,2H),7.10(t,1H),6.83(t,1H),5.90(s,2H),4.02-4.09(m,2H),3.66-3.74(m,2H),3.63-3.65(m,3H),1.99-2.04(m,2H),1.91-1.98(m2H),1.62(d,2H)。

Compound I-299

The title compound was prepared according to general procedure B except that 4-aminopiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant (5 equivalents), 8 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF/water (5:1) for 18 h. After complete consumption of the starting material, the reaction was cooled and filtered. The resulting solid was collected and purified via reverse phase HPLC to give the desired compound, compound I-299(2mg, 7% yield) as a solid.

¹H NMR (500MHz, methanol-d)₄)δppm 8.80(d,1H),8.31(d,1H),7.54(s,1H),7.23-7.35(m,1H),7.08-7.15(m,1H),7.05(t,1H),6.92(d,1H),6.81-6.90(m,1H),5.99(s,2H),4.45(dt,2H),3.96-4.13(m,2H),2.44(dt,2H),2.02(ddd,2H)。

Compound I-300

The title compound was prepared according to general procedure B except that 4-hydroxypiperidine-4-carboxylic acid (as the HCl salt) was the amine reactant (5 equivalents), 8 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF/water (5:1) for 18 h. After complete consumption of the starting material, the reaction was cooled and filtered. The filtrate was collected and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-300 as a solid (22mg, 81% yield).

¹H NMR (500MHz, methanol-d)₄)δppm 8.83(d,1H),8.22-8.35(m,1H),7.58-7.70(m,1H),7.25-7.37(m,1H),7.04-7.18(m,2H),6.90-7.02(m,2H),6.03(s,2H),4.76(d,2H),3.69-3.82(m,2H),2.16-2.33(m,2H),1.94(d,2H)。

Compound I-301

The title compound was prepared according to general procedure B, except that (S) -4, 4-difluoropyrrolidine-2-carboxylic acid was used as amine reactant (5 equivalents), 8 equivalents triethylamine was used, and the contents were heated to 90 ℃ as a solution in THF/water (5:1) for 18 h. After complete consumption of the starting material, the reaction was concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-301(20mg, 67% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.80(d,1H),8.34(d,1H),7.35-7.42(m,1H),7.24-7.34(m,1H),7.10(dd,1H),7.01-7.07(m,1H),6.91(td,2H),5.98(s,2H),5.44-5.69(m,2H)4.76-4.87(m,3H)。

Compound I-302

The title compound was prepared according to general procedure B, except that (S) -2-amino-3-ethoxypropionic acid was used as the amine reactant (4 equivalents), 6 equivalents of triethylamine was used, and the contents were heated to 100 ℃ as a solution in dioxane/water (3:1) for 18 h. After treatment, the crude material was suspended in ethyl acetate and diluted with hexane until precipitation occurred. The precipitate was filtered and collected to give the desired compound, compound I-302(9mg, 24% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.08(s,1H),8.20(d,1H),7.47(s,1H),7.27-7.40(m,2H),7.17-7.26(m,2H),7.10(t,1H),6.84(t,1H),5.81-5.98(m,2H),4.59(br.s.,1H),3.83-3.90(m,1H),3.75-3.83(m,1H),3.45-3.54(m,1H),3.37-3.44(m,1H),0.92-1.08(m,3H)。

Compound I-303

The title compound was prepared according to general procedure B, except 2-amino-3-methoxypropionic acid was the amine reactant (4 equivalents), 6 equivalents triethylamine was used, and the contents were heated to 100 ℃ as a solution in dioxane/water (3:1) for 18 h. After treatment, the crude material was suspended in ethyl acetate and diluted with hexane until precipitation occurred. The precipitate was filtered and collected to give the desired compound, compound I-303(8mg, 22% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.09(d,1H)8.22(d,1H),7.47(s,1H),7.28-7.39(m,1H),7.17-7.27(m,2H),7.10(t,1H),6.85(t,1H),6.63(br.s.,1H),5.81-5.94(m,2H),4.54-4.88(m,1H),3.72-3.87(m,2H),3.57(s,2H),3.25(s,3H)。

Compound I-304

The title compound was prepared following step 3 of the procedure described for compound I-235, except that 1- ((methylamino) methyl) cyclopropanecarboxylic acid (as TFA salt) was the amine reactant and the contents were heated to 100 ℃ for 6 h. The crude material was purified via silica gel chromatography (1-4% methanol gradient in dichloromethane) to give the desired compound, compound I-304(67mg, 72% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δ8.77(d,1H),8.10(d,1H),7.39(s,1H),7.16(app.q,1H),7.03(app.q,1H),6.92(d,1H),6.68(app.t,1H),5.98(s,2H),4.15(s,2H),3.37(d,3H),1.28(m,2H),1.07(m,2H)。

Compound I-305

The title compound was prepared following step 3 of the procedure described for compound I-235, except (2R,3S) -3-methylpiperidine-2-carboxylic acid (as acetate) was the amine reactant and the contents were heated to 100 ℃ for 21 h. The crude material was purified via silica gel chromatography (2-4% methanol gradient in dichloromethane) to give the desired compound, compound I-305 as a white solid (24mg, 46% yield).

¹H-NMR(400MHz,CDCl₃)δ8.77(d,1H),8.21(d,1H),7.47(s,1H),7.15(app.q,1H),7.02(app.q,1H),6.89(d,1H),6.66(app.t,1H),5.98(s,2H),5.04(d,1H),4.37(br.d,1H),3.70(app.t,1H),2.10(m,1H),1.90(br.d,1H),1.80-1.69(m,2H),1.52(app.q,1H),1.21(d,3H)。

Compound I-306

The title compound was prepared according to general procedure B except 4-isopropylpiperidine-4-carboxylic acid was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 3 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The solid was treated with 1N HCl solution, and the resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-306(42mg, 86% yield) as a white solid.

¹H-NMR(500MHz,CDCl₃)δ8.49(d,1H),8.35(d,1H),7.64(s,1H),7.25-7.20(m,1H),7.05-7.01(m,3H),6.67(d,1H),5.98(s,2H),4.80(d,2H),3.79-3.72(m,1H),3.23(t,1H),2.35(d,2H),1.92-1.80(m,1H),1.62(td,1H),1.41(t,1H),0.97(d,6H)。

Compound I-307

The title compound was prepared according to general procedure B except 3- (methylamino) bicyclo [1.1.1] pentane-1-carboxylic acid was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 18 h. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-307 as an off-white solid (74mg, 53% yield).

¹H-NMR(500MHz,CDCl₃)δ8.53(d,1H),8.45(d,1H),7.49(s,1H),7.26-7.21(m,2H),7.09-7.01(m,2H),6.67(d,1H),5.93(s,2H),3.36(d,3H),2.68(s,6H)。

Compound I-308

The title compound was prepared according to general procedure B except 2-azabicyclo [4.1.0] heptane-1-carboxylic acid (as the HCl salt) was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 3 h. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-308 as an off-white solid (32mg, 17% yield).

¹H-NMR(500MHz,CDCl₃)δ8.46(d,1H),8.21(d,1H),7.27(s,1H),7.23-7.18(m,1H),7.04(t,1H),6.98(t,1H),6.87(t,1H),6.59(d,1H),5.98(s,2H),4.62(br.s.,1H),3.01(br.s.,1H),2.20-2.11(m,1H),2.08-1.98(m,2H),1.83-1.72(m,2H),1.57-1.49(m,1H),1.04(br.s.,1H)。

Compound I-309

The title compound was prepared according to general procedure B except (1R,3S) -3- (Boc-amino) cyclopentane-1-carboxylic acid (as the TFA salt) was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 3 h. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give an intermediate. This intermediate was immediately dissolved in THF and cooled to 0 ℃. The contents were treated with sodium hydride (60% in mineral oil, 2 equivalents) followed by methyl iodide (10 equivalents). The reaction was allowed to warm to 23 ℃ over 3 days. The contents were poured onto water and extracted with ethyl acetate (3 ×). The organic portions were combined and washed with brine. Over MgSO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-15% methanol/dichloromethane gradient to give the desired compound, compound I-309 as an off-white solid (0.9mg, 1% yield).

¹H-NMR(500MHz,CDCl₃)δ8.45(s,1H),8.13(d,1H),7.32(s,1H),7.23-7.15(m,1H),7.03(t,1H),6.97(t,1H),6.86(t,1H),6.60(s,1H),5.97(s,2H),4.75(d,1H),3.74(s,3H),3.08-2.94(m,1H),2.42-2.30(m,1H),2.17-1.84(m,5H)。

Compound I-310

The title compound was prepared according to general procedure B except (2S,3S) -2-methyl-piperidine-3-carboxylic acid was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 3 days. The crude material was purified via silica gel chromatography with a gradient of 0-50% (acetonitrile: methanol ═ 9:1 with 0.1% TFA) in dichloromethane to give the desired compound, compound I-310 as an off-white solid (4.9mg, 2% yield).

¹H-NMR(500MHz,CDCl₃)δ8.46(d,1H),8.22(d,1H),7.31(s,1H),7.24-7.18(m,1H),7.13-7.01(m,1H),6.98(t,1H),6.87(t,1H),6.59(d,1H),5.97(s,2H),5.38(br.s.,1H),4.42(d,1H),3.22(t,1H),2.99-2.87(m,1H),2.05-1.96(m,2H),1.93-1.84(m,2H),1.32(d,3H)。

Compound I-311

The title compound was prepared according to general procedure B except (2R,3R) -2-methyl-piperidine-3-carboxylic acid was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (10:1) for 18 h. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-311 as an off-white solid (17.2mg, 12% yield).

¹H-NMR(500MHz,DMSO-d₆)δ12.51(br.s.,1H),9.09(d,1H),8.31(d,1H),7.50(s,1H),7.36-7.29(m,1H),7.25-7.18(m,2H),7.10(t,1H),6.84(t,1H),5.89(s,2H),5.09(br.s.,1H),4.37(br.s.,1H),3.10(t,1H),2.74(br.s.,1H),1.84-1.72(m,3H),1.50(br.s.,1H),1.19(d,3H)。

Compound I-312

The title compound was prepared according to general procedure B except 3-azabicyclo [3.1.0] hexane-1-carboxylic acid (as the HCl salt) was the amine reactant, the contents were heated to 100 ℃ for 18h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-312, as an off-white solid (44mg, 70% yield).

¹H-NMR(500MHz,DMSO-d₆)δ12.65(br.s.,1H),9.08(d,1H),8.26(d,1H),7.53(s,1H),7.35-7.30(m,1H),7.26(d,1H),7.25-7.20(m,1H),7.10(td,1H),6.83-6.79(m,1H),5.91(s,2H),4.09-3.98(m,3H),3.81(br.s.,1H),2.22-2.17(m,1H),1.51(dd,1H),0.97(t,1H)。

Compound I-313

The title compound was prepared according to general procedure B, except that (S) -3-aminopropane-1, 2-diol was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-313(39mg, 85% yield) as an off-white solid.

¹H-NMR(500MHz,CD₃OD) Δ 8.74(d,1H),8.07(d,1H),7.42(s,1H),7.29-7.22(m,1H),7.11-7.05(m,1H),7.02(td,1H),6.88(d,1H),6.81(td,1H),5.95(s,2H),3.88 (quintuple, 1H),3.81-3.74(m,1H),3.69-3.62(m,1H),3.59(s,1H),3.58(s, 1H).

Compound I-314

The title compound was prepared according to general procedure B, except cis-4-methylpyrrolidine-3-carboxylic acid was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-314 as an off-white solid (50mg, 72% yield).

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.09(d,1H),7.41(s,1H),7.29-7.23(m,1H),7.11-7.06(m,1H),7.02(t,1H),6.91(d,1H),6.81(t,1H),5.95(s,2H),4.22-4.13(m,2H),3.98-3.92(m,1H),3.41(t,1H),2.84-2.77(m,1H),2.58(d,1H),1.24(d,3H)。

Compound I-315

The title compound was prepared according to general procedure B, except that serinol was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-315 as an off-white solid (49mg, 84% yield).

¹H-NMR(500MHz,CD₃OD) Δ 8.75(t,1H),8.08(dd,1H),7.46(d,1H),7.30-7.23(m,1H),7.09(dd,1H),7.03(t,1H),6.91-6.88(m,1H),6.80(t,1H),5.96(s,2H),4.54 (quintuple, 1H),3.75-3.82(m, 4H).

Compound I-316

The title compound was prepared according to general procedure B, except that (R) -3-aminopropane-1, 2-diol (2 equivalents) was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-316(36mg, 78% yield) as an off-white solid.

¹H-NMR(500MHz,CD₃OD) Δ 8.73(d,1H),8.06(d,1H),7.41(s,1H),7.27-7.22(m,1H),7.10-7.04(m,1H),7.01(t,1H),6.86(d,1H),6.83-6.78(m,1H),5.94(s,2H),3.88 (quintuple, 1H),3.80-3.74(m,1H),3.68-3.62(m,1H),3.58(d, 2H).

Compound I-317

The title compound was prepared according to general procedure B except 4- (aminomethyl) -2, 6-difluorophenol was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. The crude material was purified via silica gel chromatography with a 0-30% (acetonitrile: methanol ═ 7:1) dichloromethane gradient to give the desired compound, compound I-317 as an off white solid (38mg, 30% yield).

¹H-NMR(500MHz,CD₃OD)δ8.77-8.74(m,1H),8.08(d,1H),7.37(s,1H),7.26(dd,1H),7.11-7.06(m,1H),7.06-7.01(m,3H),6.88(d,1H),6.84(t,1H),5.96(s,2H),4.69(s,2H)。

Compound I-318

The title compound was prepared according to general procedure B, except cis-piperidine-2, 4-dimethylol was the amine reactant and the contents were heated to 100 ℃ for 20 h. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-70% (acetonitrile: methanol ═ 7:1) dichloromethane gradient to give the desired compound, compound I-318 as an off white solid (39mg, 25% yield).

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.12(d,1H),7.40(s,1H),7.29-7.23(m,1H),7.11-7.05(m,1H),7.04-6.99(m,1H),6.90(d,1H),6.82(td,1H),5.99-5.91(m,2H),4.52-4.45(m,1H),4.35-4.26(m,1H),3.86-3.76(m,2H),3.58-3.42(m,3H),2.09-1.99(m,2H),1.85-1.75(m,1H),1.65-1.55(m,1H),1.45-1.36(m,1H)。

Compound I-319

The title compound was prepared according to general procedure B except 3-phenylpiperidine-2-carboxylic acid (as the AcOH salt) was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment. A portion of the crude material was purified via reverse phase HPLC using a 5-75% acetonitrile/water gradient to give the desired compound, compound I-319 as an off white solid (30mg, 9% yield).

¹H-NMR(500MHz,CDCl₃)δ8.37(d,1H),8.27(d,1H),7.34-7.28(m,4H),7.26-7.22(m,1H),7.20(s,1H),7.15(ddd,1H),6.99-6.88(m,3H),6.45(d,1H),5.91-5.82(m,2H),5.18(d,1H),4.31(d,1H),3.59(td,1H),3.26-3.17(m,1H),2.49(qd,1H),2.06-1.99(m,1H),1.98-1.81(m,2H)。

Compound I-320

The title compound was prepared according to general procedure B, except that (S) -3- (methylamino) propane-1, 2-diol was the amine reactant and the contents were heated to 100 ℃ for 20 h. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-320 as a white solid (81mg, 84% yield).

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.10(d,1H),7.42(s,1H),7.29-7.23(m,1H),7.11-7.06(m,1H),7.02(t,1H),6.88(d,1H),6.85-6.80(m,1H),5.95(s,2H),4.03-3.94(m,2H),3.73-3.66(m,1H),3.58(d,2H),3.42(d,3H)。

Compound I-321

The title compound was prepared according to general procedure B, except that (R) -3- (methylamino) propane-1, 2-diol was the amine reactant and the contents were heated to 100 ℃ for 2 days. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-321(88mg, 77% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.74(d,1H),8.09(d,1H),7.41(s,1H),7.28-7.22(m,1H),7.10-7.05(m,1H),7.04-6.99(m,1H),6.87(d,1H),6.82(td,1H),5.94(s,2H),4.02-3.93(m,2H),3.72-3.66(m,1H),3.58(d,2H),3.41(d,3H)。

Compound I-322

The title compound was prepared according to general procedure B, except that (S) -3- ((cyclopropylmethyl) amino) propane-1, 2-diol was the amine reactant and the contents were heated to 100 ℃ for 20 h. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-322 as a white foam (39mg, 62% yield).

¹H-NMR(500MHz,CDCl₃)δ8.45(d,1H),8.12(d,1H),7.29(s,1H),7.24-7.19(m,1H),7.05-6.97(m,3H),6.57(d,1H),5.99-5.94(m,1H),5.91-5.86(m,1H),4.14(dd,1H),4.02(br.s.,1H),3.93(br.s.,1H),3.86(br.s.,1H),3.68-3.57(m,4H),3.43(ddd,1H),1.15-1.06(m,1H),0.65-0.53(m,2H),0.38-0.32(m,1H),0.32-0.26(m,1H)。

Compound I-323

The title compound was prepared according to general procedure B, except that (S) -3- (isopropylamino) propane-1, 2-diol was the amine reactant and the contents were heated to 100 ℃ for 20 h. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-50% (acetonitrile: methanol ═ 7:1) dichloromethane gradient to give the desired compound, compound I-323 as a white solid (12mg, 20% yield).

¹H-NMR(500MHz,CDCl₃)δ8.45(d,1H),8.13(d,1H),7.30(s,1H),7.25-7.19(m,1H),7.06-6.98(m,3H),6.58(d,1H),6.00-5.94(d,1H),5.91-5.85(d,1H),4.95(br.s.,1H),4.67-4.58(m,1H),3.82-3.74(m,2H),3.70-3.60(m,2H),3.59-3.49(m,2H),1.32(d,3H),1.29(d,3H)。

Compound I-324

The title compound was prepared according to general procedure B except 2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol was the amine reactant, the contents were heated to 100 ℃ for 20h, and the aqueous layer was treated with sodium chloride during the treatment, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography using a 0-10% ethyl acetate/hexanes gradient to give the desired compound, compound I-324 as a white solid (5mg, 9% yield).

¹H-NMR(500MHz,CDCl₃)δ8.48(d,1H),8.36(s,1H),8.26(d,1H),7.25-7.20(m,2H),7.14(t,1H),7.05-6.99(m,2H),6.59(d,1H),5.94(s,2H),5.59(br.s.,1H),4.12(d,2H)。

Compound I-325

The title compound was prepared according to general procedure B except 1-amino-2-methylpropan-2-ol was the amine reactant and the contents were heated to 100 ℃ for 20 h. The reaction was poured into a 1:1 mixture of dichloromethane and water for treatment, and the aqueous layer was treated with sodium chloride, followed by extraction with dichloromethane. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-325 as a white solid (43mg, 93% yield).

¹H-NMR(500MHz,CDCl₃)δ8.43(d,1H),8.14(d,1H),7.27(s,1H),7.21-7.15(m,1H),7.04-6.98(m,1H),6.95(t,1H),6.84(t,1H),6.59(d,1H),5.95(s,2H),5.62(br.s.,1H),3.70(s,1H),3.63(d,2H),1.31(s,6H)。

Compound I-326

A mixture of (S) -trifluoro lactic acid (1.5 eq) and 1, 1' -carbonyldiimidazole (1.5 eq) in THF was heated to 70 ℃ for 2 h. 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (intermediate described in WO2012/3405a 1) (1 eq) was added to the reaction mixture and the contents were stirred at 70 ℃ for 3 days. The contents were cooled to 23 ℃, diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was washed with brine, over MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-326 as a white solid (3mg, 4% yield).

¹H-NMR(500MHz,CDCl₃)δ9.61(br.s.,1H),8.76(d,1H),8.49(d,1H),8.16(d,1H),7.47(s,1H),7.25-7.21(m,1H),7.11-7.03(m,1H),7.00(t,1H),6.83(t,1H),6.63(d,1H),6.36(br.s.,1H),6.06-5.95(m,2H),4.69(d,1H)。

Compound I-329 and compound I-330

Compound I-161 was resolved by chiral separation using a 10-90% isopropanol/hexane gradient with a chiralcel-ODH 20mm X250 mm semi-preparative column. The first eluting peak was collected and concentrated in vacuo to afford compound 329 as a white solid. The second eluting peak was collected and concentrated in vacuo to afford compound 330 as a white solid.

Of Compound I-329¹H-NMR(500MHz,CDCl₃)δ8.38(d,1H),8.16(d,1H),7.21(s,1H),7.20-7.15(m,1H),7.04-6.99(m,1H),6.97-6.93(m,1H),6.89-6.84(m,1H),6.48(d,1H),6.06-6.00(m,1H),5.93-5.88(m,1H),4.76(d,1H),4.15(d,1H),3.54-3.43(m,1H),2.09-1.98(m,1H),1.91-1.82(m,1H),1.81-1.64(m,3H),1.17(d,3H)。

Process for preparation of compound I-330¹H-NMR(500MHz,CD₃OD)δ8.78-8.74(d,1H),8.21(d,1H),7.45(s,1H),7.30-7.23(m,1H),7.11-7.06(m,1H),7.03(t,1H),6.86(d,1H),6.83(t,1H),5.95(s,2H),5.04(d,1H),4.37(d,1H),3.69(td,1H),2.16-2.07(m,1H),1.93-1.86(m,1H),1.82-1.70(m,2H),1.52(qd,1H),1.21(d,3H)。

Compound I-331 and compound I-332

The mixture of compound I-329 with 1, 1' -carbonyldiimidazole (1 eq) in DCM was heated to 45 ℃ until all starting material was consumed as observed on LC/MS. Cyclopropanesulfonamide (4 equivalents) and DBU (2 equivalents) were added to the reaction mixture and the contents were stirred at 45 ℃ for another 30 min. The contents were cooled to 23 ℃, quenched with 1N HCl solution, and the layers separated. The aqueous layer was extracted with dichloromethane (× 2) and the organic portions were combined and washed with brine. Through Na₂SO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-20% (acetonitrile: methanol: 7: 1)/dichloromethane gradient to give compound I-331 as a white solid (40mg, 13% yield) and compound I-332 as a white solid (3mg, 1% yield).

Process for preparation of compound I-331¹H-NMR(400MHz,DMSO-d₆)δ12.09(s,1H),9.14(d,1H),8.38(d,1H),7.25-7.18(m,1H),7.37-7.29(m,1H),7.55(s,1H),7.12-7.06(m,2H),6.87-6.80(m,1H),5.94-5.84(m,2H),4.73(d,1H),4.23(br.s.,1H),3.66-3.54(m,1H),2.94-2.85(m,1H),2.38(d,1H),1.89-1.81(m,1H),1.68-1.51(m,3H),1.15(d,3H),0.97-0.92(m,2H),0.89-0.84(m,2H)。

Of Compound I-332¹H-NMR(400MHz,DMSO-d₆)δ11.97(s,1H),9.14(d,1H),8.41(d,1H),7.65(s,1H),7.37-7.28(m,1H),7.26-7.17(m,1H),7.14-7.05(m,2H),6.88-6.79(m,1H),5.97-5.86(m,2H),4.70(d,1H),4.13(d,1H),3.83-3.72(m,1H),2.97-2.87(m,1H),2.10(d,1H),1.85(d,1H),1.74-1.60(m,2H),1.53-1.39(m,1H),1.16(d,3H),1.05-0.93(m,3H),0.87-0.78(m,1H)。

Compound I-333

A mixture of 3- (3- (4-chloropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (synthesis described in the procedure for compound I-24) (1 equivalent), (2R,3S) -3-methylpiperidine-2-carboxylic acid (as (1S) - (+) -camphorsulfonate, 1 equivalent), and triethylamine (1 equivalent) was heated as a solution in dioxane/water (2:1) to 110 ℃ for 48H. The contents were cooled to 23 ℃ and partitioned between a 1:1 mixture of dichloromethane and 1N HCl solution. The layers were separated and the aqueous layer was extracted with dichloromethane (× 2) and the organic portions were combined and washed with brine. Through Na₂SO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-20% (acetonitrile: methanol ═ 7:1) dichloromethane gradient to give the desired compound, compound I-333(10mg, 4% yield) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.64(br.s.,1H),9.10(d,1H),8.30(d,1H),7.55(br.s.,1H),7.38-7.29(m,1H),7.27-7.16(m,2H),7.15-7.06(m,1H),6.83(d,2H),5.90(s,2H),3.21(s,1H),1.94(br.s.,1H),1.89-1.80(m,1H),1.69-1.35(m,5H),1.13(d,3H)。

Compound I-334

The title compound was prepared according to general procedure B except 2-amino-2- (hydroxymethyl) propane-1, 3-diol was the amine reactant and the contents were heated to 110 ℃ for 20 h. The crude material was purified via silica gel chromatography with a gradient of 0-20% (acetonitrile: methanol ═ 7:1) in dichloromethane to give the desired compound, compound I-334 as an off white solid (185mg, 72% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.10(d,1H),8.24(d,1H),7.46(s,1H),7.36-7.29(m,1H),7.25-7.18(m,2H),7.10(td,1H),6.91-6.84(m,1H),6.36(s,1H),5.86(s,2H),4.95(br.s.,3H),3.76-3.72(m,6H)。

Compound I-335

The title compound was prepared according to general procedure B, except that (S) -2-amino-3-hydroxypropionamide was the amine reactant and the contents were heated to 110 ℃ for 20 h. The crude material was purified via silica gel chromatography with a gradient of 0-20% (acetonitrile: methanol ═ 7:1) in dichloromethane to give the desired compound, compound I-335 as a white solid (170mg, 37% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.14(d,1H),8.56(br.s.,1H),8.41(d,1H),7.70(s,2H),7.37-7.31(m,1H),7.29-7.19(m,3H),7.14-7.08(m,1H),6.86(t,1H),5.94(s,2H),4.87-4.80(m,1H),3.89-3.78(m,2H),3.06(qd,1H)。

Compound I-336

A solution of compound I-112(1 eq) in DMF was treated successively with Hunig's base (3 eq) and HATU (1 eq). After stirring for 5min, serinol (1.5 eq) was added and the reaction was stirred for 20h at 23 ℃. The mixture was partitioned between a 1:1 mixture of dichloromethane and 1N HCl solution. The layers were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic portions were washed with brine. Through Na₂SO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-20% (acetonitrile: methanol ═ 7:1) dichloromethane gradient to give the desired compound, compound I-336 as a white solid (22mg, 26% yield).

¹H-NMR(400MHz,DMSO-d₆)δ9.14(d,1H),8.96(br.s.,1H),8.45(d,1H),8.17(d,1H),7.85(s,1H),7.38-7.29(m,1H),7.28-7.18(m,2H),7.14-7.07(m,1H),6.86(t,1H),5.96(s,2H),4.94-4.86(m,1H),3.86-3.78(m,2H),3.74-3.65(m,1H),3.64-3.53(m,1H),3.53-3.46(m,1H),3.45-3.40(m,2H),3.40-3.34(m,2H),3.16-3.04(m,1H)。

Compound I-337

The title compound was prepared according to general procedure B except 3-amino-1, 1, 1-trifluoropropan-2-ol (5 equivalents) was the amine reactant and the contents were heated to 110 ℃ for 20 h. The crude material was purified via silica gel chromatography with a gradient of 0-20% (acetonitrile: methanol ═ 7:1) in dichloromethane to give the desired compound, compound I-337 as a white solid (70mg, 53% yield).

¹H-NMR(400MHz,CDCl₃)δ8.76(d,1H),8.10(d,1H),7.38(s,1H),7.30-7.23(m,1H),7.08(dd,1H),7.05-7.00(m,1H),6.88-6.82(m,2H),5.95(s,2H),4.40-4.30(m,1H),3.99(dd,1H),3.70(dd,1H)。

Compound I-339

The title compound was prepared in 2 steps:

step 1: synthesis of methyl 2- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylate

This intermediate was prepared according to general procedure B, except 1,2,3, 4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (as the HCl salt) was the amine reactant.

Treatment gave the desired methyl ester as an orange oil: methyl 2- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylate (compound I-338, 55mg, 97% yield), which was continued without further purification.

Step 2: synthesis of Compound I-339

A solution of methyl 2- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -1,2,3, 4-tetrahydroisoquinoline-8-carboxylate and lithium hydroxide hydrate (1.5 equivalents) in tetrahydrofuran, water and methanol (3:1:1 ratio) was stirred at 23 ℃ for 21H. Additional base (1.5 eq) was added and the solution was stirred for 24 h. The solution was poured into water, 1N sodium hydroxide and dichloromethane (10:1:10 ratio). The layers were separated and the aqueous layer was acidified to pH 1. The aqueous layer was extracted with dichloromethane, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the desired compound, compound I-339(9mg, 17% yield over 2 steps) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ13.14(s,1H),9.12(d,1H),8.32(d,1H),7.79-7.77(m,1H),7.48(s,1H),7.43-7.41(d,1H),7.34-7.30(m,2H),7.24-7.20(m,2H),7.11(dt,1H),6.85(dt,1H),5.89(s,2H),5.34(d,2H),4.07(t,2H),3.04(t,2H)。

Compound I-341

The title compound was prepared in 3 steps:

step 1: synthesis of cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carboxamide (Compound I-340)

To a solution of compound I-161 and triethylamine (1 equivalent) in tetrahydrofuran at 0 ℃ was added ethyl chloroformate (1.05 equivalents) dropwise over 5 minutes. The reaction mixture was maintained at 0 ℃ for 45min, and then ammonium hydroxide (7 equivalents) was added. The solution was immediately warmed to 23 ℃ and stirred for a further 15 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (20-100% hexane gradient in ethyl acetate) afforded cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carboxamide (compound I-340, 270mg, 54% yield) as a yellow foam.

¹H NMR(400MHz,CDCl₃)δppm 8.46(d,1H),8.17(d,1H),7.23(s,1H),7.22-7.17(m,1H),7.12-6.91(m,3H),6.59(d,1H),6.06-5.76(m,2H),5.34(br.s.,1H),4.76(d,1H),4.18(d,1H),3.32(ddd,1H),2.64-2.50(m,1H),2.08-1.79(m,2H),1.65-1.50(m,1H),1.49-1.37(m,1H),1.15(d,1H),1.05(d,3H)。

Step 2: synthesis of cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carbonitrile

Trifluoroacetic anhydride (2 equivalents) was added dropwise over 5 minutes to a 0 ℃ solution of cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carboxamide in pyridine. After stirring at 0 ℃ for 45min, the solution was allowed to warm to room temperature and then immediately poured into dichloromethane and saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (10-75% hexane gradient in ethyl acetate) afforded cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carbonitrile as a white foam (215mg, 83% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.44(d,1H),8.31(d,1H),7.30(s,1H),7.22-7.11(m,1H),7.06-6.91(m,2H),6.82(t,1H),6.59(d,1H),5.95(s,2H),5.40(s,1H),4.35(d,1H),3.32(td,1H),2.48-2.35(m,1H),2.20-1.84(m,2H),1.61-1.76(m,2H),1.17(d,3H)。

And step 3: synthesis of Compound I-341

A suspension of cis-1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -3-methylpiperidine-2-carbonitrile, ammonium chloride (5 equivalents) and sodium azide (5 equivalents) in N, N-dimethylformamide was heated to 90 ℃ for 60 hours. The solution was diluted with ethyl acetate and 1N aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude solid was suspended in dichloromethane and filtered to give the product contaminated with by-products. The filtrate was concentrated in vacuo and the resulting solid was suspended in ether and filtered to give the desired compound, compound I-341 as a white solid (135mg, 57% yield).

¹H-NMR(400MHz,CDCl₃)δ8.51(d,1H),8.15(d,1H),7.29(s,1H),7.25-7.20(m,2H),7.04-6.99(m,2H),6.63(d,1H),6.09(d,1H),6.00(d,1H),5.18(d,1H),3.98(dd,1H),3.31(dt,1H),2.81-2.75(m,1H),2.54-2.46(m,1H),2.13-2.02(m,1H),1.80-1.75(m,1H),1.60-1.51(m,1H),1.11(d,3H)。

Compound I-342

The title compound was prepared according to general procedure B, except that 1- ((methylamino) methyl) cyclobutanecarboxylic acid (as TFA salt) was the amine reactant. Work-up afforded the desired compound, compound I-342(64mg, quantitative yield) as a yellow solid.

¹H-NMR(400MHz,CD₃OD)δ8.81(d,1H),8.29(d,1H),7.56(m,1H),7.32-7.26(m,1H),7.11-7.02(m,2H),6.96-6.92(m,2H),5.98(s,2H),4.37(s,2H),3.48(d,3H),2.51-2.44(m,2H),2.25-2.16(m,2H),2.09-1.93(m,2H)。

Compound I-343

A suspension of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (thiazol-2-yl) -1H-pyrazol-3-yl) pyrimidin-4-ol (intermediate previously described in WO2013/101830 a 1) in phosphorus oxychloride (20 equivalents) was heated to 60 ℃ for 2H. The phosphoryl chloride was removed under a stream of nitrogen and the resulting residue was dissolved in dioxane and water (2:1 ratio). After addition of 1- ((methylamino) methyl) cyclopropanecarboxylic acid hydrochloride (3 equivalents) and triethylamine (10 equivalents), the solution was then heated to 90 ℃ for 4 h. The solution was diluted with dichloromethane and 1N hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded the desired compound, compound I-343(17mg, 52% yield) as a white solid.

¹H-NMR(400MHz,DMSO-d₆)δ12.34(s,1H),8.23(d,1H),7.98(d,1H),7.92(d,1H),7.35(s,1H),7.34-7.29(m,1H),7.23-7.18(m,1H),7.10(dt,1H),6.93(dt,1H),6.02(s,2H),4.00(s,2H),3.24(d,3H),1.15-1.12(m,2H),1.03-1.01(m,2H)。

Compound I-344

To a solution of compound I-248 in dichloromethane was added carbonyldiimidazole (1.2 equivalents). The resulting mixture was stirred at 40 ℃ for 45 min. The solution was cooled to 23 ℃ and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2 equivalents) was added followed by cyclopropanesulfonamide (3 equivalents). After stirring for 16h, the solution was poured into dichloromethane and 1N hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. First purified via silica gel chromatography (methanol in dichloromethane) to give an impure product. The impure residue was dissolved in diethyl ether and hexane was added until the solution became cloudy. After stirring for 20min, the solid was filtered off to give the desired compound, compound I-344 as a white solid (29mg, 48% yield).

¹H-NMR(400MHz,CDCl₃)δ8.44(d,1H),8.09(d,1H),7.23-7.17(m,2H),7.03-6.97(m,3H),6.51(d,1H),5.95(s,2H),3.96(dd,1H),3.69-3.63(m,1H),3.32(d,3H),2.90-2.81(m,2H),2.03-1.96(m,1H),1.18-1.14(m,2H),1.03(dd,6H),0.92-0.90(m,2H)。

Compound I-345

A suspension of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (thiazol-4-yl) -1H-pyrazol-3-yl) pyrimidin-4-ol (intermediate previously described in WO2013/101830 a 1) in phosphorus oxychloride (50 equivalents) was heated to 60 ℃ for 2H. The phosphoryl chloride was removed under a stream of nitrogen and the resulting residue was dissolved in dioxane and water (2:1) and treated with 1- ((methylamino) methyl) cyclopropanecarboxylic acid hydrochloride (3 equivalents) followed by triethylamine (10 equivalents). The resulting solution was heated to 90 ℃ for 7.5 days. The reaction mixture was poured into dichloromethane and 1N hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography (0-10% methanol gradient in dichloromethane) gave compound I-345(2.8mg, 11% yield) as a white film.

¹H-NMR(400MHz,CD₃OD)δ9.03(d,1H),8.07(d,1H),7.89(d,1H),7.24-7.19(m,2H),7.04-6.96(m,2H),6.81(t,1H),5.94(s,2H),4.13(s,2H),3.34(d,3H),1.28-1.25(m,2H),1.08-1.05(m,2H)。

Compound I-346

The title compound was prepared according to general procedure B except 3- (trifluoromethyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [4,3-c ] pyridine (as the HCl salt) was the amine reactant. After treatment, the crude solid was suspended in ether and filtered to give the desired compound, compound I-346(57mg, 84% yield) as a tan solid.

¹H-NMR(400MHz,CD₃OD)δ8.84(d,1H),8.41(d,1H),7.63(s,1H),7.33-7.28(m,1H),7.13-7.04(m,2H),6.98-6.95(m,2H),6.03(s,2H),5.19(s,2H),4.42(t,2H),3.09(t,2H)。

Compound I-347

The title compound was prepared according to general procedure B except that racemic cis-piperidine-3, 4, 5-triol was the amine reactant. LC/MS showed that after the reaction was complete, the solvent was removed in vacuo. Methanol was added and the resulting suspension was filtered to give the desired compound, compound I-347(20mg, 11% yield) as a solid.

1H-NMR(400MHz,DMSO-d₆)δ9.09(d,1H),8.28(d,1H),7.52(s,1H),7.35-7.29(m,1H),7.24-7.21(m,2H),7.09(t,1H),6.80(t,1H),5.90(s,2H),4.92(d,2H),4.80(d,1H),4.15-4.11(m,2H),3.83-3.80(m,1H),3.58-3.53(m,2H),3.27-3.21(m,2H)。

Compound I-348

The title compound was prepared according to general procedure B, except 1, 3-diaminopropan-2-ol was the amine reactant and the contents were heated to 40 ℃ for 45 min. LC/MS showed that after the reaction was complete, the dioxane was removed in vacuo and sufficient methanol was added to dissolve the crude mixture. Purification via reverse phase HPLC (5-75% acetonitrile in water containing 0.1% trifluoroacetic acid, 20min gradient) gave the desired compound, compound I-348 as a pink foam (58mg, 80% yield).

¹H-NMR(400MHz,CD₃OD)δ8.82(d,1H),8.27(d,1H),7.62(s,1H),7.32-7.27(m,1H),7.12-7.03(m,2H),6.95-6.91(m,2H),6.02(d,1H),5.97(d,1H),4.21-4.15(m,1H),3.85-3.77(m,2H),3.22-3.18(dd,1H),2.96(dd,1H)。

Compound I-349

To a solution of compound I-340 and triethylamine (5 equivalents) in dichloromethane at 0 ℃ methanesulfonyl chloride (1 equivalent) was added dropwise. After stirring for 45min, saturated aqueous sodium bicarbonate was added and the reaction mixture was warmed to 23 ℃. Dichloromethane was added and the layers were separated. The aqueous layer was extracted with dichloromethane and the organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via reverse phase HPLC (5-50% acetonitrile in water with 0.1% TFA) afforded the desired compound, compound I-349 as a white solid (6mg, 25% yield).

¹H-NMR(400MHz,CD₃OD)δ8.78(d,1H),8.24(d,1H),7.70(s,1H),7.31-7.25(m,1H),7.11-7.02(m,3H),6.92-6.88(m,1H),6.04(s,2H),4.10-4.01(m,2H),3.61-3.56(m,1H),3.18-3.17(m,2H),2.95(s,3H)。

Compound I-350

The title compound was prepared according to general procedure B except that racemic cis-piperidine-3, 4-diol (as the HCl salt) was the amine reactant. The crude material was purified via reverse phase HPLC (5-50% acetonitrile in water with 0.1% TFA, 20min gradient) to give the desired compound, compound I-350 as a clear film (1.7mg, 3% yield).

¹H-NMR(400MHz,CD₃OD)δ8.81(m,1H),8.28(d,1H),7.64(s,1H),7.32-7.26(m,1H),7.12-7.03(m,2H),6.97-6.93(m,2H),6.01(s,2H),4.52(br s,2H),4.38(dd,1H),3.97-3.90(m,2H),3.77-3.72(m,1H),2.02-1.97(m,1H),1.90-1.86(m,1H)。

Compound I-351

The title compound was prepared according to general procedure B except that 3- (aminomethyl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester was the amine reactant and the reaction was run as a solution in dioxane. During the treatment, ethyl acetate was used as a solvent. The crude material was purified via silica gel chromatography (0-5% methanol gradient in dichloromethane) to give the desired compound, compound I-351(144mg, quantitative yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.76(d,1H),8.11(d,1H),7.44(s,1H),7.30-7.25(m,1H),7.12-7.01(m,2H),6.92(d,1H),6.81(t,1H),5.97(s,2H),4.09(d,2H),3.93(br s,2H),3.78(d,2H),1.40(s,9H)。

Compound I-352

The title compound was prepared according to general procedure B except that 3- (aminomethyl) oxetan-3-ol was the amine reactant and the reaction was run as a solution in dioxane. After stirring for 1.5h at 90 ℃, an additional 2 equivalents of oxetane were added and the reaction mixture was stirred for 3h at 90 ℃. Then, the reaction solution was poured into ethyl acetate and 1N aqueous hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with 5:1 dichloromethane/isopropanol. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by reverse phase HPLC (5-75% acetonitrile in water with 0.1% TFA, 15min gradient) gave compound I-352(25mg, 53% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δ8.83(d,1H),8.29(d,1H),7.65(s,1H),7.32-7.28(m,1H),7.13-7.05(m,2H),6.99-6.94(m,2H),6.02(s,2H),4.05(d,1H),3.98(d,1H),3.78-3.63(m,4H)。

Compound I-353

To a solution of compound I-351 in dichloromethane at 23 ℃ was added a single part of trifluoroacetic acid (30 equivalents). After stirring for 30min, the solution was concentrated in vacuo and the resulting residue was dissolved in diethyl ether. The solid was filtered to give the desired compound, compound I-353(160mg, quantitative yield) as a tan solid.

¹H-NMR(400MHz,CD₃OD)δ8.83(m,1H),8.29-8.25(m,1H),7.60-7.57(m,1H),7.33-7.28(m,1H),7.14-7.04(m,2H),6.93-6.89(m,2H),6.00(s,2H),4.31(d,2H),4.05(m,2H),3.97(d,2H)。

Compound I-354

The title compound was prepared according to general procedure B except that N- (1- (aminomethyl) cyclopropyl) -1,1, 1-trifluoromethane sulfonamide (as the HCl salt) was the amine reactant. The crude material was purified via silica gel chromatography (0-50% ethyl acetate gradient in hexanes) to give the desired compound, compound I-354 as a white solid (15mg, 25% yield).

¹H-NMR(400MHz,CD₃OD)δ8.75(d,1H),8.08(d,1H),7.50(s,1H),7.28-7.24(m,1H),7.10-7.07(m,1H),7.04-7.01(m,1H),6.83-6.80(m,2H),5.96(s,2H),3.85(s,2H),1.06-1.04(m,2H),0.99-0.96(m,2H)。

Compound I-355

The title compound was prepared according to general procedure B except 2- (aminomethyl) -3,3, 3-trifluoropropane-1, 2-diol was the amine reactant and the reaction was run as a solution in dioxane. After treatment with ethyl acetate and 1N hydrochloric acid solution, purification by silica gel chromatography (0-10% methanol gradient in dichloromethane) afforded the desired compound, compound I-355 as a white solid (17mg, 36% yield).

¹H-NMR(400MHz,CD₃OD)δ8.75(d,1H),8.15(d,1H),7.39(s,1H),7.28-7.23(m,1H),7.09-7.01(m,2H),6.88-6.85(m,2H),5.96(d,1H),5.93(d,1H),4.02(d,1H),3.90(d,1H),3.75(d,1H),3.62(d,1H)。

Compound I-356

The title compound was prepared according to general procedure B, except that (S) -3-aminopyrrolidin-2-one (as the HCl salt) was the amine reactant. The crude residue was suspended in 3:1 diethyl ether and dichloromethane. The resulting solid was filtered to give the desired compound, compound I-356 as a tan solid (10mg, 22% yield).

¹H-NMR(400MHz,CD₃OD)δ8.83(s,1H),8.34(m,1H),7.63-7.62(m,1H),7.33-7.29(m,1H),7.13-7.05(m,2H),6.98-6.96(m,2H),6.03(s,2H),5.36-5.32(m,1H),3.56-3.49(m,2H),2.66-2.61(m,1H),2.38-2.30(m,1H)。

Compound I-357

The title compound was prepared in 5 steps:

step 1: synthesis of tert-butyl 3- (2,2, 2-trifluoro-1-hydroxyethyl) azetidine-1-carboxylate

Tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 1.1 equiv.) was added over the course of 10min to a 0 ℃ solution of 3-formylazetidine-1-carboxylic acid tert-butyl ester (1 equiv.) and trimethyl (trifluoromethyl) silane (1.4 equiv.) in tetrahydrofuran. The solution was immediately warmed to 23 ℃ and stirred for 19 h. The reaction mixture was poured into 1N hydrochloric acid solution and diethyl ether. The layers were separated and the aqueous layer was extracted with ether. The organics were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give tert-butyl 3- (2,2, 2-trifluoro-1-hydroxyethyl) azetidine-1-carboxylate (558mg, 79% yield) as a pale yellow solid.

Step 2: synthesis of tert-butyl 3- (2,2, 2-trifluoroacetyl) azetidine-1-carboxylate

To tert-butyl 3- (2,2, 2-trifluoro-1-hydroxyethyl) azetidine-1-carboxylate (1 eq) in dichloromethane was added a single portion of Dess-Martin periodinane (2 eq) at 0 ℃. After 5 minutes at 0 ℃, the solution was warmed to 23 ℃. After two hours, LC/MS showed complete conversion. The reaction mixture was poured into a 5:1 saturated aqueous solution of sodium dithionite and saturated aqueous solution of sodium bicarbonate (75 mL). After stirring for 10 minutes, dichloromethane was added and the layers were separated. The aqueous layer is extracted with dichloromethane and dried over magnesium sulfateOrganics, filtration and solvent removal in vacuo to give tert-butyl 3- (2,2, 2-trifluoroacetyl) azetidine-1-carboxylate (263mg, 92% yield) as a white oily solid by¹H-NMR showed it to be a mixture of ketone and hydrate.

And step 3: synthesis of tert-butyl 3- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) azetidine-1-carboxylate

To a 0 ℃ solution of 3- (2,2, 2-trifluoroacetyl) azetidine-1-carboxylic acid tert-butyl ester (1 eq) and trimethyl (trifluoromethyl) silane (1.4 eq) in tetrahydrofuran was added tetrabutylammonium fluoride (1.1 eq) as a 1M solution in tetrahydrofuran dropwise over the course of 5 min. The solution was immediately warmed to 23 ℃ and stirred for 2.5 days. Then, the solution was poured into ethyl acetate and 1N aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 ×). The organics were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-60% ethyl acetate gradient in hexanes) afforded tert-butyl 3- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) azetidine-1-carboxylate (24mg, 7% yield) as an oily solid.

And 4, step 4: synthesis of 2- (azetidin-3-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol

Tert-butyl 3- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) azetidine-1-carboxylate was stirred in trifluoroacetic acid and dichloromethane (1:2 ratio) for 1.5 h. The solution was then concentrated in vacuo to give 2- (azetidin-3-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol as a TFA salt.

And 5: synthesis of Compound I-357

The title compound was prepared according to general procedure B except 2- (azetidin-3-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (1.5 equivalents as TFA salt) was the amine reactant. The crude residue was dissolved in 1:1 dichloromethane and ether, and the solid was filtered off and washed with additional ether to give the desired compound, compound I-357 as a white solid (17mg, 64% yield).

¹H-NMR(400MHz,CD₃OD) delta 8.83(d,1H),8.27(d,1H),7.62(s,1H),7.35-7.30(m,1H),7.15-7.07(m,2H),7.00-6.96(m,2H),6.05(s,2H),4.82-4.70(m,4H),3.79 (quintuple, 1H).

Compound I-359

The compound is prepared in two steps

Step 1: synthesis of ester I-358

The title compound was prepared according to general procedure B except 1-aminomethylcyclopropanol (2 equivalents) was the amine reactant, no triethylamine was used and the contents were heated to 100 ℃ as a solution in dioxane/water (3:1) for 96 h. Ethyl acetate is the solvent used for the treatment. The crude material was first purified via silica gel chromatography with a 0-100% ethyl acetate/hexane gradient and then purified by reverse phase HPLC (water/acetonitrile containing 0.1% trifluoroacetic acid). With an excess of 10% NaHCO₃The water/acetonitrile fraction containing the product was treated (aq), concentrated to 5mL, then extracted with ethyl acetate to recover the neutral material, to give the desired compound, compound I-358 as a white solid (32mg, 28% yield).

¹H-NMR(400MHz,CDCl₃)δ8.42(d,1H),8.11(m,1H),7.24(s,1H),7.15(m,1H),6.99(m,1H),6.94(m,1H),6.85(m,1H),6.56(d,1H),5.93(s,2H),5.63(m,1H),4.77(m,1H),3.74(d,2H),0.86(m,2H),0.65(m,2H)。

Step 2: synthesis of Compound I-359

Compound I-358 was dissolved in tetrahydrofuran at room temperature and triethylamine (3 equivalents) and ethyl chloroformate (2 equivalents) were added successively. The contents were allowed to stir at room temperature for 1 h. The mixture was diluted with ethyl acetate, washed with water (3 ×), then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in tetrahydrofuran, treated with sodium borohydride (6 equivalents) and stirred for 1 h. The mixture was diluted with ethyl acetate, washed with water (3 ×), then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 10-80% ethyl acetate/hexanes gradient to give the desired compound, compound I-359 as a white solid (11mg, 76% yield).

¹H-NMR(400MHz,CDCl₃)δ8.41(d,1H),8.11(d,1H),7.28(s,1H),7.16(m,1H),7.00(m,1H),6.95(m,1H),6.87(m,1H),6.54(d,1H),5.93(s,2H),5.53(m,1H),4.61(m,1H),3.60(d,2H),3.35(d,2H),0.53(m,4H)。

Compound I-360

The title compound was prepared according to general procedure B except 1- (4-aminophenyl) cyclopropanecarboxylic acid (1 equivalent) was the amine reactant, 20 equivalents triethylamine was used, and the contents were heated to 100 ℃ as a solution in dioxane/water (3:1) for 18 h. Ethyl acetate is the solvent used for the treatment. The crude material was purified via silica gel chromatography using a 5-95% ethyl acetate/hexanes gradient to give the desired compound, compound I-360(11mg, 9% yield) as a white solid.

¹H-NMR (400MHz, acetone-d)₆)δ8.89(d,1H),8.81(br d,1H),8.30(d,1H),8.03(d,2H),7.48(s,1H),7.39(d,2H),7.30(m,1H),7.15(m,1H),7.10(m,1H),7.07(d,1H),7.05(m,1H),5.98(s,2H),1.53(m,2H),1.18(m,2H)。

Compound I-361

The title compound was synthesized in 3 steps:

step 1: synthesis of tert-butyl methyl (2-oxo-2- (phenylsulfonylamino) ethyl) carbamate

To a solution of 1, 1' -carbonyldiimidazole (1.2 eq) in dichloromethane was added 2- ((tert-butoxycarbonyl) (methyl) amino) acetic acid (1 eq). The mixture was stirred at 23 ℃ until gas evolution ceased. To this mixture was added benzenesulfonamide (3 equivalents) and DBU (1 equivalent). The mixture was stirred at 23 ℃ for 1 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried, filtered and evaporated to give a white solid. Purification via silica gel chromatography (0 to 80% ethyl acetate gradient in hexanes) afforded tert-butyl methyl (2-oxo-2- (phenylsulfonylamino) ethyl) carbamate (1.3g) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 7.91-7.95(m,2H),7.59-7.65(m,3H),3.86(s,2H),2.82-2.88(m,3H),1.20(s,9H)。

Step 2: synthesis of 2- (methylamino) -N- (phenylsulfonyl) acetamide hydrochloride

A mixture of methyl (2-oxo-2- (phenylsulphonylamino) ethyl) carbamic acid tert-butyl ester (1 eq) and HCl [ 4.0M in 1, 4-dioxane ] was stirred at 23 ℃ for 24 h. The mixture was concentrated to give 2- (methylamino) -N- (phenylsulfonyl) acetamide hydrochloride (3.2g) as a cream solid.

¹H NMR(500MHz,CD₃OD)δppm 8.04-8.07(m,2H),7.57-7.64(m,3H),3.88(s,2H),2.67(s,3H)。

And step 3: synthesis of Compound I-31

The title compound was prepared according to general procedure B except 2- (methylamino) -N- (phenylsulfonyl) acetamide hydrochloride was the amine reactant, 6 equivalents of triethylamine was used, and the contents were heated to 85 ℃ as a solution in dioxane/water (4:1) for 24 h. The mixture was cooled to 23 ℃ and diluted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, dried, filtered and evaporated to give a solid. The solid was purified by silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) to give the desired compound, compound I-361 as a light yellow solid (6.5mg, 14% yield for step 3).

¹H NMR(500MHz,CD₃OD)δppm 8.79(d,1H),8.12(d,1H),7.91-7.96(m,2H),7.43-7.49(m,1H),7.25-7.37(m,4H),7.03-7.14(m,2H),6.95(d,1H),6.85-6.91(m,1H),5.97(s,2H),4.30(s,2H),3.39(d,3H)。

Compound I-363

The title compound was prepared according to general procedure B, except that piperidine-4-sulfonic acid (2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in dioxane/water (1:1) for 2 h. During the work-up, ethyl acetate was used as extraction solvent. The organic layer was dried, filtered and concentrated in vacuo to give the desired compound, compound I-363(102mg, 69% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.12(d,1H),8.41(d,1H),7.72(s,1H),7.28-7.39(m,2H),7.18-7.27(m,1H),7.11(t,1H),6.85(t,1H),5.95(s,2H),4.65(d,2H),3.21(t,2H),2.61-2.72(m,1H),2.02-2.12(m,2H),1.52-1.70(m,2H)。

Compound I-364

The title compound was prepared according to general procedure B except that 4,5,6, 7-tetrahydroisoxazolo [5,4-c ] pyridin-3-ol (2 equivalents as the HCl salt) was the amine reactant, 4 equivalents of triethylamine were used, and the contents were heated to 70 ℃ as a solution in dioxane/water (3:1) for 2 h. During the work-up, ethyl acetate was used as extraction solvent. The organic layer was dried, filtered and concentrated in vacuo to give a solid, which was further washed with diethyl ether and dichloromethane to give the desired compound, compound I-364(46mg, 72% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 11.47(s,1H),9.10(d,1H),8.40(d,1H),7.62(s,1H),7.30-7.37(m,1H),7.27(d,1H),7.20-7.25(m,1H),7.11(t,1H),6.84(t,1H),5.91(s,2H),4.90(s,2H),3.98(t,2H),2.51-2.55(m,2H)。

Compound I-365

The title compound was prepared according to general procedure B except (1R,3S,4S) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid (2 equivalents as the HCl salt) was the amine reactant, 2.5 equivalents triethylamine was used, and the contents were heated to 60 ℃ for 24h, followed by 80 ℃ for 3 h. During the work-up, ethyl acetate was used as extraction solvent. The crude material was purified via silica gel chromatography with a 0-100% ethyl acetate/hexanes gradient to give a solid, which was further washed with diethyl ether and dichloromethane to give the desired compound, compound I-365 as a white solid (21mg, 16% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.78(d,1H),8.07-8.20(m,1H),7.23-7.35(m,2H),7.08-7.15(m,1H),7.04(t,1H),6.94(br.s.,1H),6.79-6.87(m,1H),5.92-6.01(m,2H),4.28-4.38(m,1H),2.85-2.97(m,1H),2.23(d,1H),1.72-1.98(m,4H),1.48-1.71(m,2H)。

Compound I-366

The title compound was prepared according to general procedure B, except that piperidine-4-sulfonamide (2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 75 ℃ as a solution in dioxane/water (3:1) for 2 h. The mixture was diluted with ethyl acetate and washed with 1N HCl solution. Compound I-366(64mg, 48% yield) was obtained as a white solid by collecting the insoluble solid and drying in vacuo to give the desired compound.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.35(d,1H),7.60(s,1H),7.31-7.37(m,1H),7.21-7.28(m,2H),7.11(t,1H),6.79-6.85(m,3H),5.91(s,2H),4.66(d,2H),3.24(ddt,1H),3.16(t,2H),2.13(d,2H),1.67(qd,2H)。

Compound I-367

The title compound was synthesized in 3 steps:

step 1: synthesis of 2- (1, 3-dioxoisoindolin-2-yl) -N-methylethylsulfonamide

To a solution of 2- (1, 3-dioxoisoindolin-2-yl) ethanesulfonyl chloride (1 eq) in THF was added methylamine [ 2.0M solution in THF ] (2 eq). The mixture was stirred at 23 ℃ for 1 h. The mixture was concentrated to give 2- (1, 3-dioxoisoindolin-2-yl) -N-methylethylsulfonamide (0.98g) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 7.79-7.92(m,4H),4.06-4.13(m,2H),3.42(t,2H),2.74(s,3H)。

Step 2: synthesis of 2-amino-N-methylethylsulfonamide

To a suspension of 2- (1, 3-dioxoisoindolin-2-yl) -N-methylethylsulfonamide (1 equivalent) in ethanol was added hydrazine monohydrate (1.5 equivalents). The mixture was heated to 75 ℃ for 2 h. The white precipitate formed was removed by filtration. The filtrate was concentrated in vacuo to give 2-amino-N-methylethylsulfonamide as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 3.20-3.24(m,2H),3.08-3.14(m,2H),2.71(s,3H)。

And step 3: synthesis of Compound I-367

The title compound was prepared according to general procedure B except 2-amino-N-methylethylsulfonamide (2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 65 ℃ for 2 days. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified via silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) to give the desired compound, compound I-367 as a cream solid (8.6mg, 14% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.76(d,1H),8.10(d,1H),7.49(s,1H),7.24-7.30(m,1H),7.07-7.13(m,1H),7.03(t,1H),6.87-6.90(m,1H),6.81(t,1H),5.96(s,2H),4.01(t,2H),3.42(t,2H),2.68-2.70(m,3H)。

Compound I-368

The title compound was prepared according to general procedure B except that N-methyltaurine (as sodium salt, 2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 65 ℃ as a solution in dioxane/water (3:1) for 24 h. Ethyl acetate was used as the treatment solvent. The organic layer was dried, filtered and evaporated to give a solid. The solid was collected by filtration and dried in vacuo to give the desired compound, compound I-368(31mg, 33% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.13(d,1H),8.40(d,1H),7.93(br.s.,1H),7.31-7.38(m,1H),7.21-7.27(m,1H),7.17(s,1H),7.12(t,1H),6.88(t,1H),5.96(s,2H),3.94-4.02(m,2H),3.38(d,3H),2.84-2.92(m,2H)。

Compound I-369

The title compound was prepared according to general procedure B except that cis-1-amino-1, 2,3, 4-tetrahydronaphthalene-2-carboxylic acid (2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 65 ℃ as a solution in dioxane/water (3:1) for 24 h. Ethyl acetate was used as the treatment solvent. The crude material was purified via silica gel chromatography using a 0-50% ethyl acetate/hexanes gradient to give the desired compound, compound I-369(7.0mg, 10% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.07-9.10(m,1H),8.22(d,1H),7.70(d,1H),7.57(s,1H),7.30-7.41(m,2H),7.08-7.24(m,6H),6.89(t,1H),5.91(s,2H),2.99(dt,1H),2.74-2.91(m,2H),2.28-2.37(m,1H),1.94-2.01(m,1H)。

Compound I-370

The title compound was prepared according to general procedure B except that 4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-3 (2H) -one (as the HCl salt, 3.2 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 65 ℃ as a solution in dioxane/water (1:1) for 24H. The mixture was diluted with ethyl acetate and extracted with 1N HCl solution. The aqueous layer was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried, filtered and evaporated to give the desired compound, compound I-370(83mg, 65% yield) as a light brown solid.

¹H NMR(500MHz,CDCl₃)δppm 8.38(d,1H),8.08-8.21(m,1H),7.22(s,1H),7.07-7.13(m,1H),6.91(t,1H),6.85(t,1H),6.73-6.78(m,1H),6.52(d,1H),5.85(s,2H),4.69(s,2H),3.83-3.91(m,2H),2.52(t,2H)。

Compound I-371

The title compound was prepared according to general procedure B except that cis-1-amino-2, 3-dihydro-1H-indene-2-carboxylic acid (2 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24H. The mixture was diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and concentrated in vacuo. The resulting solid was washed with a minimum amount of methanol to give the desired compound, compound I-371(11mg, 16% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H)8.25(d,1H)7.63(s,1H)7.29-7.39(m,3H)7.20-7.28(m,3H)7.09-7.19(m,2H)6.88(t,1H)6.22-6.29(m,1H)5.87-5.97(m,2H)3.67(q,1H)3.52(dd,1H)3.06(dd,1H)。

Compound I-372

The title compound was synthesized in 3 steps:

step 1: synthesis of methyl (2-oxo-2- (phenylsulfonylamino) ethyl) carbamic acid tert-butyl ester

To a suspension of 2- (((tert-butoxycarbonyl) amino) methyl) thiazole-4-carboxylic acid (1 eq) and methyl iodide (10 eq) in THF at 0 ℃ was added sodium hydride [ 60 wt% dispersion in mineral oil ] (10 eq). The mixture was stirred at 23 ℃ for 24 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil which was further purified via silica gel chromatography (0 to 50% ethyl acetate/hexanes gradient) to give 2- (((tert-butoxycarbonyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (217mg, 82% yield) as a red solid.

¹H NMR(500MHz,CDCl₃)δppm 8.26-8.34(m,1H),4.76(d,2H),3.00(d,3H),1.51(br.s,9H)。

Step 2: synthesis of ethyl 2- ((methylamino) methyl) thiazole-4-carboxylate hydrochloride

A mixture of 2- (((tert-butoxycarbonyl) (methyl) amino) methyl) thiazole-4-carboxylic acid (1 eq) and HCl solution [ 1.3M in ethanol ] (10 eq) was stirred at 23 ℃ for 24 h. The mixture was concentrated to give ethyl 2- ((methylamino) methyl) thiazole-4-carboxylate (as HCl salt, 222mg) as a yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.46(s,1H),4.63(s,2H),4.27-4.37(m,2H),2.80(s,3H),1.28-1.35(m,3H)。

And step 3: synthesis of Compound I-372

The title compound was prepared according to general procedure B except that ethyl 2- ((methylamino) methyl) thiazole-4-carboxylate (as the HCl salt, 2 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (4:1) for 24 h. The mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried, filtered and evaporated to give a solid which was purified via silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) to give the desired compound, compound I-372 as a pale yellow colloid (78mg, 77% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.45(d,1H),8.26(d,1H),8.12(s,1H),7.28(s,1H),7.17-7.23(m,1H),6.94-7.06(m,2H),6.86-6.92(m,1H),6.58(d,1H),5.97(s,2H),5.22(s,2H),4.44(q,2H),3.42(d,3H),1.42(t,3H)。

Compound I-373

A mixture of compound I-372(1 equivalent) and lithium hydroxide (10 equivalents) in a THF/water/methanol (1:1:1) mixture was stirred at 23 ℃ for 24 h. The mixture was concentrated in vacuo. The resulting solution was acidified to pH 1. The precipitate formed was collected by filtration and dried in vacuo to give the desired compound, compound I-373 as a white solid (38mg, 67% yield).

¹H NMR(400MHz,DMSO-d₆)δppm 13.05(s,1H),9.09(d,1H),8.36(t,2H),7.57(s,1H),7.30-7.37(m,1H),7.18-7.26(m,2H),7.11(t,1H),6.89(t,1H),5.89(s,2H),5.17(s,2H),3.32-3.39(m,3H)。

Compound I-374

A suspension of compound I-368(1 equivalent) in thionyl chloride (50 equivalents) was heated to reflux for 24 h. The mixture was cooled and concentrated in vacuo to give the intermediate sulfonyl chloride, 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) (methyl) amino) -ethanesulfonyl chloride (169mg) as a yellow solid. This material was then treated with ammonia [ 0.05M solution in 1, 4-dioxane ] (5 equivalents) and the mixture was allowed to stir at 23 ℃ for 24 h. The reaction was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 30% methanol gradient in dichloromethane) and recrystallized from methanol: dichloromethane mixture to give the desired compound, compound I-374(13mg, 8% yield) as a light yellow solid.

¹H NMR(400MHz,DMSO-d₆)δppm 9.10(d,1H)8.28(d,1H)7.58(s,1H)7.33(d,1H)7.19-7.25(m,1H)7.14(d,1H)7.08-7.13(m,2H)5.89(s,2H)4.00-4.06(m,2H)3.36-3.41(m,2H)3.28(d,3H)。

Compound I-375

The title compound was prepared in 3 steps:

step 1: synthesis of 2- (((tert-butoxycarbonyl) (methyl) amino) methyl) oxazole-4-carboxylic acid

To a cold suspension of 2- (((tert-butoxycarbonyl) amino) methyl) oxazole-4-carboxylic acid (1 eq) and methyl iodide (10 eq) in THF at 0 ℃ was added sodium hydride [ 60 wt% dispersion in mineral oil ] (10 eq). The mixture was allowed to warm to 23 ℃ and stirred for 24 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography (0 to 100% ethyl acetate in hexanes gradient) to give 2- (((tert-butoxycarbonyl) (methyl) amino) methyl) oxazole-4-carboxylic acid as a yellow oil (215mg, 81% yield).

¹H NMR(400MHz,CDCl₃)δppm 8.27(s,1H),4.52-4.69(m,2H),2.93(d,3H),1.37-1.53(m,9H)。

Step 2: synthesis of 2- ((methylamino) methyl) oxazole-4-carboxylic acid TFA salt

A mixture of 2- (((tert-butoxycarbonyl) (methyl) amino) methyl) oxazole-4-carboxylic acid (1 eq) and TFA (10 eq) in DCM was stirred at 23 ℃ for 1 h. The mixture was concentrated to give 2- ((methylamino) methyl) oxazole-4-carboxylic acid TFA salt (237mg) as a clear oil.

¹H NMR(500MHz,CD₃OD)δppm 8.62-8.64(m,1H),4.49(s,2H),2.86(s,3H)。

And step 3: synthesis of Compound I-375

The title compound was prepared according to general procedure B except that 2- ((methylamino) methyl) oxazole-4-carboxylic acid (as TFA salt, 4 equivalents) was the amine reactant, 8 equivalents triethylamine was used and the contents were heated to 80 ℃ as a solution in dioxane/water (4:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The crude oil obtained after treatment was treated with ether and the resulting precipitated solid was collected by filtration and dried in vacuo to give the desired compound, compound I-375 as a white solid (68% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.73(s,1H),8.36(d,1H),7.50(s,1H),7.28-7.36(m,1H),7.16-7.26(m,2H),7.10(t,1H),6.85(t,1H),5.88(s,2H),5.07(s,2H),3.35-3.40(m,3H)。

Compound I-376

The title compound was synthesized in 2 steps:

step 1: synthesis of 1-methyl-2- ((methylamino) methyl) -1H-imidazole-4-carboxylic acid hydrochloride

To a suspension of 2- (((tert-butoxycarbonyl) amino) methyl) -1H-imidazole-4-carboxylic acid (1 eq) and methyl iodide (10 eq) in THF at 0 ℃ was added sodium hydride [ 60 wt% dispersion in mineral oil ] (10 eq). The mixture was stirred at 23 ℃ for 24 h. The mixture was treated with HCl solution [ 4.0M solution in 1, 4-dioxane ]. The mixture was concentrated in vacuo and the resulting solid was suspended in diethyl ether. The precipitate was collected by filtration and dried in vacuo to give 1-methyl-2- ((methylamino) methyl) -1H-imidazole-4-carboxylic acid hydrochloride as a yellow solid (80mg, 38% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.34(br.s.,2H),7.91(s,1H),4.29(t,2H),3.71(s,3H),2.64(t,3H)。

Step 2: synthesis of Compound I-376

The title compound was prepared according to general procedure B except that 1-methyl-2- ((methylamino) methyl) -1H-imidazole-4-carboxylic acid (as HCl salt, 3 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (4:1) for 24H. The mixture was cooled to 23 ℃, diluted in ethyl acetate and washed with 1N HCl solution. The resulting precipitate was collected by filtration and dried in vacuo to give the desired compound, compound I-376(26mg, 37% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.39(d,1H),8.11(br.s.,1H),7.56(s,1H),7.28-7.39(m,1H),7.18-7.26(m,2H),7.07-7.14(m,1H),6.82(t,1H),5.91(s,2H),5.08(s,2H),3.85(s,3H),3.41(d,3H)。

Compound I-377

The title compound was prepared according to general procedure B, except 3- (2-aminoethyl) benzoic acid was the amine reactant, 4 equivalents of triethylamine were used, and the contents were heated to 90 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The crude material was purified via silica gel chromatography using a 0-80% ethyl acetate/hexanes gradient to give the desired compound, compound I-377(25mg, 31% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.44(d,1H),8.17(d,1H),8.04(s,1H),7.98(d,1H),7.50(d,1H),7.40-7.45(m,1H),7.37(s,1H),7.14-7.21(m,1H),7.00(t,1H),6.92-6.97(m,1H),6.85-6.92(m,1H),6.64(d,1H),5.99(s,2H),5.24-5.31(m,1H),3.90-3.97(m,2H),3.08(t,2H)。

Compound I-378

The title compound was prepared according to general procedure B except that 5-hydroxy-1, 2,3, 6-tetrahydropyridine-4-carboxylate (as TFA salt, 1 equivalent) was the amine reactant, 3 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The crude material was purified via silica gel chromatography using a 0-30% ethyl acetate/hexanes gradient to give the desired compound, compound I-378(68mg, 15% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 12.17(s,1H),8.46(d,1H),8.23(d,1H),7.31(s,1H),7.16-7.22(m,1H),7.02(t,1H),6.96(t,1H),6.84(t,1H),6.62(d,1H),5.98(s,2H),4.47-4.50(m,2H),4.26(q,2H),3.94(t,2H),2.51(t,2H),1.33(t,3H)。

Compound I-379

The title compound was prepared according to general procedure B except that (1SR,2SR,3RS,4RS) -3-aminobicyclo [2.2.1] heptane-2-carboxylic acid (as HCl salt, racemate, 3 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in dioxane/water (3:1) for 24 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using a 0-80% ethyl acetate/hexanes gradient to give the desired compound, compound I-379(47mg, 36% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.76-8.79(m,1H),8.07(d,1H),7.42(s,1H),7.25-7.32(m,1H),7.11(ddd,1H),7.05(td,1H),6.92(d,1H),6.83(td,1H),5.97(s,2H),4.58-4.66(m,1H),3.13(ddd,1H),2.83(br.s.,1H),2.67(br.s.,1H),1.74(d,1H),1.65-1.71(m,1H),1.58-1.64(m,1H),1.49-1.57(m,2H),1.41-1.49(m,1H)。

Compound I-380

The title compound was prepared according to general procedure B except (1S,3R) -3-aminocyclohexanecarboxylic acid (98% ee, 4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-380 as a yellow solid (70mg, 55% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.81(d,1H),8.18(d,1H),7.59(s,1H),7.29(q,1H),7.07-7.14(m,1H),7.05(t,1H),6.98(d,1H),6.92(t,1H),6.00(s,2H),4.46(t,1H),2.59(t,1H),2.31(d,1H),2.04(d,2H),1.95(d,1H),1.51-1.65(m,2H),1.35-1.51(m,2H)。

Compound I-381

The title compound was synthesized in 3 steps:

step 1: synthesis of 2- (1, 3-dioxoisoindolin-2-yl) -N- (2,2, 2-trifluoroethyl) ethanesulfonamide

A mixture of 2- [2- (chlorosulfonyl) ethyl ] benzo [ c ] oxazoline-1, 3-dione (1 eq), 2,2, 2-trifluoroethylamine hydrochloride (3 eq) and triethylamine (6 eq) in dichloromethane was stirred at 23 ℃ for 24 h. The mixture was diluted in dichloromethane and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give a white solid. The solid was purified via silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give 2- (1, 3-dioxoisoindolin-2-yl) -N- (2,2, 2-trifluoroethyl) ethanesulfonamide (370mg, 30% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 7.84-7.92(m,4H),4.05-4.09(m,2H),3.97-4.01(m,2H),3.32(s,2H)。

Step 2: synthesis of 2-amino-N- (2,2, 2-trifluoroethyl) ethanesulfonamide

A mixture of 2- (1, 3-dioxoisoindolin-2-yl) -N- (2,2, 2-trifluoroethyl) ethanesulfonamide (1 eq) and hydrazine monohydrate (1 eq) in ethanol was stirred at 80 ℃ for 24 h. The mixture was cooled to 23 ℃ and concentrated in vacuo. The resulting residue was treated with a minimum amount of methanol. The precipitate was collected by filtration and dried in vacuo to give a white solid containing 2-amino-N- (2,2, 2-trifluoroethyl) ethanesulfonamide (136 mg). The material was used for the next reaction without further purification.

And step 3: synthesis of Compound I-381

The title compound was prepared according to general procedure B except 2-amino-N- (2,2, 2-trifluoroethyl) ethanesulfonamide (1 equivalent) was the amine reactant, 3 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. The mixture was cooled, diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (0 to 70% ethyl acetate gradient in hexanes) to give the desired compound, compound I-xxx as a white solid (28mg, 14% yield, via steps 2 and 3).

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.25(d,2H),7.55(s,1H),7.30-7.37(m,1H),7.19-7.26(m,1H),7.15(d,1H),7.10(t,1H),6.82(t,1H),5.89(s,2H),3.87-3.82(m,4H),3.45(t,2H)。

Compound I-382

The title compound was synthesized in 2 steps:

step 1: synthesis of 2-hydroxy-N-2-dimethyl-3- (methylamino) propanamide

In a sealed vial, a mixture of 2-methylglycidyl ester (1 equivalent) and methylamine [ 33 wt% in THF ] (10 equivalents) was heated to 80 ℃ for 24 h. The mixture was concentrated in vacuo to give 2-hydroxy-N-2-dimethyl-3- (methylamino) propionamide (1.7g, 100% yield) as a clear oil.

¹H NMR(500MHz,CDCl₃)δppm 3.67-3.76(m,1H),3.22-3.29(m,1H),2.79-2.82(m,3H),2.40-2.43(m,3H),1.31-1.33(m,3H)。

Step 2: synthesis of Compound I-382

The title compound was prepared according to general procedure B except 2-hydroxy-N-2-dimethyl-3- (methylamino) propionamide (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 4 h. During the work-up, ethyl acetate was used as solvent. The resulting solid was treated with a minimum amount of methanol and diethyl ether, collected by filtration, and dried in vacuo to give the desired compound, compound I-382 as a white solid (67mg, 52% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.09-9.12(m,1H),8.23(d,1H),7.87(q,1H),7.54(s,1H),7.30-7.37(m,1H),7.18-7.26(m,1H),7.11(td,1H),6.88(t,1H),5.86-5.92(m,2H),4.12(d,1H),3.68(d,1H),3.22(s,3H),2.55(d,3H),1.27(s,3H)。

Compound I-383

The title compound was synthesized in 5 steps:

step 1: synthesis of benzyl (3-hydroxy-2, 2-dimethylpropyl) carbamate

To a cold mixture of 3-amino-2, 2-dimethyl-1-propanol (1 equivalent) and triethylamine (1 equivalent) in dichloromethane was added benzyl chloroformate (1 equivalent). The mixture was stirred at 23 ℃ for 30min, then diluted in dichloromethane and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give benzyl (3-hydroxy-2, 2-dimethylpropyl) carbamate as a white solid (1.9g, 86% yield).

¹H NMR(500MHz,CDCl₃)δppm 7.34-7.45(m,5H),5.14(s,2H),3.25(d,2H),3.08(d,2H),0.89(s,6H)。

Step 2: synthesis of 3- (((benzyloxy) carbonyl) amino) -2, 2-dimethylpropionic acid

To (3-hydroxy-2, 2-dimethylpropyl) carbamic acid benzyl ester (1 equivalent) in CCl₄Water and suspension in acetonitrile (1:1:1 mixture) sodium periodate (3 equivalents) and ruthenium (III) chloride (0.05 equivalents) were added. The mixture was stirred at 23 ℃ for 24 h. To this mixture was added an additional amount of sodium periodate (3 equivalents) and ruthenium (III) chloride (0.05 equivalents), and the contents were stirred at 23 ℃ for 3 days. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated sodium carbonate solution, then the aqueous layer was acidified to pH 1 and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) to give 3- (((benzyloxy) carbonyl) amino) -2, 2-dimethylpropionic acid as a red oil (943mg, 45% yield).

¹H NMR(500MHz,CDCl₃)δppm 7.35-7.42(m,5H),5.12(s,2H),3.35(d,2H),1.23-1.28(m,6H)。

And step 3: synthesis of 3- (((benzyloxy) carbonyl) (methyl) amino) -2, 2-dimethylpropionic acid

To a cold solution of 3- (((benzyloxy) carbonyl) amino) -2, 2-dimethylpropionic acid (1 eq) in THF was added sodium hydride [ 60 wt% dispersion in mineral oil ] (10 eq). The mixture was stirred at 0 ℃ for 30 min. To this mixture was added methyl iodide (10 equivalents). The mixture was allowed to warm to 23 ℃ and stirred for 24 h. The mixture was poured onto ice and acidified to pH 1. The mixture was extracted with diethyl ether, and the organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 80% ethyl acetate gradient in hexanes) to give 3- (((benzyloxy) carbonyl) (methyl) amino) -2, 2-dimethylpropionic acid as a clear oil (686mg, 69% yield).

¹H NMR(500MHz,CDCl₃)δppm 7.36-7.39(m,4H),7.32-7.35(m,1H),5.13(s,2H),3.53-3.60(m,2H),2.96(br.s.,3H),1.18-1.26(m,6H)。

And 4, step 4: synthesis of 2, 2-dimethyl-3- (methylamino) propanoic acid hydrochloride

A solution of 3- (((benzyloxy) carbonyl) (methyl) amino) -2, 2-dimethylpropionic acid (1 eq) in methanol was used, hydrogenated H-cube (0.7ml/min, catalyst: 10% Pd/C,70 ℃). The resulting mixture was treated with HCl solution [ 1.25M in ethanol ] and concentrated in vacuo to give 2, 2-dimethyl-3- (methylamino) propanoic acid hydrochloride (569mg, 100% yield) as a clear oil.

¹H NMR(500MHz,CD₃OD)δppm 3.09(s,2H),2.69-2.74(m,3H),1.25-1.31(m,6H)。

And 5: synthesis of Compound I-383

The title compound was prepared according to general procedure B except 2, 2-dimethyl-3- (methylamino) propionic acid (as HCl salt, 4 equivalents) was the amine reactant, 8 equivalents triethylamine was used and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The crude material was purified via silica gel chromatography (0 to 60% ethyl acetate gradient in hexanes) to give the desired compound, compound I-383 as a white solid (38mg, 30% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 12.51(br.s.,1H),9.10(d,1H),8.25(d,1H),7.49(s,1H),7.30-7.37(m,1H),7.18-7.25(m,2H),7.11(td,1H),6.92(t,1H),5.88(s,2H),3.96(s,2H),3.33(s,3H),1.13(s,6H)。

Compound I-384

The title compound was prepared according to general procedure B except that (1RS,2SR,3RS,4SR) -3-amino-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid (i.e., racemate, 4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The resulting solid was washed with methanol and ether, collected by filtration, and dried in vacuo to give the desired compound, compound I-384(43mg, 33% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 12.40(br.s.,1H),9.10(d,1H),8.23(d,1H),7.54(s,1H),7.30-7.36(m,1H),7.20-7.25(m,2H),7.09-7.13(m,1H),6.94(d,1H),6.83-6.87(m,1H),5.89(s,2H),4.86(t,1H),4.72(d,1H),4.47(d,1H),3.10(d,1H),1.53-1.68(m,4H)。

Compound I-436

The title compound was prepared according to general procedure B, except 2-aminoethanesulfonamide was the amine reactant, 3 equivalents of triethylamine were used and the contents were heated to 65 ℃ as a solution in dioxane for 24 h. The mixture was diluted in ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified via silica gel chromatography (0-100% ethyl acetate gradient in hexanes) to give the desired compound, compound I-436(26mg, 42% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.77(d,1H),8.12(d,1H),7.50(s,1H),7.25-7.32(m,1H),7.03-7.14(m,2H),6.90(d,1H),6.82-6.88(m,1H),5.98(s,2H),4.07-4.15(m,5H),3.47(t,2H)。

Compound I-385

To a solution of acetic acid (10 equiv) in DMF was added CDI (10 equiv). The mixture was stirred at 45 ℃ for 30 min. To this mixture was added compound I-436 and DBU (10 equivalents). The mixture was stirred at 23 ℃ for 3 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (0 to 10% methanol gradient in dichloromethane) to give the desired compound, compound I-385(8.2mg, 25% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.24(d,1H),7.55(s,1H),7.30-7.37(m,1H),7.17-7.26(m,2H),7.11(t,1H),6.86(t,1H),5.90(s,2H),3.75-3.87(m,4H),1.99(s,3H)。

Compound I-387

The title compound was synthesized in 3 steps:

step 1: synthesis of tert-butyl (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) carbamate (Compound I-21)

The intermediate was prepared according to general procedure B, except that 3- (tert-butoxycarbonylamino) azetidine was the amine reactant, 3 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and concentrated in vacuo to give the desired intermediate, tert-butyl (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) carbamate (480mg, 100% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.09(d,1H),8.28(d,1H),7.65(d,1H),7.53(s,1H),7.29-7.35(m,1H),7.20-7.25(m,2H),7.08-7.12(m,1H),6.81(t,1H),5.91(s,2H),4.49(br.s.,3H),4.12(br.s.,2H),1.40(s,9H)。

Step 2: synthesis of 1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-amine (Compound I-40)

A mixture of tert-butyl (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) carbamate (1 eq) and TFA (10 eq) in dichloromethane was stirred at 23 ℃ for 24H. The mixture was concentrated in vacuo. The resulting oil was treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The precipitate formed was collected and dried in vacuo. The organic layer was also dried, filtered and evaporated to give 1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-amine as a white solid (116mg (combined), 36% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.81-8.83(m,1H)8.32(d,1H)7.52-7.55(m,1H)7.27-7.34(m,1H)7.02-7.14(m,2H)6.89-6.95(m,2H)6.00(s,2H)4.84-4.88(m,2H)4.55(d,2H)4.35-4.42(m,1H)。

And step 3: synthesis of Compound I-387

To a white suspension containing 1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-amine (1 equivalent) and pyridine (10 equivalents) in THF was added trifluoromethanesulfonic anhydride (2 equivalents). The mixture was stirred at 23 ℃ for 30 min. The mixture was diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 80% ethyl acetate gradient in hexanes) to give the desired compound, compound I-387(61mg, 48% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 10.10(d,1H),9.08(d,1H),8.30(d,1H),7.52(s,1H),7.30-7.36(m,1H),7.16-7.27(m,2H),7.10(t,1H),6.81(t,1H),5.90(s,2H),4.71-4.83(m,1H),4.52-4.63(m,2H),4.27(dd,2H)。

Compound I-388

To a cold suspension of 1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-amine (generated in step 2 of the procedure for compound I-387, 1 equivalent) and pyridine (4 equivalents) in dichloromethane at-78 ℃ was added trifluoromethanesulfonic anhydride (2 equivalents). The mixture was stirred at-78 ℃ for 2 h. Then, it was removed from the dry ice-acetone bath and warmed to 23 ℃. Stirring was continued for 1h at 23 ℃. The mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) and the isolated material was recrystallized from a mixture of ether and methanol to give the desired compound, compound I-388(90mg, 19% yield) as a light yellow solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.35(br.s.,1H),7.57(br.s.,1H),7.31-7.37(m,1H),7.19-7.28(m,2H),7.11(t,1H),6.82(t,1H),5.92(s,2H),4.67(br.s.,2H),4.61(br.s.,1H),4.22(br.s.,2H)。

Compound I-389

The title compound was synthesized in 2 steps:

step 1: synthesis of 3-amino-2-hydroxy-2-methylpropanamide

A mixture of ammonia [ 7M in methanol ] (20 equivalents) and methyl 2-methylglycidyl ester (1 equivalent) was stirred in a sealed vial at 80 ℃ for 24 h. The mixture was concentrated in vacuo to give 3-amino-2-hydroxy-2-methylpropanamide (731mg, 100% yield) as a clear oil which turned into a white solid on standing at 23 ℃.

¹H NMR(500MHz,CD₃OD)δppm 2.90-2.96(m,1H)2.60-2.66(m,1H)1.32-1.35(m,3H)。

Step 2: synthesis of Compound I-389

The title compound was prepared according to general procedure B except 3-amino-2-hydroxy-2-methylpropanamide (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. The mixture was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified by silica gel chromatography (0 to 5% methanol gradient in dichloromethane) to give the desired compound, compound I-389(78mg, 25% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 8.23(d,1H),7.50(s,1H),7.30-7.35(m,2H),7.27(t,1H),7.25-7.29(m,1H),7.20-7.24(m,3H),7.10(td,1H),6.86(t,1H),5.94(s,1H),5.89(s,2H),3.75(dd,1H),3.59(dd,1H),1.28(s,3H)。

Compound I-390

The title compound was prepared according to general procedure B, except that tert-butyl N- (2-aminoethyl) carbamate (4 equivalents) was the amine reactant, 4 equivalents of triethylamine was used, and the contents were heated to 85 ℃ as a solution in dioxane/water (3:1) for 3 h. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and concentrated in vacuo to give the desired compound, compound I-390 as a white solid (200mg, 75% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.13(s,1H),8.30(d,1H),7.71(s,1H),7.31-7.37(m,1H),7.19-7.26(m,2H),7.11(t,1H),6.98(t,1H),6.86(t,1H),5.92(s,2H),3.50-3.59(m,3H),3.25(q,2H),1.31-1.37(m,9H)。

Compound I-391

A mixture of compound I-390(1 eq) and HCl [ 4.0M in 1, 4-dioxane ] (50 eq) was stirred at 23 ℃ for 24 h. The mixture was concentrated in vacuo to give the desired compound, compound I-391 (as HCl salt, 157mg, 100% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.11(s,1H),8.31(br.s.,1H),7.73(br.s.,1H),7.26-7.38(m,2H),7.21-7.26(m,1H),7.11(t,1H),6.83(t,1H),5.91(s,2H),3.74(br.s.,2H),3.07-3.15(m,2H)。

Compound I-392 a mixture containing compound I-391(1 equivalent), DBU (2.0 equivalents), triethylamine (2 equivalents) and N-phenyl-bis (trifluoromethanesulfonimide) (1.2 equivalents) in acetonitrile was stirred at 23 ℃ for 24 h. The mixture was concentrated in vacuo. The resulting residue was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (gradient of 0 to 100% ethyl acetate in hexanes). The purified material was recrystallized to give the desired compound, compound I-392 as a white solid (123mg, 19% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.56(s,1H),9.11(d,1H),8.22(d,1H),7.87(t,1H),7.51(s,1H),7.30-7.35(m,1H),7.20-7.24(m,1H),7.08-7.13(m,2H),6.83-6.87(m,1H),5.89(s,2H),3.60(q,2H),3.46(d,2H)。

Compound I-393

The title compound was synthesized in 3 steps:

step 1: synthesis of methyl 2-hydroxy-2-methyl-3- (methylamino) propionate

A mixture of methylamine [ 2.0M in THF ] (1.3 equivalents) and 2-methylglycidyl ester (1 equivalent) in ethanol was heated to 80 ℃ for 24 h. The mixture was concentrated to give methyl 2-hydroxy-2-methyl-3- (methylamino) propionate (2.26g) as a clear oil. The mixture was taken to the next step without further purification.

Step 2: synthesis of 2-hydroxy-2-methyl-3- (methylamino) propanamide

A mixture of methyl 2-hydroxy-2-methyl-3- (methylamino) propionate (1 eq) and ammonia [ 7.0M in methanol ] (5 eq) was heated to 85 ℃ in a sealed vial for 24 h. The mixture was concentrated to give 2-hydroxy-2-methyl-3- (methylamino) propionamide as a viscous oil. The material was used for the next reaction without further purification.

And step 3: synthesis of Compound I-393

The title compound was prepared according to general procedure B except 2-hydroxy-2-methyl-3- (methylamino) propionamide (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 85 ℃ as a solution in dioxane/water (3:1) for 24 h. The mixture was cooled to 23 ℃ and the white precipitate formed was collected by filtration, washed with ether and dried in vacuo to give the desired compound, compound I-393 as a white solid (45mg, 11% yield, via step 3).

¹H NMR(500MHz,DMSO-d₆)δppm 9.09(d,1H),8.21(d,1H),7.52(s,1H),7.27-7.36(m,2H),7.19-7.26(m,1H),7.10(t,1H),6.88(t,1H),5.88(s,2H),4.11(d,1H),3.72(d,1H),3.26(d,3H),1.25(s,3H)。

Compound I-394

The title compound was synthesized in 3 steps:

step 1: synthesis of tert-butyl 3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) azetidine-1-carboxylate

The intermediate was prepared according to general procedure B, except that tert-butyl 3-aminoazetidine-1-carboxylate (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and evaporated to give tert-butyl 3- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) azetidine-1-carboxylate (505mg, 100% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.45(br.s.,1H),8.36(d,1H),8.27(d,1H),7.53-7.57(m,1H),7.30-7.37(m,1H),7.19-7.28(m,1H),7.11(t,1H),6.83-6.91(m,1H),5.90(s,2H),4.81-4.90(m,1H),4.21(br.s.,2H),3.92(dd,2H),1.36-1.41(m,9H)。

Step 2: synthesis of N- (azetidin-3-yl) -5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine hydrochloride

A mixture of tert-butyl 3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) azetidine-1-carboxylate (1 eq) and hydrogen chloride [ 4.0M in 1, 4-dioxane ] (10 eq) was stirred at 23 ℃ for 4H. The mixture was concentrated in vacuo to give N- (azetidin-3-yl) -5-fluoro-2- (1- (2-fluorobenzyl) 5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (450 mg, 100% yield as HCl salt) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.13-9.16(m,1H),8.40-8.49(m,1H),7.62-7.70(m,1H),7.32-7.39(m,1H),7.28(dd,1H),7.21-7.25(m,1H),7.12(td,1H),6.89(t,1H),5.93(s,2H),4.95-5.02(m,1H),4.26-4.35(m,3H),4.17-4.25(m,2H)。

And step 3: synthesis of Compound I-394

To a cold mixture of N- (azetidin-3-yl) -5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine hydrochloride (1 eq), triethylamine (3 eq) and pyridine (245 μ l,3 eq) in dichloromethane at-78 ℃ was added trifluoromethanesulfonic anhydride (4 eq). The mixture was stirred at-78 ℃ for 2h, after which it was allowed to warm up to 23 ℃. The mixture was then treated with 1N HCl solution and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography (0 to 30% ethyl acetate gradient in hexanes) to give the desired compound, compound I-394 as a white solid (90mg, 16% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),8.32(d,1H),7.62(s,1H),7.29-7.34(m,1H),7.05-7.13(m,2H),6.96-7.00(m,2H),6.03(s,2H),4.98(br.s.,2H),4.74-4.83(m,1H),4.53(br.s.,2H)。

Compound I-395

The title compound was prepared following general procedure B, except (1R,2S) - (+) -cis-1-amino-2-indanol (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 3 h. During the work-up, ethyl acetate was used as solvent. The crude material was purified via silica gel chromatography using a 0-50% ethyl acetate/hexanes gradient to give the desired compound, compound I-395 as a cream solid (4mg, 27% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.07(d,1H),8.28(d,1H),7.55(s,1H),7.30-7.37(m,2H),7.26-7.29(m,1H),7.13-7.25(m,5H),7.10(td,1H),6.80-6.87(m,1H),5.89(s,2H),5.75(dd,1H),5.27(d,1H),4.60(d,1H),3.15(dd,1H),2.93(dd,1H)。

Compound I-396

The title compound was prepared according to general procedure B, except that 3- (trifluoromethyl) azetidin-3-ol (3 equivalents) was the amine reactant, 3 equivalents triethylamine was used and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 3 h. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and concentrated in vacuo to give a solid, which was washed with a minimum amount of methanol and diethyl ether and dried in vacuo to give the desired compound, compound I-396 as a white solid (57mg, 45% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.09(d,1H),8.37(d,1H),7.57(s,2H),7.30-7.36(m,1H),7.19-7.26(m,2H),7.10(td,1H),6.82(t,1H),5.91(s,2H),4.52(d,2H),4.30(d,2H)。

Compound I-397

The title compound was prepared according to general procedure B except that 4- (aminomethyl) tetrahydro-2H-pyran-4-ol (3 equivalents) was the amine reactant, 3 equivalents of triethylamine was used and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24H. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and concentrated in vacuo to give the desired compound, compound I-397(30mg, 24% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.80(d,1H),8.20(d,1H),7.57(s,1H),7.24-7.32(m,1H),7.02-7.13(m,2H),6.87-6.97(m,2H),5.99(s,2H),3.74-3.80(m,6H),1.76-1.85(m,2H),1.59(d,2H)。

Compound I-398

The title compound was prepared according to general procedure B except 2-amino-4, 4-difluorobutanoic acid (3 equivalents) was the amine reactant, 3 equivalents triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (4:1) for 24 h. During the work-up, ethyl acetate was used as solvent. The organic layer was dried, filtered and concentrated in vacuo to give a solid, which was washed with a minimum amount of methanol and diethyl ether and dried in vacuo to give the desired compound, compound I-398(123mg, 52% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.29(d,1H),8.12(d,1H),7.42(s,1H),7.32(d,1H),7.18-7.24(m,1H),7.16(d,1H),7.10(t,1H),6.85(t,1H),6.09-6.37(m,2H),5.87(s,2H),4.85(d,1H),4.04(s,1H)。

Compound I-399

To a suspension of compound I-398(1 eq) in THF was added lithium aluminum hydride [1.0M solution in THF ] (3 eq). The mixture was stirred at 23 ℃ for a further 24 h. The mixture was quenched with water, followed by 15% NaOH solution, followed by water. The mixture was diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (0 to 100% ethyl acetate gradient in hexanes) to give the desired compound, compound I-399 as a white solid (23mg, 12% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.75(d,1H),8.08(d,1H),7.43(s,1H),7.23-7.30(m,1H),7.06-7.12(m,1H),7.03(t,1H),6.87-6.89(m,1H),6.81(t,1H),6.05-6.21(m,1H),5.93-5.98(m,2H),4.71(dq,1H),3.63-3.75(m,2H),2.18-2.35(m,2H)。

Compound I-400

A mixture of 2, 2-bis (trifluoromethyl) -2-hydroxyacetic acid (1.5 eq) and CDI (1.5 eq) in THF was heated to reflux for 2 h. To this mixture was added one part of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate previously described in patent application publication WO2012/3405a 1) (1 equivalent). The mixture was heated to reflux for 3 h. Then, it was cooled to 23 ℃, diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (0 to 80% ethyl acetate gradient in hexanes) to give the desired compound, compound I-400 as a white solid (111mg, 35% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.79-8.82(m,1H),8.75-8.77(m,1H),8.07-8.10(m,1H),7.54-7.56(m,1H),7.22-7.31(m,1H),6.99-7.12(m,2H),6.86-6.93(m,2H),5.95-6.00(m,2H)。

Compound I-401

The title compound was synthesized in 2 steps.

Step 1: synthesis of (S) -4- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -5-methoxy-5-oxopentanoic acid

The intermediate was prepared according to general procedure B, except that methyl L-glutamate (4 equivalents) was the amine reactant, 4 equivalents of triethylamine was used, and the contents were heated to 80 ℃ as a solution in dioxane/water (3:1) for 24 h. The mixture was concentrated in vacuo. The resulting solid was washed with ether and water, and collected by filtration and dried in vacuo to give (S) -4- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -5-methoxy-5-oxopentanoic acid (274mg, 69% yield) as a yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.76-8.78(m,1H)8.15(d,1H)7.37(s,1H)7.23-7.31(m,2H)6.99-7.13(m,2H)6.84(t,1H)5.94-5.99(m,2H)3.73(s,1H)3.34(s,3H)2.29-2.43(m,2H)2.12-2.24(m,2H)。

Step 2: synthesis of Compound I-401

To a suspension of (S) -4- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -5-methoxy-5-oxopentanoic acid (1 eq) in THF was added oxalyl chloride (1.5 eq) and one drop of DMF. The mixture was stirred at 23 ℃ for 30 min. Then, it was heated to reflux for 30 min. The mixture was cooled to 23 ℃, diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography (0 to 50% ethyl acetate gradient in hexanes) to give the desired compound, compound I-401 as a light yellow solid (81mg, 33% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.76-8.78(m,1H),8.71-8.74(m,1H),7.32-7.35(m,1H),7.23-7.30(m,1H),7.06-7.12(m,1H),7.00-7.05(m,1H),6.81-6.90(m,2H),5.94(s,2H),5.10(dd,1H),3.75(s,3H),2.59-2.80(m,3H),2.23-2.33(m,1H)。

Compound I-403

The title compound was prepared according to general procedure B except 2-amino-3, 3, 3-trifluoropropionic acid (3 equivalents) was the amine reactant, 3 equivalents triethylamine was used, and the contents were heated to 70 ℃ as a solution in dioxane/water (3:1) for 24 h. During the treatment, ethyl acetate was used as a solvent. The organic layer was dried, filtered and concentrated in vacuo to give a solid, which was washed with a minimum amount of methanol and diethyl ether and dried in vacuo to give the desired compound, compound I-403 as a yellow solid (71mg, 17% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.76(d,1H),8.27(d,1H),7.48-7.51(m,1H),7.24-7.31(m,1H),7.07-7.13(m,1H),7.00-7.06(m,1H),6.92(d,1H),6.80(t,1H),6.10-6.16(m,1H),5.98(s,2H)。

Compound I-404

To a suspension of compound I-403(1 equivalent) in THF was added lithium aluminum hydride [1.0M solution in THF ] (2 equivalents). The mixture was stirred at 23 ℃ for 1 h. The mixture was quenched with water, followed by 15% NaOH solution, followed by water. The mixture was diluted with ethyl acetate and washed with 1n hcl solution. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified via silica gel chromatography (0 to 50% ethyl acetate gradient in hexanes) to give the desired compound, compound I-404 as a white solid (19mg, 12% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.75-8.77(m,1H),8.21(d,1H),7.46-7.48(m,1H),7.24-7.31(m,1H),7.06-7.14(m,1H),7.03(t,1H),6.89-6.94(m,1H),6.79(t,1H),5.97(d,2H),5.47-5.54(m,1H),3.87-4.01(m,2H)。

Compound I-405

The title compound was synthesized in 3 steps.

Step 1: synthesis of 2- (trifluoromethyl) oxirane-2-carboxamide

To a solution of 2- (bromomethyl) -3,3, 3-trifluoro-2-hydroxypropionamide (1 eq) in acetone was added potassium carbonate (2 eq). The mixture was heated to reflux for 2 h. The mixture was concentrated in vacuo. The resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to give 2- (trifluoromethyl) oxirane-2-carboxamide as a yellow gum (1.44g, 76% yield).

¹H NMR(500MHz,CD₃OD)δppm 3.17(dd,2H)。

Step 2: synthesis of 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionamide

A mixture of ammonia [ 7M in methanol ] (10 equiv.) and 2- (trifluoromethyl) oxirane-2-carboxamide (1 equiv.) was stirred in a sealed vial at 80 ℃ for 24 h. The mixture was concentrated in vacuo to give 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionamide (1.3g, 84% yield) as a brown gum.

¹H NMR(500MHz,DMSO-d₆)δ3.01-3.11(m,1H),2.84(d,1H)。

And step 3: synthesis of Compound I-405

The title compound was prepared according to general procedure B except 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionamide (4 equivalents) was the amine reactant, 4 equivalents triethylamine was used and the contents were heated to 90 ℃ as a solution in dioxane/water (3:1) for 24 h. The mixture was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified via silica gel chromatography (0 to 80% ethyl acetate gradient in hexanes) to give the desired compound, compound I-405 as a white solid (262mg, 40% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.08-9.13(m,1H),8.33(d,1H),7.49-7.55(m,1H),7.28-7.37(m,1H),7.17-7.25(m,2H),7.10(t,1H),6.98(t,1H),5.86-5.92(m,2H),3.92-4.04(m,2H)。

Compound I-406

The title compound was prepared according to general procedure B except 3-methylpiperidine-3-carboxylic acid (1.7 equivalents as the HCl salt) was the amine reactant and the contents were heated to 100 ℃ for 19 h. The reaction mixture was acidified to pH 3 with 1N HCl solution and the resulting solid was collected by vacuum filtration to give the desired compound, compound I-406 as a white solid (95mg, 94% yield).

¹H-NMR(500MHz,CD₃OD)δ8.75(d,1H),8.10(d,1H),7.40(s,1H),7.26(app.q,1H),7.09(dd,1H),7.03(app.t,1H),6.91(d,1H),6.81(app.t,1H),5.95(s,2H),4.58(d,1H),4.39(br d,1H),3.43(m,1H),3.41(d,1H),2.24(m,1H),1.77(m,2H),1.61(m,1H),1.23(s,3H)。

Compound I-407

The title compound was prepared according to general procedure B except 2-aminoethanol (10 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated to 100 ℃ for 40 min. The reaction mixture was acidified to pH 3 with 1N HCl solution and the resulting solid was collected by vacuum filtration to give the desired compound, compound I-407(57mg, 58% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.08(d,1H),8.17(d,1H),7.61(app.t,1H),7.50(s,1H),7.33(app.q,1H),7.24(d,1H),7.22(app.t,1H),7.10(app.t,1H),6.82(app.t,1H),5.89(s,2H),4.78(t,1H),3.58(m,4H)。

Compound I-408

The title compound was prepared according to general procedure B except 3-aminopropan-1-ol (10 equivalents) was the amine reactant, triethylamine was not used, and the contents were heated to 100 ℃ for 2 h. The reaction mixture was acidified to pH 3 with 1N HCl solution and the resulting solid was collected by vacuum filtration to give the desired compound, compound I-408(26mg, 37% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.08(d,1H),8.16(d,1H),7.66(app.t,1H),7.49(s,1H),7.32(app.q,1H),7.23(d,1H),7.21(m,1H),7.10(app.t,1H),6.83(app.t,1H),5.89(s,2H),4.54(t,1H),3.51(m,4H),1.75(app. quintet, 2H).

Compound I-409

The title compound was synthesized in 2 steps.

Step 1 Synthesis of 1- (((tert-butoxycarbonyl) (ethyl) amino) methyl) cyclopropanecarboxylic acid

A solution of 1- (((tert-butoxycarbonyl) amino) methyl) cyclopropanecarboxylic acid in THF at 0 deg.C was treated with iodoethane (10 equivalents) followed by sodium hydride (60% w/w in mineral oil, 10 equivalents, added in 6 parts). After 2 days, the reaction mixture was carefully quenched with water and washed with ethyl acetate. The aqueous layer was acidified to pH 3 with 3N HCl and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo to give 1- (((tert-butoxycarbonyl) (ethyl) amino) methyl) cyclopropanecarboxylic acid as a pale yellow oil (92% yield), which was used without further purification.

Step 2 Synthesis of N- ((1-carboxycyclopropyl) methyl) ethylammonium trifluoroacetate

A solution of 1- (((tert-butoxycarbonyl) (ethyl) amino) methyl) cyclopropanecarboxylic acid in dichloromethane was treated with trifluoroacetic acid (30 equivalents). After 2h, the reaction mixture was concentrated in vacuo to give N- ((1-carboxycyclopropyl) methyl) ethylammonium trifluoroacetate (> 99% yield) as a dark yellow oil, which was used without further work-up.

And step 3: synthesis of Compound I-409

The title compound was prepared according to general procedure B except that N- ((1-carboxycyclopropyl) methyl) ethylammonium trifluoroacetate (1.5 equivalents) was the amine reactant and the contents were heated to 100 ℃ for 3 days. The crude material was purified via reverse phase HPLC (20-70% acetonitrile/water gradient with 0.1% TFA) to give the desired compound, compound I-409 as a white solid (86mg, 51% yield).

¹H-NMR(500MHz,CD₃OD)δ8.82(d,1H),8.28(d,1H),7.52(s,1H),7.30(app.q,1H),7.10(m,1H),7.06(app.t,1H),6.97(d,1H),6.96(m,1H),6.00(s,2H),4.30(s,2H),4.00(q,2H),1.41(q,2H),1.37(t,3H),1.16(q,2H)。

Compound I-410

The title compound was synthesized in 5 steps.

Step 1: synthesis of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

To ethyl 3-methyl-1H-pyrazole-5-carboxylate in DMF was added sodium hydride (60 wt% in mineral oil, 1.2 equivalents). After 10min, 2-fluorobenzyl bromide (1.2 eq) was added and the reaction was stirred for 20 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (10-40% ethyl acetate/hexanes gradient) afforded ethyl 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylate (79% yield) and ethyl 1- (2-fluorobenzyl) -3-methyl-1H-pyrazole-5-carboxylate (9% yield).

Step 2: synthesis of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylate in THF/MeOH/water (3:1:1 ratio) was added lithium hydroxide hydrate (1.5 equiv). After 23h, the volatile organics were removed in vacuo and the resulting mixture was acidified to pH 3 with 1N HCl. 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid (92% yield) was collected by vacuum filtration.

And step 3: synthesis of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carbonitrile

To a suspension of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid, 2-methylpropan-2-amine (3 eq) and triethylamine (2 eq) in ethyl acetate was added n-propylphosphonic anhydride (T3P, 50 wt% solution in ethyl acetate, 3 eq). The resulting yellow solution was heated at 65 ℃ for 2.5 h. The solvent was removed in vacuo. Phosphorus oxychloride (12 equivalents) was added and the resulting mixture was stirred at 70 ℃ for 1 hour 40 min. The reaction was quenched by careful pouring into a mixture of water and ice, neutralized to pH 7 by addition of saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Purification by silica gel chromatography (10% ethyl acetate/hexanes gradient) afforded 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carbonitrile (49% yield).

And 4, step 4: synthesis of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxamidine

A solution of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carbonitrile in methanol was treated with sodium methoxide (25 wt% solution in MeOH, 5 eq) and stirred for 24H. Ammonium chloride (10 equivalents) was added. After 26 hours, the reaction mixture was concentrated in vacuo and partitioned between half saturated sodium bicarbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is contaminated with starting material due to incomplete reaction. This material was again subjected to similar conditions to give 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxamidine (92% yield).

And 5: synthesis of Compound I-410

The suspension of 1- (2-fluorobenzyl) -5-methyl-1H-pyrazole-3-carboxamidine was treated with sodium (Z) -3-ethoxy-2-fluoro-3-oxoprop-1-en-1-ol (see also general procedure a, step 4, 3.0 equivalents) and heated at 90 ℃ for 1H. After cooling to ambient temperature, the reaction mixture was neutralized by adding HCl (1.25M solution in EtOH). The resulting tan suspension was concentrated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous layer was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. Trituration in dichloromethane yield afforded the title compound as a white solid (206mg, 62% yield).

¹H-NMR(500MHz,DMSO-d₆)δ12.9(br s,1H),8.07(br s,1H),7.38(app.q,1H),7.25(m,1H),7.18(app.t,1H),7.11(m,1H),6.72(s,1H),5.44(s,2H),2.30(s,3H)。

Compound I-411

The title compound was synthesized in 2 steps.

Step 1: synthesis of 4-chloro-5-fluoro-2- (1- (2-fluorobenzyl) -5-methyl-1H-pyrazol-3-yl) pyrimidine

The intermediates were generated using the procedure described for the synthesis of intermediate 1, except that compound I-410 was used as the starting pyrimidinone. An off-white solid was obtained (210mg, 96% yield), and the contents were used without further purification.

Step 2: synthesis of Compound I-411

The title compound was prepared according to general procedure B, except that 1- ((methylamino) methyl) cyclopropanecarboxylic acid (as the HCl salt) was the amine reactant. The reaction mixture was acidified to pH 3 and the resulting precipitate was collected by vacuum filtration to give the desired compound, compound I-411(48mg, 93% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δ12.3(s,1H),8.16(d,1H),7.36(app.q,1H),7.25(m,1H),7.17(app.t,1H),6.99(app.t,1H),6.61(s,1H),5.38(s,2H),3.97(s,2H),3.22(d,3H),2.29(s,3H),1.13(m,2H),1.01(m,2H)。

Compound I-412

The title compound was prepared according to general procedure B except (2R,3S) -3-methylpiperidine-2-carboxylic acid was the amine reactant and the contents were heated to 100 ℃ for 20 h. The crude material was purified via reverse phase HPLC (25-80% acetonitrile/water gradient with 0.1% TFA) to give the desired compound, compound I-412 as a white solid (12mg, 23% yield).

¹H-NMR(500MHz,CD₃OD)δ8.33(d,1H),7.36(app.q,1H),7.15(m,2H),7.06(app.t,1H),6.89(s,1H),5.52(s,2H),5.36(d,1H),4.58(br s,1H),3.83(app.t,1H),2.36(s,3H),1.99(m,1H),1.96(m,1H),1.79(m,2H),1.58(m,1H),1.24(d,3H)。

Compound I-413

The title compound was prepared according to general procedure B, except serinol (10 equivalents) was the amine reactant and no triethylamine was used, and the contents were heated to 90 ℃ for 40min, followed by 100 ℃ for 20 min. The reaction mixture was acidified to pH 3 and the resulting precipitate was collected by vacuum filtration to give the desired compound, compound I-413 as a white solid (46mg, 88% yield).

¹H-NMR(500MHz,DMSO-d₆)δ8.11(d,1H),7.35(app.q,1H),7.24(m,1H),7.16(app.t,1H),7.03(d,1H),6.92(app.t,1H),6.64(s,1H),5.40(s,2H),4.71(t,2H),4.24(m,1H),3.56(m,4H),3.12(s,3H)。

Compound I-414

The title compound was prepared according to general procedure B except 2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (2.2 equivalents) was the amine reactant, 5 equivalents triethylamine was used and the contents were heated to 90 ℃ for 18h, followed by heating to 100 ℃ for 4 days. The crude material was purified via reverse phase HPLC (35-80% acetonitrile/water gradient with 0.1% TFA) to give the desired compound, compound I-414 as a white solid (35mg, 58% yield).

¹H-NMR(500MHz,MeOH-d₄)δ8.29(d,1H),7.35(app.q,1H),7.13(m,3H),6.79(s,1H),5.50(s,2H),4.29(s,2H),2.36(s,3H)。

Compound I-416

The title compound was synthesized in 3 steps.

Step 1: synthesis of 3- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -1,2, 4-triazin-5 (4H) -one

A solution of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine hydrochloride in absolute ethanol was treated with hydrazine hydrate (1.5 eq) at ambient temperature. After 45min, ethyl 2-oxoacetate (50 wt% solution in toluene, 3.0 equivalents) was added and the resulting solution was heated at 50-60 ℃ for 65 h. The reaction mixture was then concentrated in vacuo, dissolved in dichloromethane, filtered and concentrated in vacuo to give an orange oil. Purification via silica gel chromatography (10-20% acetonitrile-methanol in dichloromethane (7:1)) afforded the desired compound as 3- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -1,2, 4-triazin-5 (4H) -one (320mg, 73% yield) as a pale tan solid.

¹H-NMR(500MHz,CDCl₃)δ8.54(d,1H),7.84(br s,1H),7.44(s,1H),7.31(m,1H),7.12-7.04(m,3H),6.63(d,1H),5.95(s,2H)。

Step 2: synthesis of 3- (3- (5-chloro-1, 2, 4-triazin-3-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole

3- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -1,2, 4-triazin-5 (4H) -one was treated with phosphorus oxychloride (42 equivalents, excess). The resulting mixture was heated at 65 ℃ for 4 h. The resulting tan suspension was blown dry under a stream of nitrogen and azeotropically dried with toluene. The chloro-triazine is used in the next step without further work-up.

And step 3: synthesis of Compound I-416

The title compound was prepared according to general procedure B, except serinol (10 equivalents) was used as amine reactant, 3- (3- (5-chloro-1, 2, 4-triazin-3-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole was used instead of intermediate 1, triethylamine was not used, and the contents were heated as a solution in dioxane/DMSO (7.5:1) at 100 ℃ for 24H. The reaction mixture was diluted with water, neutralized to pH 4 with 1N HCl solution and extracted with dichloromethane/isopropanol (4: 1). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude material was purified via reverse phase HPLC (10-70% acetonitrile/water gradient with 0.1% TFA) to give the desired compound, compound I-416(5.2mg, 9.8% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD) δ 8.84(d,1H),8.35(s,1H),7.74(s,1H),7.32(app.q,1H),7.11(m,1H),7.08(app.t,1H),6.99(app.t,1H),6.96(d,1H),6.06(s,2H),4.62(app. quintet, 1H),3.84(m, 4H).

Compound I-417

The title compound was prepared according to general procedure B except glycinamide (as the HCl salt, 3.0 equivalents) was the amine reactant and the contents were heated to 100 ℃ for 22 h. The reaction mixture was acidified to pH 4 with 1N HCl solution and the resulting solid was collected by vacuum filtration to give the desired compound, compound I-417(110mg, 94% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.09(d,1H),8.22(d,1H),7.83(app.t,1H),7.51(br s,1H),7.48(s,1H),7.31(app.q,1H),7.21(m,1H),7.18(d,1H),7.12-7.08(m,2H),6.81(app.t,1H),5.89(s,2H),4.01(d,2H)。

Compound I-418

The title compound was prepared according to general procedure B except 3-amino-4, 4, 4-trifluorobutanoic acid (3 equivalents) was the amine reactant and the contents were heated as a solution in dioxane/DMSO (2:1) to 100 ℃ for 3.5h, then to 120 ℃ for 18 h. An additional 2 equivalents of intermediate 1 were added to the reaction and the contents were stirred at 120 ℃ for an additional 4 days. A dichloromethane isopropanol (4:1) mixture was used as solvent during the work-up. The crude material was purified by silica gel chromatography (5% methanol/dichloromethane isocratic) to give the desired compound, compound I-418 as an off-white solid (38mg, 10% yield).

¹H NMR(500MHz,DMSO-d6)δppm 12.65(br.s.,1H),9.09(d,1H),8.35(d,1H),8.29(d,1H),7.51(s,1H),7.32(q,1H),7.26(d,1H),7.24-7.19(m,1H),7.10(t,1H),6.83(t,1H),5.91(s,2H),5.53(br.s.,1H),2.96-2.85(m,2H)。

Compound I-419

A solution of compound I-418 in dichloromethane was treated with N, N-diisopropylethylamine (2.0 equivalents), followed by O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 1.2 equivalents). After 15min, ammonia (0.5N solution in dioxane, 2.0 eq) was added and the resulting light brown suspension was stirred for 1.5 h. The reaction mixture was diluted with water and extracted with dichloromethane/2-propanol (4: 1). The organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-3% methanol/dichloromethane gradient) afforded the desired compound, compound I-419 as an off-white solid (20mg, 57% yield).

¹H-NMR(500MHz,DMSO-d₆)δ9.10(d,1H),8.34(d,1H),8.24(d,1H),7.51(m,2H),7.32(app.q,1H),7.25(d,1H),7.22(app.t,1H),7.10(app.t,1H),7.06(br s,1H),6.82(app.t,1H),5.91(s,2H),5.55(br s,1H),2.77(dd,1H),2.67(dd,1H)。

Compound I-420

The title compound was prepared in 2 steps.

Step 1: synthesis of diethyl 2- (dicyanomethyl) -2-methylmalonate

A mixture of diethyl 2-bromo-2-methylmalonate (1 eq), malononitrile (1 eq) and potassium tert-butoxide (1 eq) in THF was heated to reflux for 15 h. The mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The oil was purified by silica gel chromatography (10-15% ethyl acetate gradient in hexanes) to give diethyl 2- (dicyanomethyl) -2-methylmalonate as a colorless oil (5.76g, 32% yield).

¹H NMR(500MHz,CDCl₃)δppm 4.53(s,1H),4.27-4.39(m,4H),1.81(s,3H),1.33(t,6H)。

Step 2: synthesis of Compound I-420

A mixture of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine hydrochloride (formed in step 3 of general procedure a by using 1- (isoxazol-3-yl) ethanone in step 1 and 2-fluorobenzylhydrazine in step 2) (1 eq), diethyl 2- (dicyanomethyl) -2-methylmalonate (1.15 eq) and potassium bicarbonate (2 eq) in t-BuOH was heated to reflux for 5H. After cooling, water was added to the reaction mixture and stirred for 30 min. The precipitate was filtered, washed with a minimum amount of water and diethyl ether, and dried under high vacuum overnight to give compound I-420 as a white solid (385mg, 52% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 11.30(s,1H),9.10(d,1H),7.38(s,1H),7.29-7.36(m,1H),7.18-7.26(m,2H),7.08-7.14(m,1H),6.81-6.90(m,1H),6.65(br.s.,2H),5.88(s,2H),4.04-4.16(m,2H),1.59(s,3H),1.11(t,3H)。

Compound I-421

Ammonia (7.0M in MeOH) (200 equivalents) was added to compound I-420(1 equivalent). The reaction mixture was heated at 50 ℃ for 16 h. The resulting solution was then concentrated in vacuo and the residue was purified via reverse phase HPLC (5-60% acetonitrile in 1% TFA in water) to give the desired compound, compound I-421(24mg, 63% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆)δppm 11.35(br.s.,1H),9.08-9.13(m,1H),7.47(s,1H),7.43(s,1H),7.28-7.38(m,1H),7.23-7.27(m,1H),7.17-7.23(m,2H),7.06-7.14(m,1H),6.77-7.00(m,3H),5.91(s,2H),1.56(s,3H)。

Compound I-422

Cyclopropylamine (150 equivalents) was added to compound I-420(1 equivalent). And the reaction mixture was heated at 50 ℃ for 30 h. Then, the resulting solution was concentrated in vacuo and the residue was purified via reverse phase HPLC (25-50% acetonitrile in water with 1% TFA) to give the desired compound, compound I-422 as a white solid (29mg, 57% yield).

¹H NMR(400MHz,DMSO-d₆)δppm 11.29(br.s.,1H),9.11(d,1H),7.59-7.66(m,1H),7.42(s,1H),7.29-7.37(m,1H),7.16-7.28(m,2H),7.06-7.15(m,1H),6.65-6.89(m,3H),5.90(s,2H),2.59-2.69(m,1H),1.54(s,3H),0.53-0.65(m,2H),0.39-0.52(m,2H)。

Compound I-423

The title compound was prepared according to general procedure B except that 4- (piperidin-4-ylsulfonyl) morpholine (1.7 equivalents as TFA salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 105 ℃ for 12 h. Ethyl acetate was the solvent used for the treatment. The crude material was purified via silica gel chromatography using a gradient of 1 to 5% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-423 as a white solid (32.7mg, 35% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.48(d,1H),8.25(d,1H),7.30(s,1H),7.20-7.25(m,1H),7.03-7.08(m,1H),6.96-7.01(m,1H),6.83-6.88(m,1H),6.60(d,1H),5.98(s,2H),4.83(d,2H),3.76(m,4H),3.41(m,4H),3.23-3.29(m,1H),3.06-3.11(m,2H),2.20-2.26(m,2H),1.91-2.03(m,2H)。

Compound I-424

The title compound was prepared according to general procedure B except trans-4- (trifluoromethyl) pyrrolidine-3-carboxylic acid (as TFA salt, 1.5 equivalents) was the amine reactant. 4 equivalents of triethylamine were used and the contents were heated to 105 ℃ for 3 h. Dichloromethane isopropanol mixture (5:1) was used as the treatment solvent. The dried and filtered organic layer was concentrated in vacuo to give the desired compound, compound I-424(108.3mg, 89% yield) as an off-white solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.50(d,1H),8.18(d,1H),7.40(s,1H),7.19-7.25(m,1H),6.98-7.07(m,3H),6.65(d,1H),5.94(s,2H),4.26(m,1H),4.11-4.18(m,2H),4.03-4.09(m,1H),3.48-3.55(m,1H),3.39-3.54(m,1H)。

Compound I-425

To a suspension of compound I-366(1 equivalent) in dichloromethane was added cyclopropanecarbonyl chloride (1.08 equivalents) and triethylamine (1.1 equivalents). After stirring at room temperature for 24h, the reaction was still heterogeneous and LC/MS analysis indicated incomplete. An additional 4 equivalents of acid chloride and 1, 8-diazabicycloundec-7-ene were added, and the reaction was then heated to 60 ℃ for 1h, after which the reaction was tan and completely homogeneous. The reaction was diluted in water, acidified by addition of 1N hydrochloric acid solution, extracted with dichloromethane (3 ×), dried (sodium sulfate), filtered and concentrated to give a white solid. Purification was achieved by silica gel using 1 to 8% methanol in dichloromethane over 38 minutes to give the desired compound, compound I-425 as a white solid (40.4mg, 71% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(d,1H),8.23(d,1H),7.82(br.s,1H),7.29(s,1H),7.17-7.23(m,1H),7.01-7.06(m,1H),6.95-6.99(m,1H),6.81-6.87(m,1H),6.60(d,1H),5.96(s,2H),4.79-4.84(m,2H),3.83-3.94(m,1H),3.08-3.15(m,2H),2.23-2.29(m,2H),2.01-2.06(m,1H),1.27(m,2H),1.19(m,2H),0.99-1.04(m,2H)。

Compound I-426

To a suspension of compound I-366(1 eq) in dichloromethane was added acetic anhydride (1.25 eq) and 1, 8-diazabicycloundec-7-ene (1.25 eq). After stirring at room temperature for 24h, the reaction was still heterogeneous and the LC/MS indication was incomplete. Additional 4 equivalents of acetic anhydride and 1, 8-diazabicycloundecen-7-ene were added, and then the reaction was heated to 60 ℃ for 1h, after which the reaction was tan and completely homogeneous. The reaction was diluted in water, acidified by addition of 1N hydrochloric acid solution, extracted with dichloromethane (3 ×), dried (sodium sulfate), filtered and concentrated to give a white solid. Purification was achieved by silica gel chromatography using a gradient of 1 to 8% methanol in dichloromethane over 38 minutes to give the desired compound, compound I-426 as a white solid (24.7mg, 44% yield).

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(d,1H),8.23(d,1H),7.85(br.s,1H),7.29(s,1H),7.18-7.25(m,1H),7.02-7.08(m,1H),6.96-7.02(m,1H),6.84-6.89(m,1H),6.61(d,1H),6.00(s,2H),4.80-4.90(m,2H),3.85-3.95(m,1H),3.08-3.17(m,2H),2.23-2.31(m,2H),2.17(s,3H),1.97-2.08(m,2H)。

Compound I-427

The title compound was prepared according to general procedure B except pyrrolidine-3-sulfonamide (1.35 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 105 ℃ for 2 h. After cooling, the reaction was poured into a 1:1 mixture of water and ethyl acetate, and the resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-427 as an off-white solid (46.7mg, 39% yield).

¹H NMR(500MHz,DMSO-d₆)δ(ppm):9.05-9.13(m,1H),8.24-8.31(m,1H),7.51-7.57(m,1H),7.28-7.37(m,1H),7.18-7.27(m,2H),7.06-7.17(m,3H),6.76-6.87(m,1H),5.87-5.93(m,2H),4.00-4.09(m,2H),3.84-3.97(m,2H),3.75-3.84(m,1H),2.29-2.42(m,2H)。

Compound I-428

The title compound was prepared according to general procedure B, except diethanolamine (1.3 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 12 h. A dichloromethane-isopropanol mixture (5:1) was used as the treatment solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 8% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-428 as a white solid (24.7mg, 26% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.48(d,1H),8.17(d,1H),7.24(s,1H),7.18-7.23(m,1H),7.01-7.06(m,1H),6.96-7.01(m,1H),6.87-6.92(m,1H),6.58(d,1H),5.95(s,2H),3.99(m,4H),3.89(m,4H),3.30(br.s,2H)。

Compound I-429

To a solution of compound I-427(1 equivalent) in dichloromethane was added cyclopropanecarbonyl chloride (6 equivalents) followed by 1, 8-diazabicycloundec-7-ene (8 equivalents). The reaction was heated at 100 ℃ for 1h, after which it was cooled, diluted in water and 1M hydrochloric acid solution, extracted with dichloromethane (2 ×), concentrated and purified directly via silica gel chromatography using a gradient of 1 to 8% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-429(26.5mg, 70% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.47(d,1H),8.18(d,1H),7.31(s,1H),7.18-7.23(m,1H),7.01-7.06(m,1H),6.96-7.01(m,1H),6.83-6.88(m,1H),6.60(d,1H),5.97(s,2H),4.40-4.47(m,2H),4.04-4.15(m,2H),3.90-3.97(m,1H),2.65-2.73(m,1H),2.45-2.53(m,1H),1.30(m,1H),1.17(m,2H),0.99(m,2H)。

Compound I-430

The title compound was prepared according to general procedure B except that (2R,3R) -2- (hydroxymethyl) pyrrolidin-3-ol (1.7 equivalents as TFA salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 2 h. After cooling, the reaction was diluted with water and methanol, and the resulting precipitate was filtered, washed with water and dried in vacuo to give the desired compound, compound I-430 as a white solid (79.3mg, 64% yield).

¹H NMR(500MHz,DMSO-d₆)δ(ppm):9.09(d,1H),8.24(d,1H),7.51(s,1H),7.30-7.36(m,1H),7.19-7.25(m,2H),7.08-7.13(m,1H),6.82-6.87(m,1H),5.90(d,1H),5.85(d,1H),5.23(d,1H),4.71(br.s,1H),4.35-4.42(m,1H),4.15-4.20(m,1H),3.77-3.87(m,2H),3.64-3.74(m,2H),2.04-2.09(m,2H)。

Compound I-431

The title compound was prepared according to general procedure B except that diisopropanolamine (1 equivalent) was the amine reactant, 4 equivalents of triethylamine were used, and the contents were heated to 100 ℃ for 24 h. Ethyl acetate was used as the treatment solvent. The crude material was purified via silica gel chromatography using a gradient of 1 to 8% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-431 as a white solid (47.1mg, 42% yield).

¹H NMR(500MHz,CD₃OD) delta (ppm) 8.72(d,1H),8.11(d,1H),7.35(s,1H),7.23-7.28(m,1H),7.05-7.11(m,1H),7.01-7.05(m,1H),6.83-6.88(m,2H,2 synchro-shifts), 5.96(d,1H),5.92(d,1H),4.10-4.21(m,2H),3.90-3.97(m,2H),3.61-3.67(m,2H),1.21(s, 6H).

Compound I-432

The title compound was prepared in 3 steps.

Step 1: synthesis of 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonic acid

The intermediate was prepared according to general procedure B, except taurine (1.3 equivalents) was the amine reactant, 2 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 8 h. After cooling, the reaction was diluted with 1N HCl solution, filtered, washed with water and dried in vacuo to give the desired intermediate 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonic acid as a white solid (60.2mg, 64% yield). The intermediate was used without further purification.

Step 2: synthesis of 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonyl chloride

A suspension of 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonic acid (1 eq) and thionyl chloride (5 eq) in dichloromethane was stirred at room temperature, after which 2 drops of DMF were added. The suspension was heated to 60 ℃ for 12h, after which LC/MS indicated formation of sulfonyl chloride. The reaction mixture was concentrated to dryness to give 90mg of an off-white solid.

And step 3: synthesis of Compound I-432

To a suspension of crude 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonyl chloride in tetrahydrofuran was added 50% aqueous hydroxylamine solution (10 equivalents). The reaction immediately became homogeneous and LC/MS showed the reaction was complete. The reaction was concentrated to one third of its volume and purified directly on silica gel using 3 to 10% methanol in dichloromethane over 45 minutes to give the desired compound, compound I-432(8.2mg, 25% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δ(ppm):8.76(d,1H),8.13(d,1H),7.60(s,1H),7.25-7.31(m,1H),7.07-7.13(m,1H),7.03-7.07(m,1H),6.89(d,1H),6.83-6.88(m,1H),6.00(s,2H),4.07(t,2H),3.62(t,2H)。

Compound I-433

The title compound was prepared according to general procedure B except that piperidine-3, 5-dione (1.4 equivalents as the HCl salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 1 h. Ethyl acetate was used as the treatment solvent. The crude material was purified via silica gel chromatography using a 3 to 20% methanol gradient in dichloromethane over 40 minutes to give the desired compound, compound I-433 as a white solid (45.6mg, 44% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.77(s,1H),8.30(d,1H),7.50(s,1H),7.26-7.32(m,1H),7.07-7.13(m,1H),7.03-7.07(m,1H),6.94(d,1H),6.83-6.88(m,1H),5.98(s,2H),4.58(s,4H)。

Compound I-434

The title compound was prepared according to general procedure B except that 4- (hydroxymethyl) piperidin-4-ol (1.4 equivalents as the HCl salt) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 1 h. After cooling, the reaction was diluted with water and 1N HCl solution, and the resulting precipitate was filtered, washed with water and dried in vacuo to give the desired compound, compound I-434 as a white solid (88.5mg, 82% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.77(d,1H),8.15(d,1H),7.43(s,1H),7.23-7.30(m,1H),7.06-7.12(m,1H),7.00-7.05(m,1H),6.91(d,1H),6.79-6.84(m,1H),5.96(s,2H),4.49-4.57(m,2H),3.49-3.57(m,2H),3.40(s,2H),1.65-1.71(m,2H),1.77-1.84(m,2H)。

Compound I-435

The title compound was prepared according to general procedure B except (3R,5S) -5- (hydroxymethyl) pyrrolidin-3-ol (2.7 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 30 min. After cooling, the reaction was diluted with water and methanol, and the resulting precipitate was filtered, washed with water and dried in vacuo to give the desired compound, compound I-435 as a white solid (77.3mg, 87% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.75(d,1H),8.12(d,1H),7.40(s,1H),7.24-7.28(m,1H),7.06-7.10(m,1H),7.01-7.05(m,1H),6.90(d,1H),6.80-6.85(m,1H),5.95(s,2H),4.63-4.68(m,1H),4.53-4.57(m,1H),3.81-3.94(m,3H),3.73-3.80(m,1H),2.10-2.25(m,2H)。

Compound I-437

This compound was prepared in two steps.

Step 1: ketal intermediates

To a suspension of crude 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonyl chloride (synthesis described in step 2 of the procedure for preparing compound I-432, 1 equivalent) in dioxane was added (S) - (2, 2-dimethyl-1, 3-dioxolan-4-yl) methylamine (2 equivalents). The reaction was stirred for 24h, after which the reaction mixture was diluted in 5:1 dichloromethane/isopropanol and acidified by addition of 1M hydrochloric acid, extracted with 5:1 dichloromethane/isopropanol (3 × 30mL), dried (sodium sulfate), filtered and concentrated to give a residue. Purification was achieved by silica gel chromatography using a 7 to 12% methanol gradient in dichloromethane over 45 minutes to give the desired compound, compound I-43 as a white solid (31.0mg, 42% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.78(d,1H),8.13(d,1H),7.52(s,1H),7.26-7.32(m,1H),7.10-7.15(m,1H),7.04-7.08(m,1H),6.91(d,1H),6.80-6.85(m,1H),6.00(s,2H),4.16-4.20(m,1H),4.03-4.12(m,2H),3.98-4.02(m,1H),3.70-3.74(m,1H),3.45-3.52(m,2H),3.22(d,2H),1.34(s,3H),1.27(s,3H)。

Step 2: compound I-437

To a solution of the intermediate prepared in step 1(1 eq) in dichloromethane was added a 4M solution of hydrogen chloride in dioxane (20 eq). After 1h, the reaction was concentrated to dryness, diluted in water, extracted with 5:1 dichloromethane/isopropanol (3 ×), dried (sodium sulfate), filtered and concentrated to give a residue. Purification was achieved via silica gel chromatography to give the desired compound, compound I-437 as an off-white solid (10.3mg, 38.2% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.77(d,1H),8.12(d,1H),7.53(s,1H),7.26-7.32(m,1H),7.08-7.13(m,1H),7.03-7.08(m,1H),6.93(d,1H),6.81-6.86(m,1H),6.00(s,2H),4.03-4.13(m,2H),3.70-3.75(m,1H),3.47-3.54(m,3H),3.24-3.29(m,2H),3.08-3.13(m,1H)。

Compound I-438

The title compound was prepared according to general procedure B except 4-hydroxypiperidine-4-carboxamide (1.4 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 30 min. Ethyl acetate was used as the treatment solvent and the purification was achieved by triturating the crude product in acetonitrile with water to precipitate the product. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-438 as a white solid (26.3mg, 26% yield).

¹H NMR(500MHz,DMSO-d₆) δ (ppm) 9.08(d,1H),8.29(d,1H),7.55(s,1H),7.30-7.35(m,2H,2 synchro-shifts), 7.26(d,2H),7.19-7.25(m,1H),7.16(br.s,1H),7.08-7.13(m,1H),6.79-6.84(m,1H),5.90(s,2H),4.39(m,2H),3.34-3.39(m,2H),1.95-2.01(m,2H),1.58(m, 2H).

Compound I-439

To a suspension of 2- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) ethanesulfonyl chloride (synthesis described in step 2 of the procedure for compound I-432, 1 equivalent) in dioxane was added ethanolamine (2.2 equivalents). The reaction was stirred at room temperature for 24h, after which the reaction mixture was diluted in 5:1 dichloromethane/isopropanol and acidified by addition of 1M hydrochloric acid, extracted with 5:1 dichloromethane/isopropanol (3 ×), dried (sodium sulfate), filtered and concentrated to give a residue. Purification was achieved by silica gel chromatography using a 3 to 8% methanol gradient in dichloromethane over 45min to give the desired compound, compound I-439 as a white solid (31.3mg, 65% yield).

¹H NMR(500MHz,DMSO-d₆)δ(ppm):9.09(d,1H),8.24(d,1H),7.78-7.83(m,1H),7.54(s,1H),7.30-7.35(m,1H),7.21-7.25(m,2H),7.17(d,1H),7.08-7.13(m,1H),6.81-6.86(m,1H),5.90(s,2H),4.80(t,1H),3.84(q,2H),3.44(q,2H),3.39(t,2H),3.03(q,2H)。

Compound I-440

The title compound was synthesized in 2 steps.

Step 1: synthesis of 1- (benzyloxy) -N- (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) cyclopropanecarboxamide

An intermediate was prepared according to general procedure B, except that N- (azetidin-3-yl) -1- (benzyloxy) cyclopropanecarboxamide (as TFA salt, 1.2 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 2 h. After cooling, the reaction mixture was diluted with water and the resulting precipitate was filtered, washed with water and dried in vacuo to give the desired intermediate, 1- (benzyloxy) -N- (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) cyclopropanecarboxamide as a white solid (104.3mg, 86% yield).

Step 2: synthesis of Compound I-440

To a suspension of 1- (benzyloxy) -N- (1- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) azetidin-3-yl) cyclopropanecarboxamide in ethanol was added 10% palladium on charcoal (0.1 eq), the reaction mixture was evacuated to dryness and the hydrogen balloon was applied. Ethyl acetate was added for solubility purposes. After 24h, a mixture of starting materials, products and by-products was observed. The reaction mixture was filtered through celite, then purified by silica gel chromatography using a gradient of 1 to 8% dichloromethane in methanol over 60 minutes to afford the desired compound, compound I-440(3.8mg, 5% yield). Several later fractions containing the desired product are contaminated with by-products that come out of proximity and are discarded.

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.44(d,1H),8.09(d,1H),7.92(br.s,1H),7.20-7.25(m,1H),6.93-7.03(m,2H,2 synchronous shifts), 6.83-6.88(m,2H),6.56(d,1H),5.94(s,2H),4.81-4.91(m,1H),4.55-4.63(m,1H),4.05-4.12(m,2H),2.31-2.36(m,1H),1.33-1.37(m,2H),1.04-1.09(m, 2H).

Compound I-441

The title compound was prepared according to general procedure B except 3- (aminomethyl) -1H-1,2, 4-triazol-5 (4H) -one (1.3 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 100 ℃ for 12H. After cooling, the reaction was filtered and purified via silica gel chromatography using a gradient of 3 to 10% methanol in dichloromethane over 40 minutes to give the desired compound, compound I-441 as a white solid (12.9mg, 13% yield).

¹H NMR(500MHz,CD₃OD) delta (ppm) 8.78(d,1H),8.17(m,1H),7.42(s,1H),7.25-7.31(m,1H),7.07-7.12(m,1H),7.02-7.07(m,1H),6.88-6.93(m,2H,2 synchro-shifts), 6.02(s,2H),4.61(s, 2H).

Compound I-442

To a suspension of 1,2, 4-triazolin-3-one (0.5 eq), potassium carbonate (1.5 eq) and copper (I) iodide (0.05 eq) in N, N-dimethylformamide was added intermediate 1(1 eq) followed by trans-1, 2-bis (methylamino) cyclohexane (0.1 eq). The reaction was heated to 100 ℃ for 24h before diluting the reaction in water and extracting with ethyl acetate, drying (sodium sulfate), filtering and concentrating. Two attempts at purification by silica gel chromatography (5-7% methanol in dichloromethane) gave one peak as a complex of the three compounds. Further purification by reverse phase HPLC (5 to 75% acetonitrile in water supplemented with 0.1% trifluoroacetic acid over 20 minutes) afforded the desired compound, compound I-442 as a white solid (0.9mg, 0.8% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.96(s,1H),8.81(d,1H),8.12(s,1H),7.66(s,1H),7.25-7.31(m,1H),7.09-7.15(m,1H),7.02-7.07(m,1H),6.89-6.94(m,1H),5.98(s,2H)。

Compound I-443

The title compound was prepared according to general procedure B, except that 3-amino-2-hydroxypropionamide (2 equivalents) was the amine reactant, 4 equivalents triethylamine was used, and the contents were heated to 110 ℃ for 6 h. A dichloromethane-isopropanol mixture (5:1) was used as the treatment solvent. The crude material was purified via silica gel chromatography using a 3 to 10% methanol gradient in dichloromethane over 45 minutes to give the desired compound, compound I-443 as a white solid (17.3mg, 14% yield).

¹H NMR(500MHz,CD₃OD)δ(ppm):8.78(d,1H),8.11(d,1H),7.52(s,1H),7.27-7.31(m,1H),7.09-7.13(m,1H),7.03-7.08(m,1H),6.95(d,1H),6.83-6.88(m,1H),5.99(s,2H),4.37(dd,1H),4.05(dd,1H),3.81(dd,1H)。

Compound I-444

To a solution of intermediate-2 (intermediate described in patent application publication WO2012/3405a 1) (1 equivalent) in dichloromethane was added 2,2, 2-trifluoroethanesulfonyl chloride (1.08 equivalents) followed by 1, 8-diazabicycloundec-7-ene (1.2 equivalents). The reaction was allowed to stir at 23 ℃ for 16h, after which the reaction mixture was diluted in water and 1N hydrochloric acid solution, extracted with ethyl acetate (3 ×), washed with 1N hydrochloric acid solution (2 ×), dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography using an isocratic 5% methanol gradient in dichloromethane to give the desired compound, compound I-444 as a white solid (28.9mg, 27% yield).

¹H NMR(500MHz,CD₃OD) delta (ppm) is 8.82(d,1H),8.24(br.s,1H),7.57(s,1H),7.26-7.32(m,1H),7.08-7.13(m,1H),7.03-7.08(m,1H),6.93-6.99(m,2H,2 overlay shifts), 6.79-6.85(br.s,1H),6.01(s,2H),4.49-4.58(m, 2H).

Compound I-445

To a suspension of sodium hydride (1.2 equiv) in anhydrous tetrahydrofuran at 23 ℃ was added intermediate-2 (1 equiv). The reaction was allowed to stir at 23 ℃ for 30 min. 3,3, 3-trifluoropropane-1-sulfonyl chloride (1 eq), dissolved in tetrahydrofuran, was added to the reaction mixture, which was stirred for 18 h. The reaction mixture was diluted in water and 1N hydrochloric acid solution, extracted with ethyl acetate (3 ×), washed with 1N hydrochloric acid solution (2 ×), dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-445(17.1mg, 20% yield) as an off white solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.51(d,1H),8.25(br.s,1H),7.20-7.29(m,2H),6.98-7.08(m,3H),6.59(d,1H),5.80-5.99(m,2H),3.64(br.s,2H),2.69-2.88(m,2H)。

Compound I-446

To a suspension of sodium hydride (1.2 eq) in anhydrous tetrahydrofuran at 23 ℃ was added intermediate-21 eq). The reaction was allowed to stir at 23 ℃ for 30 min. 2-Methoxyethanesulfonyl chloride (1 eq) dissolved in tetrahydrofuran was added to the reaction mixture, which was stirred for 18 h. The reaction mixture was diluted in water and 1N hydrochloric acid solution, extracted with ethyl acetate (3 ×), washed with 1N hydrochloric acid solution (2 ×), dried (sodium sulfate), filtered and concentrated. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-446(9.1mg, 13.5% yield) as an off white solid.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.50(d,1H),8.37(br.s,1H),7.19-7.27(m,2H),6.92-7.07(m,3H),6.61(d,1H),5.94(s,2H),3.85-3.92(m,2H),3.78(br.s,2H),3.28(s,3H)。

Compound I-447

Oxalyl chloride (4 equivalents) was added to a solution of triethylamine (4 equivalents) and compound I-214(1 equivalent) in DCM maintained at 0 ℃. The reaction was allowed to warm and stir at room temperature for 2 h. The reaction was then quenched by addition of water, extracted with dichloromethane, and the organic extracts concentrated in vacuo to give the desired compound, compound I-447(3.7mg, 69% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.90(d,1H),7.65(s,1H),7.30-7.37(m,1H),7.27(d,1H),7.19-7.26(m,1H),7.11(t,1H),6.87(t,1H),5.93(s,2H),4.00-4.07(m,2H),2.57(t,2H),2.13-2.21(m,2H)。

Compound I-448

The title compound was prepared according to general procedure B, except 5- (aminomethyl) thiophene-2-carboxylic acid (4 equivalents) was the amine reactant, 9 equivalents triethylamine was used, and the contents were heated to 110 ℃ as a solution in dioxane/water (4.5:1) for 2 days. The contents were diluted with ethyl acetate and 1N HCl solution, and the resulting precipitate was filtered. The solid was collected and dried in vacuo to give the desired compound, compound I-448(12mg, 27% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δppm 12.9(br.s.,1H),9.11(d,1H),8.92-9.08(m,1H),8.35(t,1H),7.61-7.67(m,1H),7.56(d,1H),7.30-7.38(m,1H),7.19-7.26(m,3H),7.12(t,1H),6.92(t,1H),5.92(s,2H),4.88-4.97(m,2H)。

Compound I-449

The title compound was prepared according to general procedure B except 5-aminopentanoic acid (4 equivalents) was the amine reactant, 9 equivalents triethylamine was used and the contents were heated to 110 ℃ as a solution in dioxane/water (4.5:1) for 2 days. The contents were diluted with ethyl acetate and 1n hcl solution, and the resulting precipitate was filtered. The solid was collected and dried in vacuo to give the desired compound, compound I-449(34mg, 84% yield) as a solid.

¹H NMR(500MHz,DMSO-d₆)δppm 12.01(s,1H),9.12(s,1H),8.32-8.62(m,1H),8.27(br.s.,1H),7.61(br.s.,1H),7.29-7.40(m,1H),7.18-7.27(m,2H),7.11(t,1H),6.88(t,1H),5.93(br.s.,2H),2.29(t,3H),1.49-1.72(m,5H)。

Compound I-450

A suspension of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-ol (using 1- (isoxazol-3-yl) ethanone in step 1 and 2-fluorobenzylhydrazine in step 2 via general procedure a) (1 eq) and sodium methoxide in methanol (0.5M solution, 4 eq) was heated in a microwave vessel at 130 ℃ for 4H. The reaction was quenched with 1n hcl solution to pH 2 and the resulting residue was filtered. The solid was washed with methanol and dried in vacuo to give the desired compound, compound I-450 as a white solid (1.45g, 68% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.04(d,1H),7.71(s,1H),7.23-7.36(m,1H),7.00-7.18(m,2H),6.90(t,1H),5.94(s,2H),2.56(s,3H)。

Compound I-451

The title compound was prepared in 2 steps.

Step 1: synthesis of 1- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) ethanone

Compound I-450 was charged with phosphorus oxychloride (60 equivalents) and the resulting mixture was stirred at 45 ℃ until the reaction was complete as judged by LC/MS. The reaction was then carefully poured onto ice, extracted with 4:1 dichloromethane/isopropanol and the layers separated. The organic portions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The material was taken to the next step without further purification.

Step 2: synthesis of Compound I-451

The title compound was prepared according to general procedure B except 1- ((methylamino) methyl) cyclopropanecarboxylic acid was the amine reactant, 1- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) ethanone was used instead of intermediate 1, and the contents were heated to 100 ℃ as a solution in dioxane for 36H. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-451 as a tan solid (50mg, 69% yield).

¹H NMR(500MHz,DMSO-d6)δppm 12.53(br.s,1H),8.19(d,1H),7.65(s,1H),7.33(d,1H),7.17-7.26(m,1H),7.11(t,1H),6.86(t,1H),5.81(s,2H),4.00(s,2H),3.24(d,3H),2.57(s,3H),1.03(d,2H),0.74-0.91(m,2H)。

Compound I-452 and compound I-453

The title compound was prepared according to general procedure B, except that 4- (trifluoromethyl) piperidine-2-carboxylic acid was the amine reactant, Hunig's base (8 equivalents) was used instead of triethylamine, and the contents were heated to 120 ℃ as a solution in THF/water (1:1) for 18 h. The solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC, then silica gel chromatography with a 0-10% methanol/dichloromethane gradient to give the desired compound, compound I-452 as a solid (14mg, 15% yield) and compound I-453 as a solid (18.4mg, 21% yield). The distribution of trans to cis is carried out in any mode during synthesis; each diastereomer is a mixture of racemates.

Of Compound I-452¹H NMR(500MHz,CD₃OD)δ8.72-8.79(m,1H),8.20-8.25(m,1H),7.41-7.47(m,1H),7.22-7.32(m,1H),6.99-7.14(m,2H),6.87-6.92(m,1H),6.76-6.84(m,1H),5.93-5.99(m,2H),5.59-5.76(m,1H),4.64-4.80(m,1H),3.38-3.46(m,1H),2.55-2.63(m,1H),2.40-2.54(m,1H),2.00-2.08(m,1H),1.84-1.96(m,1H),1.64-1.75(m,1H)。

Process for preparation of Compound I-453¹H NMR(500MHz,CD₃OD)δ8.73-8.79(m,1H),8.23-8.33(m,1H),7.43(s,1H),7.24-7.31(m,1H),7.07-7.13(m,1H),7.00-7.06(m,1H),6.82-6.88(m,2H),5.96(s,2H),4.52-4.60(m,1H),4.05-4.14(m,1H),3.75-3.85(m,1H),2.64-2.78(m,1H),2.41-2.49(m,1H),2.12(dd,2H),1.77-1.87(m,1H)。

Compound I-454

The title compound was prepared according to general procedure B except 3- (trifluoromethyl) piperidine-2-carboxylic acid (5 equivalents) was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (3:1) for 18 h. The solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC, then silica gel chromatography with a 0-15% methanol/dichloromethane gradient to give the desired compound, compound I-454(1.6mg, 4% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.76-8.80(m,1H),8.28-8.33(m,1H),7.49(s,1H),7.25-7.32(m,1H),7.02-7.13(m,2H),6.84-6.90(m,2H),5.94-6.00(m,2H),5.37-5.41(m,1H),4.35-4.43(m,1H),3.80-3.89(m,1H),2.89-3.00(m,1H),1.93-2.08(m,3H),1.77-1.90(m,1H)。

Compound I-455

The title compound was prepared according to general procedure B except 3-ethylpiperidine-2-carboxylic acid (1 equivalent) was the amine reactant and the contents were heated to 90 ℃ as a solution in THF/water (5:1) for 18 h. The solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-455(5mg, 15% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.81-8.86(m,1H),8.33-8.40(m,1H),7.53-7.59(m,1H),7.27-7.35(m,1H),7.03-7.16(m,2H),6.91-7.00(m,2H),5.99-6.05(m,2H),5.39-5.47(m,1H),4.55-4.68(m,1H),3.78-3.89(m,1H),1.75-2.06(m,5H),1.46-1.60(m,2H),1.07-1.13(m,3H)。

Compound I-362

The title compound was prepared according to general procedure B except that 1- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) ethanone (described in step 1 of the synthesis for compound I-451) was used instead of intermediate 1,2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol as the amine reactant and the contents were heated to 100 ℃ as a solution in dioxane for 36H. The resulting crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient followed by further purification by reverse phase HPLC to afford the desired compound, compound I-362 as an off white solid (7mg, 14% yield).

¹H-NMR(500MHz,DMSO-d6)δppm 8.54(s,1H),8.36(d,1H),8.07(br.s.,1H),7.58-7.69(m,1H),7.33(q,1H),7.16-7.26(m,1H),7.10(t,1H),6.92-7.02(m,1H),5.81(s,2H),4.12(d,2H),2.56(s,3H)。

Compound I-462

The title compound was prepared according to general procedure B except that 1- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) ethanone (described in step 1 of the synthesis for compound I-451) was used instead of intermediate 1, 2-aminopropane-1, 3-diol as the amine reactant and the contents were heated to 100 ℃ as a solution in dioxane for 36H. The resulting crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient followed by further purification by reverse phase HPLC to afford the desired compound, compound I-462 as an off white solid (10mg, 26% yield).

¹H-NMR(500MHz,DMSO-d6)δppm 8.18(d,1H),7.65(d,1H),7.33(q,1H),7.21(dd,2H),7.10(t,1H),6.79(t,1H),5.82(s,2H),4.72(t,2H),4.33(d,1H),3.52-3.64(m,4H),2.57(s,3H)。

Compound I-463

The title compound was prepared according to general procedure B except that 1- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) ethanone (described in step 1 of the synthesis for compound I-451) was used instead of intermediate 1, (2R,3S) -3-methylpiperidine-2-carboxylic acid was the amine reactant and the contents were heated to 100 ℃ as a solution in dioxane for 36H. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient followed by further purification by reverse phase HPLC to afford the desired compound, compound I-463 as an off white solid (6.5mg, 15% yield).

¹H-NMR (500MHz, DMSO-d6) delta ppm 8.38(d,1H),7.69(s,1H),7.33(q,1H),7.17-7.27(m,1H),7.11(t,1H),6.77-6.89(m,1H),5.82(s,2H),4.85(d,1H),4.26-4.28(m,1H),3.48-3.57(m,1H),2.56(s,3H),1.98-2.12(m,1H),1.83(d,1H),1.58-1.71(m,2H),1.34-1.47(m,1H),1.11(d,3H), COOH proton exchange.

Compound I-519

2- ((tert-butoxycarbonyl) amino) acetic acid (1 eq), HATU (1.1 eq) and Hunig's base (1.3 eq) were stirred as a solution in DMF at 23 ℃ for 2 h. A single portion of intermediate 2(1 eq) was then added and the contents heated in a microwave at 100 ℃ for 30 min. The reaction was quenched by addition of water, extracted with ethyl acetate and washed with water and brine. And (3) organic extraction. The mixture was dried, filtered, concentrated in vacuo, and purified via silica gel chromatography to give the desired compound, compound I-519(60mg, 53% yield) as a yellow solid.

¹H-NMR(500MHz,DMSO-d6)δppm 11.03-11.19(m,1H),9.11(d,1H),8.73(d,1H),7.93-8.04(m,1H),7.65(s,1H),7.33(q,1H),7.20-7.29(m,2H),7.06-7.16(m,2H),6.89(t,1H),5.92(s,2H),3.83(d,2H),1.36-1.42(m,9H)。

Compound I-520

To a solution of compound I-519 in dichloromethane at 0 ℃ was added an equal volume of trifluoroacetic acid and the contents were allowed to warm to 23 ℃ over a period of 12 h. The contents were dried in vacuo and the resulting residue was dissolved in saturated NaHCO₃To the solution and extracted with a mixture of isopropanol/dichloromethane. The contents were dried, filtered, and concentrated in vacuo to give the desired compound, compound I-520(37mg, 79% yield) as a brown solid.

¹H-NMR(400MHz,DMSO-d₆) δ ppm 9.10(d,1H),8.74(d,1H),8.04(d,1H),7.68(s,1H),7.34(q,1H),7.29(d,1H),7.18-7.26(m,1H),7.11(t,1H),6.88(t,1H),5.93(s,2H),3.36(s,2H), NH proton exchange.

Compound I-535

To a solution of compound I-520(1 eq) and triethylamine (2 eq) in dichloromethane maintained at 0 ℃ was added acetyl chloride (1.2 eq) and the resulting mixture was warmed to 23 ℃ over a period of 18 h. The solvent was removed in vacuo and the resulting residue was triturated with an ethyl acetate/hexane mixture. The contents were filtered and the resulting solid was dried in vacuo to give the desired compound, compound I-535(6mg, 53% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d6)δppm 11.18(s,1H),9.11(d,1H),8.73(d,1H),8.22(t,1H),7.98(d,1H),7.66(s,1H),7.30-7.39(m,1H),7.27(d,1H),7.20-7.26(m,1H),7.12(td,1H),6.89(t,1H),5.93(s,2H),3.97(d,2H),1.83-1.93(m,3H)。

Compound I-543

To a solution of compound I-520(1 eq) and triethylamine (6 eq) in dichloromethane maintained at 0 ℃ was added methanesulfonyl chloride (3.3 eq) and the resulting mixture was warmed to 23 ℃ over a period of 3 h. The reaction was quenched by addition of water and the mixture was extracted with dichloromethane. The contents were dried, concentrated in vacuo, and purified via silica gel chromatography to give the desired compound, compound I-543(6.2mg, 47% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.17(s,1H),9.11(d,1H),8.76(d,1H),8.00(d,1H),7.66(s,1H),7.54(t,1H),7.30-7.39(m,1H),7.27(d,1H),7.21-7.26(m,1H),7.12(t,1H),6.89(t,1H),5.93(s,2H),3.99(d,2H),2.98(s,3H)。

Compound I-584

To a solution of compound I-520(1 eq) in dichloromethane was added isocyanatotrimethylsilane (1.1 eq) and the resulting suspension was heated to 40 ℃ for 18 h. After completion of the reaction, the solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-584 as a white solid (16mg, 55% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.02(s,1H),9.10(d,1H),8.73(d,1H),7.99(d,1H),7.59-7.68(m,1H),7.30-7.37(m,1H),7.19-7.27(m,2H),7.12(t,1H),6.89(t,1H),6.25(t,1H),5.93(s,2H),5.72(s,2H),3.90(d,2H)。

Compound I-585

To a solution of compound I-520(1 eq) in dichloromethane was added isopropyl isocyanate (1.1 eq) and the resulting mixture was heated to 40 ℃ for 18 h. After completion of the reaction, the solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-585 as a white solid (19mg, 59% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.04(s,1H),9.10(d,1H),8.72(d,1H),7.98(d,1H),7.64(s,1H),7.30-7.38(m,1H),7.19-7.28(m,2H),7.12(td,1H),6.85-6.95(m,1H),6.09(d,1H),6.01(t,1H),5.92(s,2H),3.92(d,2H),3.58-3.71(m,1H),1.03(d,6H)。

Compound I-586

To a solution of compound I-520(1 eq) and triethylamine (2 eq) in dichloromethane was added dimethylsulfamoyl chloride (1.5 eq) and the mixture was heated to 40 ℃ for 18 h. After completion of the reaction, the solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-586 as a white solid (9mg, 28% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.12(s,1H),9.10(d,1H),8.75(d,1H),8.00(d,1H),7.64(s,1H),7.58(t,1H),7.30-7.38(m,1H),7.19-7.27(m,2H),7.12(td,1H),6.90(t,1H),5.92(s,2H),3.92(d,2H),2.67(s,6H)。

Compound I-633

The title compound was prepared according to general procedure B except that (3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) methanol was the amine reactant and the contents were heated to 100 ℃ as a solution in THF/dioxane/water (1:10:1) for 48 h. The crude material was purified via silica gel chromatography with a 0-10% methanol/dichloromethane gradient followed by reverse phase HPLC to give the desired compound, compound I-633 as an off white solid (6mg, 36% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.46(d,1H),7.67(s,1H),7.30-7.38(m,1H),7.28(d,1H),7.19-7.25(m,1H),7.11(t,1H),6.85(t,1H),5.88-5.98(m,2H),5.61(d,1H),5.20(t,1H),5.13(br.s.,1H),4.82(d,1H),4.38-4.51(m,2H),3.64(dt,1H),3.50-3.59(m,1H)。

Compound I-466

The title compound was prepared according to general procedure B except 2,2, 2-trifluoroethylamine (as the HCl salt) was the amine reactant and the contents were heated to 90-100 ℃ for 42 h. The crude material was purified via preparative HPLC using a 25-80% acetonitrile/water gradient (containing 0.1% TFA) to give the desired compound, compound I-466 as a white solid (35mg, 60% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.76(d,1H),8.20(d,1H),7.46(s,1H),7.28(app.q,1H),7.10(m,1H),7.03(app.t,1H),6.92(d,1H),6.80(app.t,1H),5.97(s,2H),4.44(q,2H)。

Compound I-487

The title compound was prepared according to general procedure B except 2- (methylsulfonyl) ethylamine (as the HCl salt) was the amine reactant and the contents were heated to 100 ℃ for 17 h. The contents were cooled to ambient temperature, diluted with water and acidified to pH 3 with 1N HCl solution. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-487, as a white solid (56mg, 91% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.24(d,1H),7.93(br.t,1H),7.54(s,1H),7.33(app.q,1H),7.22(m,1H),7.18(d,1H),7.11(app.t,1H),6.88(app.t,1H),5.89(s,2H),3.87(dt,2H),3.46(t,2H),3.06(s,3H)。

Compound I-502

The title compound was prepared according to general procedure B except (1-aminocyclopropyl) methanol (as the HCl salt) was the amine reactant and the contents were heated to 100 ℃ for 6.5 h. The crude material was purified via silica gel chromatography with a 15% acetonitrile-methanol in dichloromethane (7:1) gradient to give the desired compound, compound I-502(54mg, 90% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.10(d,1H),8.18(d,1H),8.00(s,1H),7.41(s,1H),7.33(app.q,1H),7.24-7.20(m,1H),7.22(d,1H),7.11(app.t,1H),6.89(app.t,1H),5.86(s,2H),4.89(t,1H),3.63(d,2H),0.85(m,2H),0.77(m,2H)。

Compound I-581

The title compound was prepared according to general procedure B, except 3-aminopropionamide (as the HCl salt) was the amine reactant and the contents were heated to 100 ℃ for 21 h. The contents were cooled to ambient temperature, diluted with water and acidified to pH 4 with 1N HCl solution. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-581 as a white solid (66mg, 89% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.08(d,1H),8.17(d,1H),7.65(t,1H),7.50(s,1H),7.34(br.s,1H),7.32(app.q,1H),7.24-7.18(m,1H),7.21(d,1H),7.10(app.t,1H),6.86(br.s,1H),6.84(m,1H),5.90(s,2H),3.67(dt,2H),2.45(t,2H)。

Compound I-515

A solution of compound I-358 in dichloromethane was treated with N, N-diisopropylethylamine (2 equivalents), followed by O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After 1h, ammonia (0.5N solution in dioxane, 3 equivalents) was added and the light brown orange was stirred for 21 h. The resulting brownish suspension was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a gradient of 10-15% acetonitrile: methanol in dichloromethane 7:1 to give the desired compound, compound I-515 as a white solid (36mg, 73% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.76(s,1H),8.10(d,1H),7.42(s,1H),7.28(app.q,1H),7.10(m,1H),7.05(app.t,1H),6.90(s,1H),6.89(m,1H),5.96(s,2H),3.88(s,2H),1.20(m,2H),1.02(m,2H)。

Compound I-536

A solution of compound I-86 in dichloromethane was treated with N, N-diisopropylethylamine (2 equivalents) followed by HATU (1.5 equivalents). After 1h, ammonia (0.5N solution in dioxane, 3 equivalents) was added and the reaction was stirred for 24 h. The resulting mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a gradient of 10-25% acetonitrile: methanol to 7:1 in dichloromethane to afford the desired compound, compound I-536, as an off-white solid (33mg, 81% yield).

¹H-NMR(500MHz,CDCl₃)δppm 8.47(d,1H),8.15(d,1H),7.28(s,1H),7.22(app.q,1H),7.03(app.t,1H),6.99(app.t,1H),6.94(app.t,1H),6.61(d,1H),6.56(br.s,1H),5.99(d,1H),5.89(d,1H),5.60(d,1H),5.50(br.s,1H),4.57(app.t,1H),2.32(m,1H),1.09(d,3H),1.07(d,3H)。

Compound I-537

A solution of compound I-69 in dichloromethane was treated with N, N-diisopropylethylamine (2 equivalents) followed by HATU (1.5 equivalents). After 1h, ammonia (0.5N solution in dioxane, 3 equivalents) was added and the reaction was stirred for 24 h. The resulting mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a gradient of 10-25% acetonitrile: methanol in dichloromethane 7:1 to give the desired compound, compound I-537 as a white solid (27mg, 65% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.23(d,1H),7.57(br.s,1H),7.53(s,1H),7.38-7.30(m,2H),7.24-7.16(m,2H),7.16(d,1H),7.10(app.t,1H),6.85(app.t,1H),5.87(s,2H),4.42(app.t,1H),2.20(m,1H),0.97(app.t,6H)。

Compound I-538

A solution of compound I-85 in dichloromethane was treated with N, N-diisopropylethylamine (2 equivalents) followed by HATU (1.5 equivalents). After 1h, ammonia (0.5N solution in dioxane, 3 equivalents) was added and the reaction was stirred for 24 h. The resulting mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a gradient of 10-25% acetonitrile: methanol to 7:1 in dichloromethane to give the desired compound, compound I-538(36mg, 86% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.10(d,1H),8.22(m,2H),7.40(br.s,1H),7.36-7.28(m,2H),7.23(m,1H),7.15(s,1H),7.11(app.t,1H),6.98(br.s,1H),6.86(app.t,1H),5.86(s,2H),1.42(m,2H),1.02(m,2H)。

Compound I-546

A suspension of compound I-67 in dichloromethane was treated with bis (1H-imidazol-1-yl) methanone (CDI, 3 equivalents) and the resulting mixture was heated at 45 ℃ for 1H 40 min. After cooling to ambient temperature, methanesulfonamide (5 equivalents) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 1 equivalent) were added and the reaction was heated at 45 ℃ for 1 h. The resulting mixture was cooled to ambient temperature, quenched with 1N HCl solution, and extracted with dichloromethane/isopropanol (4: 1). The crude solid was dissolved in water with the aid of 1N NaOH solution and acidified to pH 3-4 by dropwise addition of 1N hcl. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-546(39mg, 80% yield) as a tan solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 12.1(s,1H),9.11(d,1H),8.27(d,1H),8.17(br.s,1H),7.52(s,1H),7.32(app.q,1H),7.22(m,1H),7.12(d,1H),7.10(m,1H),6.79(app.t,1H),5.88(s,2H),4.12(d,2H),3.17(s,3H)。

Compound I-566

The title compound was synthesized in 4 steps.

Step 1:synthesis of 2- ((4-methoxybenzyl) oxy) acetic acid

To a solution of (4-methoxyphenyl) methanol (1 eq) and 2-bromoacetic acid (1.2 eq) in anhydrous THF at 0 deg.C was added 3 parts of sodium hydride (60% w/w in mineral oil, 3 eq). The mixture was stirred at 70 ℃ for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was washed with hexane. The aqueous phase was acidified to pH 2 with 1N HCl and extracted with ethyl acetate. The organic layer was dried, filtered and the solvent removed in vacuo. Purification via silica gel chromatography with 50% ethyl acetate in hexanes afforded 2- ((4-methoxybenzyl) oxy) acetic acid (0.51g, 71% yield) as a clear solid.

¹H NMR(500MHz,CDCl₃)δppm 7.29(m,2H),6.90(m,2H),4.59(s,2H),4.10(s,2H),3.81(s,3H)。

Step 2:synthesis of 2- ((4-methoxybenzyl) oxy) -N- (2,2, 2-trifluoroethyl) acetamide

A solution of 2- ((4-methoxybenzyl) oxy) acetic acid (1 eq) in dichloromethane was treated with N, N-diisopropylethylamine (1.5 eq), followed by HATU (1.2 eq). After 30min, N-diisopropylethylamine (2 eq) and 2,2, 2-trifluoroethylamine hydrochloride (2 eq) were added and the reaction was stirred for 17 h. The resulting mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a 10-20% ethyl acetate/hexanes gradient to give 2- ((4-methoxybenzyl) oxy) -N- (2,2, 2-trifluoroethyl) acetamide as a white solid (0.28g, 78% yield).

¹H NMR(500MHz,CDCl₃)δppm 7.26(d,2H),6.91(d,2H),6.89(br.s,1H),4.52(s,2H),4.02(s,2H),3.93(dq,2H),3.82(s,3H)。

And step 3:synthesis of N- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -2- ((4-methoxybenzyl) oxy) -N- (2,2, 2-trifluoroethyl) acetamide

A suspension of 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (1 eq), 2- ((4-methoxybenzyl) oxy) - -N- (2,2, 2-trifluoroethyl) acetamide (1 eq) and cesium carbonate (0.8 eq) in anhydrous dioxane was heated at 100 ℃ for 4 days. The resulting mixture was poured into half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography using a 10-20% ethyl acetate/hexanes gradient to give N- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -2- ((4-methoxybenzyl) oxy) -N- (2,2, 2-trifluoroethyl) acetamide as a clear oil (16mg, 12% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.65(d,1H),8.49(d,1H),7.32(s,1H),7.22(app.q,1H),7.07-6.96(m,4H),6.89(app.t,1H),6.73(d,2H),6.60(d,1H),6.01(s,2H),4.68(q,2H),4.33(s,2H),4.31(s,2H),3.71(s,3H)。

Step 4: synthesis of Compound I-566

A biphasic solution of N- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-yl) -2- ((4-methoxybenzyl) oxy) -N- (2,2, 2-trifluoroethyl) acetamide (1 eq) in dichloromethane/water (10:1) was treated with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ, 1.2 eq) and stirred for 20H. An additional amount of DDQ (2.4 equivalents) was added and the reaction was stirred for 5 days. The reaction mixture was diluted with dichloromethane and filtered. The crude solution was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography using a 15-50% ethyl acetate/hexanes gradient to give the desired compound, compound I-566 as a white solid (2.6mg, 45% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.78(d,1H),8.55(d,1H),7.44(s,1H),7.26(app.q,1H),7.09(m,1H),7.03(app.t,1H),6.87(d,1H),6.80(app.t,1H),5.97(s,2H),5.16(s,2H),3.94(q,2H)。

Compound I-457

The title compound was synthesized in 2 steps.

Step 1:synthesis of 3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile

A suspension of 3- (5-fluoro-6-oxo-1, 6-dihydropyrimidin-2-yl) - -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile, which compound is described in the previous patent application publication WO2013/101830, in phosphorus oxychloride (50 equivalents) as solvent was heated to 65 ℃ for 2H 15 min. The reaction mixture was blow dried under a stream of nitrogen and then concentrated twice from toluene. The resulting reddish brown oil/solid was dried in vacuo and used in the next step without further manipulation.

Step 2: synthesis of Compound I-457

The title compound was prepared according to general procedure B except 3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile was the chloropyrimidine reactant and (2R,3S) -3-methylpiperidine-2-carboxylic acid was the amine reactant, and the contents were heated to 100 ℃ for 18H. The contents were cooled to ambient temperature, diluted with water, acidified to pH 3 with 1N HCl solution, and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via reverse phase HPLC using a 25-80% acetonitrile/water gradient (containing 0.1% TFA) to give the desired compound, compound I-457 as a white solid (18mg, 38% yield over 2 steps).

¹H-NMR(500MHz,CD₃OD)δppm 8.32(d,1H),7.65(s,1H),7.41(app.q,1H),7.36(app.t,1H),7.23-7.13(m,2H),5.71(s,2H),5.17(d,1H),4.48(br.d,1H),3.78(app.t,1H),2.13(m,1H),1.94(m,1H),1.78(m,2H),1.54(m,1H),1.22(d,3H)。

Compound I-474 the title compound was prepared following general procedure B except that 3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile (generated in step 1 of the synthesis for compound I-457) was used as the amine reactant instead of intermediate 1,2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol, and the contents were heated to 100 ℃ for 16H. The contents were cooled to ambient temperature, diluted with water, acidified to pH 3 with 1N HCl solution, and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via reverse phase HPLC with a 25-80% acetonitrile/water gradient (containing 0.1% TFA) to give the desired compound, compound I-474 as a white solid (31mg, 49% yield from 3- (5-fluoro-6-oxo-1, 6-dihydropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile over 2 steps).

¹H-NMR(500MHz,CDCl₃) δ ppm 8.30(s,1H),7.49(app.t,1H),7.38(s,1H),7.35(app.q,1H),7.17(app.t,1H),7.12(app.t,1H),5.65(br.s,1H),5.60(s,2H),4.12(d, 2H). Not observedOne of the protons may be exchanged.

Compound I-480

The title compound was prepared according to general procedure B except that 3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile (generated in step 1 of the synthesis for compound I-457) was used instead of intermediate 1, and 1- (1-carboxycyclopropyl) -N-methyl methylamine (as the HCl salt) was the amine reactant, and the contents were heated to 100 ℃ for 17H. The contents were cooled to ambient temperature, diluted with water, acidified to pH 3 with 1N HCl solution, and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified by preparative HPLC using a 15-70% acetonitrile/water gradient (containing 0.1% TFA) to give the desired compound, compound I-480 as an off-white solid (90mg, 66% yield from 3- (5-fluoro-6-oxo-1, 6-dihydropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazole-5-carbonitrile over 2 steps).

¹H-NMR(500MHz,DMSO-d₆)δppm 12.3(br.s,1H),8.24(d,1H),7.66(s,1H),7.44(app.q,1H),7.36(app.t,1H),7.30-7.22(m,2H),5.65(s,2H),3.99(s,2H),3.24(d,3H),1.13(m,2H),1.01(m,2H)。

Compound I-476

A solution of compound I-474 in 1N NaOH solution (excess) was heated at 65 ℃ for 70 min. The reaction mixture was cooled to ambient temperature and acidified to pH 3 with 1N HCl solution. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-476 as a white solid (13mg, 77% yield).

¹H-NMR(500MHz,DMSO-d₆) δ ppm 8.50(s,1H),8.34(d,1H),8.03(br.t,1H),7.35(app.q,1H),7.32(s,1H),7.22(m,1H),7.13(app.t,1H),7.02(app.t,1H),5.87(s,2H),4.13(d, 2H). Exchangeable carboxylic acid protons were not observed.

Compound I-481

A suspension of compound I-480 in water was treated with 1N NaOH solution (2 equiv.) and stirred at ambient temperature for 18 h. The reaction mixture was acidified to pH 3 with 1N HCl solution. The resulting precipitate was filtered and dried in vacuo to give the desired compound, compound I-481 as a white solid (7.4mg, 64% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 12.3(br.s,1H),8.22(d,1H),8.14(br.s,1H),7.60(br.s,1H),7.53(s,1H),7.33(app.q,1H),7.21(m,1H),7.12(app.t,1H),6.90(app.t,1H),5.90(s,2H),3.99(s,2H),3.24(d,3H),1.14(m,2H),1.02(m,2H)。

Compound I-327

To a solution of 1, 2-diethoxycyclobutenedione (1.3 equiv.) and sodium hydride [ 60% dispersion in mineral oil ] in THF](1 eq) to the mixture was added intermediate 2(1 eq). The mixture was stirred at 0 ℃ for 1h, then removed from the ice bath and allowed to stir at 23 ℃ for 24 h. The mixture was diluted with ethyl acetate and washed with 1N HCl solution. The organic layer was purified over MgSO₄Dried, filtered and evaporated to give a solid. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-327 as a light yellow solid (90mg, 43% yield).

¹H NMR(400MHz,DMSO-d₆)δppm 9.12(d,1H),8.69(d,1H),7.67(s,1H),7.30-7.38(m,1H),7.29(d,1H),7.24(d,1H),7.20(d,1H),7.09-7.15(m,1H),6.86-6.92(m,1H),5.92(s,2H),4.81(q,2H),1.36(t,3H)。

Compound I-402

A mixture of compound I-327(1 eq) and HCl [1.0M in water ] (1 eq) in MeOH was heated to 65 ℃ for 2 h. After cooling the mixture to 23 ℃, a yellow precipitate formed, which was collected via filtration and washed with a minimum amount of methanol. The collected precipitate was dried in vacuo to give the desired compound, compound I-402(50mg, 76% yield) as a yellow solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.08-9.17(m,1H),8.64(d,1H),7.73(s,1H),7.30-7.42(m,1H),7.28(s,1H),7.17-7.26(m,2H),7.12(t,1H),6.90-7.04(m,1H),5.85-6.03(m,2H)。

Compound I-456

To a cold solution of triethylamine (1.5 eq) in dichloromethane at 0 ℃ was added chlorosulfonyl isocyanate (1.5 eq). The mixture was stirred at 0 ℃ for 30 min. To this mixture was added intermediate 2(1 eq) and tert-butanol (1.5 eq) and the contents were stirred at 23 ℃ for 24 h. The mixture was diluted with ethyl acetate and washed with water. The precipitate was removed by filtration. The organic layer was purified over MgSO₄Dried, filtered and concentrated in vacuo to give a crude oil which was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give tert-butyl N- (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) sulfamoylcarbamate, the desired Boc-protected sulfonamide intermediate. This intermediate was dissolved in methanol and dissolved with a 4.0M solution of HCl [1, 4-dioxane](5 equivalents) and stirred at 23 ℃ for 24 h. The mixture was concentrated in vacuo to give the desired compound, compound I-456(26mg, 6% yield, HCl salt) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.85(d,1H),8.54(d,1H),7.88(s,1H),7.26-7.34(m,2H),7.00-7.14(m,4H),6.05-6.08(m,2H)。

Compound I-467

The title compound was synthesized in 3 steps.

Step 1:synthesis of 2- (bromomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid

A mixture of 2- (bromomethyl) -3,3, 3-trifluoro-2-hydroxypropionitrile (1 eq), water (1 eq), and concentrated sulfuric acid (4 eq) was heated to 110 ℃ in a sealed vial for 1 h. The mixture was poured onto ice and extracted with ether. The organic layer was purified over MgSO₄Drying, filtering and vacuum concentrating to obtain2- (bromomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid as a clear oil (1.3g, 33% yield).

¹H NMR(500MHz,CDCl₃)δppm 3.89(d,1H),3.63-3.69(m,1H)。

Step 2:synthesis of 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid

A mixture of ammonium hydroxide [ 28% aqueous solution ] (10 equivalents) and 2- (bromomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid (1 equivalent) was stirred at 23 ℃ for 24 h. The mixture was concentrated in vacuo. The resulting solid was treated with a minimum amount of ethanol. The precipitate was collected by filtration and dried in vacuo to give 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid (412mg, 43% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 2.86-3.27(m,2H)。

And step 3:synthesis of Compound I-467

The title compound was prepared according to general procedure B except 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid (4 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated to 85 ℃ as a solution in 1, 4-dioxane/water (4:1) for 24 h. The mixture was cooled to 23 ℃ and diluted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution over MgSO₄Dried, filtered and concentrated in vacuo to give a crude solid. The crude material was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-467(50mg, 7% yield for step 3) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 8.28(d,1H),7.59(t,1H),7.46(s,1H),7.30-7.36(m,1H),7.16-7.24(m,2H),7.10(t,1H),6.91(t,1H),5.88(s,2H),4.24(dd,1H),3.84(dd,1H)。

Compound I-468

A mixture of CDI (6 equivalents) and 3,3, 3-trifluoro-2-hydroxy-2- (trifluoromethyl) propionic acid (6 equivalents) in THF was heated to 90 ℃ for 1 h. To this mixture was added 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-morpholinopyrimidin-4-amine (this intermediate is described in the previously published patent application WO2012/3405a1, 1 equivalent). The mixture was stirred at 90 ℃ for 24 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was purified over MgSO₄Dried, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-468(18mg, 62%) as a light yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.76(d,1H),8.64(s,1H),7.60-7.63(m,1H),7.20-7.26(m,1H),7.00-7.06(m,1H),6.98(t,1H),6.92(d,1H),6.74-6.83(m,1H),5.93(s,2H),3.88-3.92(m,4H),3.04-3.09(m,4H)。

Compound I-473

To 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (this intermediate is described in the previously published patent application WO2012/3405a1, 1 equivalent) and 3,3, 3-trifluoro-2- (trifluoromethyl) -2- (((trimethylsilyl) oxy) propionyl chloride (3 equivalents) [ prepared according to the procedure described in Aicher, t.d. et al j.med.chem.2000,43,245, Method j]LiHMDS (2.0M in THF, 3 equivalents) was added very slowly to the mixture at 23 ℃ in THF. The exothermic reaction immediately turned dark brown. The mixture was stirred at 23 ℃ for 1h, then diluted in ethyl acetate and washed with 1N HCl solution. The precipitate was removed by filtration. The organic layer was purified over MgSO₄Dried, filtered and concentrated in vacuo to give a crude oil. The oil was purified by silica gel chromatography using a 0-30% ethyl acetate/hexanes gradient to give the desired compound, compound I-473 as a yellow solid (11mg, 3% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),8.80(s,1H),7.60(s,1H),7.27-7.33(m,1H),7.09-7.15(m,1H),7.06(t,1H),6.94(d,1H),6.90(t,1H),6.00(s,2H)。

Compound I-477

To a mixture of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (described in WO2012/3405a1, 1 eq) and morpholine-4-carbonyl chloride (1.2 eq) in THF at 23 ℃ LiHMDS (2.0M in THF, 1.2 eq) was added very slowly. The mixture was stirred at 23 ℃ for 24 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was purified over MgSO₄Dried, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography with a gradient of 0-5% methanol in DCM to give the desired product, compound I-477(24mg, 18% yield) as a light yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.49-8.54(m,1H),7.47(s,1H),7.33-7.42(m,1H),7.23-7.30(m,1H),7.12-7.22(m,1H),6.99-7.11(m,2H),6.87(d,1H),5.95(s,2H),3.72(q,4H),3.56-3.62(m,4H)。

Compound I-482

To a cold mixture of triphosgene (0.75 equivalents) and 3-bromo-1, 1, 1-trifluoro-propan-2-ol (1.5 equivalents) in dichloromethane was added pyridine (1.5 equivalents). The mixture was stirred at 0 ℃ for 30 min. In a separate flask, a suspension of intermediate 2(1 eq) in pyridine was cooled to 0 ℃. To this suspension was transferred a mixture of triphosgene and bromopropanol via syringe. The mixture was heated to 60 ℃ for 24 h. The contents were diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was purified over MgSO₄Dried, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-482(46mg, 9% yield) as a white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.79(d,1H),8.50(d,1H),8.11-8.14(m,1H),7.43(s,1H),7.19-7.27(m,1H),6.96-7.10(m,2H),6.87-6.93(m,1H),6.62(d,1H),5.99-6.03(m,2H),4.99-5.07(m,1H),4.57-4.65(m,1H),4.49-4.56(m,1H)。

Compound I-492

A solution of 2, 2-bis (trifluoromethyl) -2-hydroxyacetic acid (3eq) and CDI (3eq) in THF was heated to 80 ℃ for 1 h. To this mixture was added a solution of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate described in the previous WO2012/3405 a 1; 1 equivalent) in NMP. The resulting mixture was heated to 200 ℃ in a microwave for 1 h. The contents were diluted in ethyl acetate and washed with water. The organic layer was purified over MgSO₄Dried, filtered and dried in vacuo to give a crude oil. The oil was purified by silica gel chromatography with a 0-100% ethyl acetate/hexanes gradient to give the desired product, compound I-492 as a yellow solid (25mg, 8% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.48(d,1H),7.37(s,1H),7.18-7.25(m,2H),7.00-7.06(m,1H),6.98(t,1H),6.85(t,1H),6.59(d,1H),5.99(s,2H)。

Compound I-493

A mixture of compound I-403(1 eq), HOBT (3eq), triethylamine (3eq), HATU (3eq) and cyclopropylamine (3eq) in DMF was stirred at 23 ℃ for 24 h. The mixture was diluted with ethyl acetate and washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution and brine. The organic layer was purified over MgSO₄Dried, filtered and concentrated in vacuo to give a crude oil. The oil was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired product, compound I-493 as a white solid (20.4mg, 27% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.76-8.80(m,1H),8.25-8.29(m,1H),7.47-7.49(m,1H),7.24-7.31(m,1H),7.07-7.14(m,1H),7.03(t,1H),6.87-6.90(m,1H),6.77(t,1H),5.95-5.99(m,2H),5.87-5.94(m,1H),2.70-2.77(m,1H),0.70-0.78(m,2H),0.47-0.54(m,2H)。

Compound I-504

The title compound was synthesized in 2 steps.

Step 1:synthesis of (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) carbamic acid 2-bromo-3, 3, 3-trifluoropropyl ester

To a cold mixture of triphosgene (0.9 eq) and 2-bromo-3, 3, 3-trifluoropropan-1-ol (2 eq) in THF was added pyridine (2 eq). The mixture was stirred at 0 ℃ for 30 min. In a separate flask, a suspension of intermediate 2(1 eq) in pyridine (2 eq) was cooled to 0 ℃. To this suspension was added a mixture of triphosgene and bromopropanol via syringe and the resulting mixture was heated to 60 ℃ for 24 h. The contents were concentrated in vacuo and the residue was diluted with ethyl acetate and washed with 1n hcl solution. The organic layer was purified over MgSO₄Dried, filtered and concentrated in vacuo to give a crude oil. The oil was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired carbamate intermediate, 2-bromo-3, 3, 3-trifluoropropyl (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) carbamate as a light brown oil (77mg, 4% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.46-8.48(m,1H),8.07(br.s.,1H),7.86(d,1H),7.44-7.47(m,1H),7.17-7.24(m,1H),7.00-7.07(m,1H),6.93-7.00(m,1H),6.78-6.85(m,1H),6.57-6.62(m,1H),6.02(s,2H),4.28(quind,1H),3.93-4.15(m,2H)。

Step 2:synthesis of Compound I-504

To a solution of 2-bromo-3, 3, 3-trifluoropropyl (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) carbamate (1eq) in THF was added LiHMDS (2.0M in THF, 1 eq). The mixture was sealed and heated to 60 ℃ for 2 days. The mixture was diluted with ethyl acetate and washed with water. The organic layer was purified over MgSO₄Dried, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography using a 0-100% ethyl acetate/hexane gradient and mixed from ether-hexaneThe compound was recrystallized to give the desired product, compound I-504 as a white solid (7mg, 11% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.13(s,1H),8.84(s,1H),7.99(d,1H),7.70(s,1H),7.31-7.38(m,1H),7.19-7.26(m,2H),7.12(t,1H),6.91(t,1H),6.03-6.09(m,1H),5.86-5.98(m,2H),4.73-4.80(m,2H)。

Compound I-544

A mixture of compound I-419(1 equivalent) and lithium aluminum hydride (2 equivalents) in THF was heated to 60 ℃ for 24 h. The mixture was cooled to 23 ℃ and then treated sequentially with water (x mL/x g lithium aluminum hydride), 15% NaOH (aq) (x mL/x g lithium aluminum hydride), and water (3x mL/x g lithium aluminum hydride). The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give the intermediate amine as a yellow solid. The intermediate was suspended in THF and a solution of methanesulfonyl chloride (1M in THF, 2 equivalents) and pyridine (3 equivalents) in THF was added dropwise to the suspension via syringe. The mixture was stirred at 23 ℃ for 3h, then diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired product, compound I-544 as a yellow solid (4mg, 19% yield).

¹H NMR(400MHz,CD₃OD)δppm 8.71-8.78(m,1H),8.22(d,1H),7.51(s,1H),7.22-7.32(m,1H),6.97-7.15(m,2H),6.89-6.96(m,1H),6.69-6.83(m,1H),5.99-6.05(m,2H),5.56(s,1H),3.03-3.23(m,2H),2.68-2.83(s,3H),1.95-2.08(m,2H)。

Compound I-575

The title compound was synthesized in 3 steps.

Step 1:synthesis of (R) -1- ((tert-butyldimethylsilyl) oxy) -3- ((5-fluoro-2- - (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) propan-2-ol

A mixture of compound I-316(1 equivalent), imidazole (2 equivalents), and TBDMS-Cl (1 equivalent) in DMF was stirred at rt for 24 h. The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give a crude oil. The oil was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired intermediate, (R) -1- ((tert-butyldimethylsilyl) oxy) -3- - ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) propan-2-ol (258mg, 63% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.34(d,1H),8.04-8.07(m,1H),7.23(br.s.,1H),7.06-7.13(m,1H),6.82-6.97(m,3H),6.76(t,1H),5.84-5.90(m,2H),3.80-3.89(m,1H),3.47-3.66(m,4H),0.79-0.84(m,9H),0.03(m,6H)。

Step 2:synthesis of (R) -5- (((tert-butyldimethylsilyl) oxy) methyl) -3- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) oxazolidin-2-one.

A mixture of (R) -1- ((tert-butyldimethylsilyl) oxy) -3- ((5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) propan-2-ol (1 equivalent), 2, 6-lutidine (2 equivalents), and triphosgene (0.7 equivalent) in THF was stirred at 23 ℃ for 30 min. The mixture was then heated to 60 ℃ for 24 h. The contents were diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give a crude oil. The oil was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient to give the desired TBS-protected carbamic acid intermediate, namely (R) -5- (((tert-butyldimethylsilyl) oxy) methyl) -3- (5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) oxazolidin-2-one (221mg, 82% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.54(d,1H),8.36(d,1H),7.24(s,1H),7.05-7.13(m,1H),6.84-6.97(m,2H),6.72-6.81(m,1H),6.47(d,1H),5.87(s,2H),4.65-4.74(m,1H),4.24-4.32(m,1H),4.16(dd,1H),3.83(m,2H),0.74-0.82(m,9H),0.00(d,6H)。

And step 3:synthesis of Compound I-575

To a cold solution of (R) -5- (((tert-butyldimethylsilyl) oxy) methyl) -3- (5-fluoro-2- - (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) oxazolidin-2-one (1eq) in THF at 25 ℃ was added a TBAF solution (1M in THF, 1 eq). After stirring the mixture at 23 ℃ for 30min, the mixture was quenched with water and diluted with ethyl acetate. The organic layer was dried, filtered and evaporated to give a crude oil. The oil was purified via silica gel chromatography using a 0-100% ethyl acetate/hexanes gradient. Further purification by recrystallization from a dichloromethane-diethyl ether mixture afforded the desired compound, compound I-575(10mg, 4% yield over 3 steps) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 8.25(d,1H),8.02(t,1H),7.53(s,1H),7.30-7.39(m,1H),7.17-7.25(m,2H),7.11(td,1H),6.85-6.91(m,1H),5.88(s,2H),5.06(dq,1H),4.61(t,1H),4.45(dd,1H),3.83(m,2H)。

Compound I-490

A mixture of 4,4, 4-trifluoro-3-hydroxy-3- (trifluoromethyl) butanoic acid (1.5 eq) and CDI (1.5 eq) in THF was heated to reflux for 2 h. To this mixture was added one portion of intermediate 2(1 eq). The mixture was diluted in ethyl acetate and washed with 1N HCl solution. The organic layer was dried, filtered and evaporated to give an oil. The oil was purified via silica gel chromatography using an 80% isocratic ethyl acetate gradient in hexanes to give the desired product, compound I-490(2mg, 1.2% yield) as a white solid.

¹H-NMR(500MHz,CDCl₃)δppm 8.80(d,1H),8.51(s,1H),8.05(d,1H),7.44-7.50(m,1H),7.19-7.32(m,2H),6.95-7.08(m,2H),6.87(d,1H),6.58-6.65(m,1H),5.97(s,2H),2.93-2.99(m,2H)。

Compound I-496

The title compound was prepared according to general procedure B except (5-methyl-1, 3, 4-oxadiazol-2-yl) methylamine (as the HCl salt) was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 24 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The resulting residue was purified via reverse phase HPLC to give the desired product, compound I-496 as a white solid (81mg, 64% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.09-9.12(m,1H),8.57(br.s.,1H),8.32(d,1H),7.48(s,1H),7.30-7.36(m,1H),7.19-7.25(m,1H),7.16(d,1H),7.11(t,1H),6.84(t,1H),5.88(s,2H),4.92(d,2H),2.45(s,3H)。

Compound I-508

The title compound was prepared in 3 steps.

Step 1:synthesis of tert-butyl (1- (cyclopropylamino) -3-methyl-1-oxobutan-2-yl) carbamate

To a solution of 2- ((tert-butoxycarbonyl) amino) -3-methylbutyric acid (1eq) and cyclopropylamine (1eq) in THF (10ml) was added PyAOP (1.0eq) followed by DIPEA (3 eq). The reaction mixture was stirred at room temperature for 4 hours. After complete conversion of the starting material to the desired product, the solvent was removed by vacuum and purified by flash chromatography eluting with ethyl acetate/hexane 1: 1. Fractions containing the desired product were collected and concentrated to give the amide intermediate as an oil.

Step 2:synthesis of 2-amino-N-cyclopropyl-3-methylbutanamide

The amide intermediate tert-butyl (1- (cyclopropylamino) -3-methyl-1-oxobutan-2-yl) carbamate (1eq) was dissolved in dichloromethane and TFA (3:1 ratio) and stirred at 23 ℃ for 4 h. The solvent was removed in vacuo to give the free amine intermediate 2-amino-N-cyclopropyl-3-methylbutanamide (0.25g, 42% yield) as a semi-solid.

And step 3:synthesis of Compound I-508

The title compound was prepared according to general procedure B except 2-amino-N-cyclopropyl-3-methylbutanamide was the amine intermediate and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 24 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The resulting residue was purified via reverse phase HPLC to give the desired product, compound I-508 as a white solid (15mg, 22% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.51-8.55(m,1H),8.15(d,1H),7.40-7.45(m,1H),7.23-7.28(m,1H),6.99-7.12(m,2H),6.70-6.75(m,1H),6.62-6.69(m,1H),6.65(br.s.,1H),5.93-5.98(m,2H),4.58(t,1H),2.75(tq,1H),2.31(dq,1H),0.99-1.08(m,6H),0.67-0.79(m,2H),0.44-0.55(m,2H)。

Compound I-509

The title compound was prepared according to general procedure B, except 2- ((trifluoromethyl) thio) ethylamine was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 24 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The resulting residue was purified using a gradient of 5-50% ethyl acetate in hexanes to give the desired product, compound I-509(81mg, 60% yield) as an off-white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.45-8.48(m,1H),8.20(d,1H),7.30(s,2H),7.16-7.23(m,1H),7.00-7.06(m,1H),6.97(t,1H),6.86(t,1H),6.57-6.60(m,1H),5.95-6.01(m,2H),3.96(q,2H),3.27(t,2H)。

Compound I-514

To a stirred solution of compound I-509(1 equivalent) in dichloromethane was added mCPBA (2 equivalents), and the mixture was stirred for 12 h. The solvent was removed in vacuo and the resulting residue was purified via reverse phase HPLC to give the desired product, compound I-514 as a white solid (5mg, 6% yield).

¹H NMR(500MHz,CDCl₃)δppm 8.41(d,1H),8.17(d,1H),7.28-7.32(m,1H),7.10-7.17(m,1H),6.89-6.99(m,2H),6.80-6.86(m,1H),6.53(d,1H),5.99(d,1H),5.90(s,2H),4.20(q,2H),3.70(t,2H)。

Compound I-529

The title compound was prepared according to general procedure B except 1,1,1,3,3, 3-hexafluoro-2- ((methylamino) methyl) propan-2-ol was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 24 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The resulting residue was purified via reverse phase HPLC to give the desired product, compound I-529(2.5mg, 2% yield) as an off-white solid.

¹H NMR(500MHz,CDCl₃)δppm 8.53(d,1H),8.36(d,1H),7.42(br.s.,1H),7.23-7.28(m,2H),7.03-7.25(m.2H),6.64(s,1H),5.95(s,2H),4.22(br.s.,1H),3.49-3.53(m,3H),3.02-3.08br.2H)。

Compound I-545

The title compound was prepared according to general procedure B except that (1- (methylsulfonyl) cyclopropyl) methylamine (as the HCl salt) was the amine reactant and the contents were heated to 110 ℃ as a solution in THF/water (10:1) for 24 h. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The resulting residue was purified via reverse phase HPLC to give the desired product, compound I-545(81mg, 59% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 9.12(d,1H),8.30(d,1H),8.19(br.s.,1H),7.55-7.61(m,1H),7.31-7.38(m,1H),7.19-7.26(m,2H),7.13(t,1H),6.96(t,1H),5.89(s,2H),4.04(d,2H),3.09(s,3H),1.22(s,4H)。

Compound I-567

The title compound was prepared in 5 steps.

Step 1:synthesis of methyl 1- (((tert-butoxycarbonyl) amino) methyl) cyclopropanecarboxylate

To a stirred solution of 1- (((tert-butoxycarbonyl) amino) methyl) cyclopropanecarboxylic acid (1eq) in ether and methanol (5:1 ratio) was slowly added (diazomethyl) trimethylsilane (1eq) at 25 ℃. The mixture was stirred overnight and the solvent was removed in vacuo to afford the desired methyl ester intermediate, methyl 1- (((tert-butoxycarbonyl) amino) methyl) cyclopropanecarboxylate (0.400g, 75% yield).

Step 2:synthesis of tert-butyl ((1- (hydroxymethyl) cyclopropyl) methyl) carbamate

Methyl 1- (((tert-butoxycarbonyl) amino) methyl) cyclopropanecarboxylate (1eq) was dissolved in THF and cooled to 0 ℃. Lithium aluminum hydride (3 equivalents) was slowly added to the vessel and the contents were stirred while allowing the temperature to rise to 23 ℃ over a period of 4 h. Then, the reaction solution was cooled again to 0 ℃ and then water (x mL water/LiAlH for x g)₄) 15% sodium hydroxide solution (x mL water/LiAlH for x g)₄) And water (3X mL water/LiAlH for x g₄) Slowly added to the reaction in a sequential manner. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography to give the desired alcohol intermediate, i.e., (1- (hydroxymethyl) cyclopropyl) methyl) carbamic acid tert-butyl ester (0.41g, 88% yield).

And step 3:synthesis of tert-butyl ((1-formylcyclopropyl) methyl) carbamate

To a solution of tert-butyl (1- (hydroxymethyl) cyclopropyl) methyl) carbamate (1eq) in dichloromethane at 25 ℃ was added a single part of PCC (1.15 eq). The reaction was stirred for 2 h. Diethyl ether was added to the vessel and the heterogeneous mixture was filtered through silica gel to give the desired aldehyde intermediate, which was used without further purification.

And 4, step 4:synthesis of (1- (1H-imidazol-2-yl) cyclopropyl) methylamine

A stirred solution of tert-butyl ((1-formylcyclopropyl) methyl) carbamate (1eq) in methanol was treated with ammonium hydroxide (10 eq) followed by glyoxal (1.1 eq). The contents were allowed to stir at 23 ℃ for 3h, after which the methanol was removed in vacuo. The residue was then treated with TFA/dichloromethane (1:1 ratio) and stirred at 23 ℃ for 5 h. The mixture was diluted with brine and extracted with dichloromethane. The organics were dried over sodium sulfate and concentrated in vacuo to give the desired imidazole intermediate, (1- (1H-imidazol-2-yl) cyclopropyl) methylamine (0.124g, 100% yield), which was carried on to the next reaction without further purification.

And 4, step 4:synthesis of Compound I-567

The title compound was prepared according to general procedure B, except that (1- (1H-imidazol-2-yl) cyclopropyl) methylamine was the amine reactant and the contents were heated to 110 ℃ as a solution in dioxane/water (10:1) for 24H. The contents were cooled to 23 ℃ and the organic solvent was removed in vacuo. The residue was purified via reverse phase HPLC to give the desired product, compound I-567 as a white solid (36mg, 27% yield).

¹H NMR(400MHz,CDCl₃)δppm 9.16(br.s.,1H),8.53(d,1H),7.98-8.05(m,1H),7.51(s,1H),7.22-7.31(m,2H),6.97-7.09(m,2H),6.90(s,2H),6.81(d,2H),5.92(s,2H),4.05(d,2H),1.40-1.47(m,2H),1.32-1.39(m,2H)。

Compound I-589

A solution of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate described in the previous patent WO2012/3405 a 1) (1 equivalent), 2- (methylsulfonyl) propionic acid (3 equivalents), triethylamine (10 equivalents), and 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphospha-cyclohexane 2,4, 6-trioxide (4 equivalents) in DMF was heated to 90 ℃ for 4H. The reaction was cooled to 23 ℃ and then poured into a 1:1 mixture of ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 ×). The organics were washed with water (3 ×), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via reverse phase HPLC to give the desired product, compound I-589(10mg, 28% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 11.49(s,1H),9.11(d,1H),8.92(d,1H),7.61(s,1H),7.31-7.37(m,1H),7.27(d,1H),7.19-7.25(m,1H),7.12(td,1H),6.92-6.97(m,1H),5.92(s,2H),4.40(d,1H),3.07(s,3H),1.58(d,3H)。

Compound I-608

The title compound was prepared in 4 steps.

Step 1:synthesis of tert-butyl (2-hydrazino-2-oxoethyl) carbamate

To a solution of methyl 2- ((tert-butoxycarbonyl) amino) acetate (1eq) in ethanol was added hydrazine hydrate (15 eq) and the reaction was allowed to stir overnight. The solvent was removed in vacuo and the residue triturated with hexanes, filtered and dried under high vacuum to give the desired acylhydrazine intermediate, tert-butyl (2-hydrazino-2-oxoethyl) carbamate as a white solid, intermediate B (0.89g, 92% yield).

Step 2:synthesis of tert-butyl (2-oxo-2- (2- (2,2, 2-trifluoroacetyl) hydrazino) ethyl) carbamate

To a solution of tert-butyl (2-hydrazino-2-oxoethyl) carbamate (1 equivalent) in acetonitrile was added DIEA (1.1 equivalent). The contents were cooled to-45 ℃ and 2,2, 2-trifluoroacetic anhydride (1.1 equivalents) was added to the reaction. The resulting mixture was stirred while slowly warming to 23 ℃. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water and brine over Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography using a 5-45% ethyl acetate gradient in hexane to give the desired intermediate, i.e., (2-oxo-2- (2- (2,2, 2-trifluoroacetyl) hydrazino) ethyl) carbamic acid tert-butyl ester (0.73g, 54% yield).

And step 3:synthesis of (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) methylamine

To a suspension of tert-butyl (2-oxo-2- (2- (2,2, 2-trifluoroacetyl) hydrazino) ethyl) carbamate (1eq) in acetonitrile was added DIEA (5.8 eq) and triphenylphosphine (4.1 eq) and stirred for 5 min. Perchloroethane (2.3 equivalents) was then added to the reaction and the mixture was stirred at 23 ℃ for 20 h. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water and brine over Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography with a gradient of 5-45% ethyl acetate in hexane to afford the N-Boc protectedThe oxadiazole intermediate, tert-butyl ((5- (trifluoromethyl) - -1,3, 4-oxadiazol-2-yl) methyl) carbamate (0.24g, 35% yield). To a stirred solution of this N-Boc protected oxadiazole intermediate (1eq) in dichloromethane was added TFA (8 eq) and the mixture was stirred at 23 ℃ for 4 h. The solvent was removed in vacuo to give the desired free amine oxadiazole intermediate, (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) methylamine (0.15 g, 100% yield as the HCl salt), which was used in the next step without further purification.

And 4, step 4:synthesis of Compound I-608

To a stirred solution of (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) methylamine (as the HCl salt, 2 equivalents) in dioxane cooled to 0 ℃ was added cesium carbonate (3 equivalents) and the mixture was stirred for 1 h. Intermediate 1(1 eq) was added to the reaction and the resulting mixture was stirred at 90 ℃ for 24 h. The reaction was cooled to 23 ℃ and diluted with ethyl acetate. The organics were washed with water and brine, concentrated in vacuo, and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-608 as a white solid (2.5mg, 5% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.67(d,1H),8.15(d,1H),7.31(s,1H),7.17(ddd,1H),6.96-7.01(m,1H),6.90-6.95(m,1H),6.76(d,1H),6.70-6.74(m,1H),5.85(s,2H),5.09(s,2H)。

Compound I-622

The title compound was prepared in 4 steps.

Step 1:synthesis of (R) - (1-hydrazino-1-oxoprop-2-yl) carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in step 1 for the synthesis of compound I-608, except that methyl (R) -2- ((tert-butoxycarbonyl) amino) propionate was used as starting material (97% yield).

Step 2:synthesis of (R) - (1-oxo-1- (2- (2,2, 2-trifluoroacetyl) hydrazino) propan-2-yl) carbamic acid tert-butyl ester this compound was prepared according to the procedure described in step 2 for the synthesis of compound I-608, except that (R) - (1-hydrazino-1-oxopropan-2-yl) carbamic acid tert-butyl ester was used as the starting material (82% yield).

And step 3:synthesis of (R) -1- (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) ethylamine

This compound was prepared according to the procedure described in step 3 for the synthesis of compound I-608, except that (R) - (1-oxo-1- (2- (2,2, 2-trifluoroacetyl) hydrazino) but-2-yl) -carbamic acid tert-butyl ester was used as starting material (37% yield).

And 4, step 4:synthesis of Compound I-622

To a stirred solution of (R) -1- (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) ethylamine, (R) -1- (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) ethylamine (2 equivalents) and intermediate 1(1 equivalent) in DMF was added cesium carbonate (3 equivalents). The mixture was heated to 90 ℃ and stirred for 24 h. The contents were cooled to 23 ℃ and diluted with ethyl acetate. The mixture was washed with water and brine, concentrated in vacuo, and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-622(5mg, 9% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.66-8.69(m,1H),8.14(d,1H),7.27(s,1H),7.15-7.21(m,1H),6.99(dd,1H),6.93(t,1H),6.76(d,1H),6.72(t,1H),5.87-5.91(m,1H),5.85(s,2H),1.74(d,3H)。

Compound I-616

To a stirred solution of 2- (methylsulfonyl) acetamide (1eq) in DMF was added cesium carbonate (3eq) at 0 ℃ and the mixture was stirred for 1 h. Intermediate 1(1 eq) was added to the vessel and the reaction was heated to 90 ℃ and stirred for 24 h. The contents were cooled to 23 ℃ and diluted with ethyl acetate. The mixture was washed with water and brine, concentrated in vacuo, and the resulting residue was purified via reverse phase HPLC to give the desired compound, compound I-616(11mg, 22% yield) as a white solid.

¹H NMR(500MHz,CD₃OD)δppm 8.67(d,1H),8.59(d,1H),7.45(s,1H),7.17(ddd,1H),6.91-7.02(m,2H),6.77-6.82(m,2H),5.87(s,2H),4.58(br.s.,2H),3.11(s,3H)。

Compound I-386

The title compound was prepared according to general procedure C, except 1H-pyrazole-3-carboxylic acid was the acid reactant and the crude material was purified via silica gel chromatography using a 3-8% methanol gradient in dichloromethane to afford the desired compound, compound I-386(20.2mg, 40% yield) as a light tan solid.

¹H-NMR(500MHz,CDCl₃) δ ppm 9.93(s,1H),8.77(d,1H),8.50(s,1H),8.33(d,1H),7.51(s,1H),7.44(d,1H),7.19-7.25(m,1H),7.02-7.08(m,1H),6.96-7.02(m,1H),6.94(d,1H),6.83-6.87(m,1H),6.65(s,1H),6.02(s, 2H); no 1N-H proton was observed.

Compound I-164

To a solution of intermediate 2(1 eq) in dichloromethane was added trifluoroacetic anhydride (3eq) followed by triethylamine (3 eq). The reaction was heated to 60 ℃ for 20min, after which the reaction was concentrated in vacuo. The crude material was purified via silica gel chromatography with a 1-3% methanol gradient in dichloromethane to give the desired compound, compound I-635 as a white solid (16.4mg, 32% yield).

¹H-NMR(500MHz,CDCl₃)δ8.95(br.s,1H),8.86(d,1H),8.49(d,1H),8.10(d,1H),7.49(s,1H),7.20-7.26(m,1H),7.03-7.07(m,1H),6.98-7.02(m,1H),6.82-6.87(m,1H),6.62(d,1H),6.04(s,2H)。

Compound I-458

The title compound was prepared according to general procedure C except 3-hydroxy-5-oxocyclohex-3-enecarboxylic acid (1.3 equivalents) was used as the acid reactant and 2.5 equivalents of T3P were used. The crude material was purified via silica gel chromatography with a 3-10% methanol gradient in dichloromethane to give the desired compound, compound I-458(26.4mg, 30% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD) Δ 8.79(m,1H),8.68(d,1H),8.13(d,1H),7.53(s,1H),7.24-7.33(m,1H),7.08-7.13(m,1H),7.01-7.08(m,1H),6.86-6.92(m,2H,2 synchro-shifts), 5.97(s,2H),2.66-2.75(m,2H),2.56-2.64(m, 2H); no 1C-H proton (in sync with the solvent peak) was observed.

Compound I-459

The title compound was prepared according to general procedure C except 5-oxopyrrolidine-2-carboxylic acid (1.2 equivalents) was the acid reactant and 2.5 equivalents of T3P were used. The crude material was purified via silica gel chromatography with a 3-10% methanol gradient in dichloromethane, followed by a second purification via silica gel chromatography with a 7-12% (7:1 methanol/acetonitrile) gradient in dichloromethane to give the desired compound, compound I-459(12.6mg, 15% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD) delta 8.79(s,1H),8.70(d,1H),8.13(d,1H),7.52(s,1H),7.26-7.32(m,1H),7.08-7.13(m,1H),7.02-7.08(m,1H),6.87-6.93(m,2H,2 synchro-shifts), 5.95(s,2H),4.41-4.49(m,1H),2.52-2.60(m,1H),2.40-2.50(m,1H),2.32-2.40(m,1H),2.20-2.30(m, 1H).

Compound I-464

The title compound was prepared according to general procedure C except 5-oxopyrrolidine-3-carboxylic acid (1.2 equivalents) was used as the acid reactant and 2.5 equivalents of T3P were used. The crude material was purified via silica gel chromatography with a 3-10% methanol gradient in dichloromethane to give the desired compound, compound I-464 as a white solid (31.3mg, 31% yield).

¹H-NMR(500MHz,CD₃OD) delta 8.79(s,1H),8.69(d,1H),8.13(d,1H),7.51(s,1H),7.26-7.31(m,1H),7.07-7.13(m,1H),7.02-7.07(m,1H),6.86-6.93(m,2H,2 synchro-shifts), 5.97(s,2H),3.67-3.76(m,1H),3.57-3.65(m,2H),2.60-2.72(m, 2H).

Compound I-461

The title compound was prepared according to general procedure C except 1- (benzyloxy) cyclopropanecarboxylic acid (1 equivalent) was the acid reactant and 2.5 equivalents of T3P were used. The crude material was purified via silica gel chromatography with a gradient of 30-50% ethyl acetate in hexanes to give the desired compound, compound I-461 as a tan solid (14.2mg, 19% yield).

¹H-NMR(500MHz,CDCl₃)δ9.33(s,1H),8.73(d,1H),8.48(d,1H),8.08(d,1H),7.42(s,1H),7.34-7.41(m,4H),7.29-7.32(m,1H),7.18-7.23(m,1H),7.02-7.06(m,1H),6.97-7.01(m,1H),6.84-6.88(m,1H),6.61(d,1H),6.03(s,2H),4.68(s,2H),1.45-1.51(m,2H),1.32-1.37(m,2H)。

Compound I-469

The title compound was prepared following general procedure C, except 2- (thiazol-2-yl) acetic acid was the acid reactant. The crude material was purified via silica gel chromatography with a 3-8% methanol gradient in dichloromethane followed by a second purification via reverse phase HPLC with a 10-95% acetonitrile gradient in water to afford the desired compound, compound I-469(4.3mg, 6% yield) as a tan solid.

¹H-NMR(500MHz,CD₃OD) Δ 8.81(s,1H),8.69(d,1H),8.20(d,1H),7.81(d,1H),7.61(d,1H),7.57(s,1H),7.25-7.33(m,1H),7.08-7.13(m,1H),7.02-7.07(m,1H),6.87-6.96(m,2H,2 synchroshifts), 5.99(s,2H),3.30(s, 2H).

Compound I-465

To a solution of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (intermediate described in WO2012/3405 a 1; 1eq) in dichloromethane was added trifluoroacetic anhydride (3eq) followed by triethylamine (3 eq). The reaction was heated to 60 ℃ for 20min, after which the reaction was concentrated in vacuo. The crude material was purified via silica gel chromatography with a 1-3% methanol gradient in dichloromethane to give the desired compound, compound I-465 as a white solid (26.8mg, 28% yield).

¹H-NMR(500MHz,CDCl₃)δ8.77(s,1H),8.56(br.s,1H),8.40(s,1H),7.44(s,1H),7.19-7.25(m,1H),7.02-7.08(m,1H),6.96-7.02(m,1H),6.81-6.88(m,1H),6.62(d,1H),6.02(s,2H)。

Compound I-470

To a mixture of compound I-38(1 equivalent), 1-hydroxycyclopropanecarboxylic acid (1.1 equivalent) and 4-dimethylaminopyridine (0.1 equivalent) in dichloromethane was added triethylamine (3 equivalents), followed by 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.1 equivalent). The reaction was stirred at room temperature for 12h, after which the reaction was diluted with water and 1N hydrochloric acid solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 10-95% acetonitrile in water to afford the desired compound, compound I-470 as a white solid (1.3mg, 4% yield).

¹H-NMR(500MHz,CDCl₃) δ 8.50(d,1H),8.26(s,1H),7.33(s,1H),7.19-7.26(m,1H),6.97-7.07(m,3H),6.67(m,1H),5.93(s,2H),5.31(m,1H),4.91-5.04(m,2H),4.42-4.75(m,2H),4.16-4.32(m,1H),1.28-1.43(m,2H),0.79-0.92(m, 2H); no 1 exchangeable proton was observed.

Compound I-471 the title compound was prepared according to general procedure C, except 3,3, 3-trifluoropropionic acid was used as the acid reactant, 2.5 equivalents of T3P were used, and the reaction was stirred at 23 ℃ for 24 h. The crude material was purified via silica gel chromatography using a 3-10% methanol gradient in dichloromethane to afford the desired compound, compound I-471(79.3mg, 85% yield) as a tan solid.

¹H-NMR(500MHz,CDCl₃)δ8.78(d,1H),8.48(d,1H),8.47(br.s,1H),8.09(d,1H),8.03(s,1H),7.47(s,1H),7.19-7.24(m,1H),7.02-7.09(m,1H),6.96-7.01(m,1H),6.81-6.86(m,1H),6.61(d,1H),6.03(s,1H),3.29(q,2H)。

Compound I-472

To a solution of intermediate 2(1 equivalent) in dichloromethane was added methylsulfonylmethylsulfonyl chloride (1.08 equivalents), followed by 1, 8-diazabicyclo [5.4.0] undec-7-ene (1 equivalent). The reaction was heated to 60 ℃ for 1h, after which it was diluted with water and 1N hydrochloric acid solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 3-8% methanol gradient in dichloromethane to give the desired compound, compound I-472 as a white solid (39.6mg, 37% yield).

¹H-NMR(500MHz,CDCl₃) δ 8.55(d,1H),8.26(br.s,1H),7.36(s,1H),7.26-7.30(m,1H),7.07-7.16(m,3H),6.84-6.91(m,1H),6.62-6.67(m,1H),5.95(s,2H),4.60(s,2H),3.17(s, 3H); no 1N-H proton was observed.

Compound I-486

The title compound was prepared according to general procedure C, except that 4-sulfamoylbutyric acid was the acid reactant, and 2.5 equivalents of T3P were used. The crude material was purified via silica gel chromatography with a 3-10% methanol gradient in dichloromethane to give the desired compound, compound I-486(14.7mg, 15% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD) Δ 8.78(s,1H),8.66(d,1H),8.12(d,1H),7.52(s,1H),7.25-7.32(m,1H),7.07-7.13(m,1H),7.02-7.07(m,1H),6.86-6.91(m,2H,2 synchro-shifts), 5.97(s,2H),3.19(t,2H),2.71(t,2H),2.21(m, 2H).

Compound I-496

To a 0 ℃ suspension of intermediate 2(1 eq) in dichloromethane was added trimethylaluminum (2M solution in toluene, 0.45 eq.) the reaction was allowed to warm to 23 ℃, followed by the addition of α -dimethyl- γ -butyrolactone (1.1 eq.) the reaction was heated to 80 ℃ for 16h, cooled to 23 ℃, then diluted with saturated ammonium chloride solution, extracted with ethyl acetate and washed with 1N hydrochloric acid solution.

¹H-NMR(500MHz,CDCl₃)δ8.71(d,1H),8.47(d,1H),8.34(d,1H),7.41(s,1H),7.17-7.24(m,1H),7.01-7.07(m,1H),6.95-6.99(m,1H),6.85-6.90(m,1H),6.60(d,1H),6.00(s,2H),4.15(t,2H),2.04(t,2H),1.29(s,6H)。

Compound I-501

To a mixture of intermediate 1(1 eq) and 5- (trifluoromethyl) pyrrolidin-2-one (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water, extracted with dichloromethane and washed with saturated sodium bicarbonate solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 10-95% acetonitrile in water to afford the desired compound, compound I-501(13.4mg, 13% yield) as an off white solid.

¹H-NMR(500MHz,CDCl₃)δ8.76(d,1H),8.49(d,1H),7.38(s,1H),7.21-7.26(m,1H),7.03-7.07(m,1H),6.98-7.02(m,1H),6.86-6.92(m,1H),6.61(d,1H),6.01(s,2H),5.34-5.39(m,1H),2.88-2.99(m,1H),2.58-2.70(m,2H),2.40-2.46(m,1H)。

Compound I-503

To a mixture of intermediate 1(1 equivalent) and isothiazolidine 1, 1-dioxide (1.2 equivalents) in 1, 4-dioxane was added cesium carbonate (1.5 equivalents). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 3-10% methanol gradient in dichloromethane to give the desired compound, compound I-503 as an off-white solid (71.3mg, 73% yield).

¹H-NMR(500MHz,CDCl₃)δ8.57(d,1H),8.47(d,1H),7.36(s,1H),7.20-7.25(m,1H),7.03-7.07(m,1H),6.96-7.01(m,1H),6.84-6.88(m,1H),6.61(m,1H),5.99(s,2H),4.27(t,2H),3.44(t,2H),2.66(t,2H)。

Compound I-506

To a mixture of intermediate 1(1 eq) and piperidin-2-one (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water, extracted with dichloromethane and washed with 1N sodium hydroxide solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 5-95% acetonitrile in water to afford the desired compound, compound I-506, as a white solid (4.9mg, 5% yield).

¹H-NMR(500MHz,CDCl₃)δ8.64(d,1H),8.48(d,1H),7.38(s,1H),7.19-7.23(m,1H),7.03-7.07(m,1H),6.97-7.01(m,1H),6.85-6.88(m,1H),6.60(d,1H),6.00(s,2H),4.00(t,2H),2.65(t,2H),1.98-2.07(m,4H)。

Compound I-512

To a mixture of intermediate 1(1 eq) and 5, 5-dimethylpyrrolidin-2-one (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water, extracted with dichloromethane and washed with saturated sodium bicarbonate solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 10-95% acetonitrile in water to afford the desired compound, compound I-512 as an off white solid (0.6mg, 1% yield).

¹H-NMR(500MHz,CDCl₃)δ8.69(d,1H),8.49(d,1H),7.28(s,1H),7.20-7.25(m,1H),7.01-7.06(m,1H),6.98-7.01(m,1H),6.89-6.95(m,1H),6.60(d,1H),5.97(s,2H),2.67(t,2H),2.14(t,2H),1.63(s,6H)。

Compound I-526 and Compound I-527

Cesium carbonate (1.5 equivalents) was added to a mixture of intermediate 1(1 equivalent) and an inseparable mixture of 3-methyl-3- (methylsulfonyl) pyrrolidin-2-one and 4-hydroxy-2-methyl-2- (methylsulfonyl) - -butanamide (combined, 1 equivalent) in 1, 4-dioxane. The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 5-95% acetonitrile in water to afford the desired compounds, compound I-526(0.5mg, 2% yield) and compound I-527(1.3mg, 5% yield) as white solids.

Of Compound I-526¹H-NMR(500MHz,CDCl₃)δ8.73(d,1H),8.49(d,1H),7.37(s,1H),7.20-7.25(m,1H),7.02-7.06(m,1H),6.96-7.01(m,1H),6.84-6.89(m,1H),6.61(d,1H),6.01(s,2H),4.28-4.33(m,1H),4.18-4.23(m,1H),3.20-3.25(m,1H),3.12(s,3H),2.29-2.35(m,1H),2.87(s,3H)。

Of Compound I-527¹H-NMR(500MHz,CDCl₃)δ8.50(d,1H),8.44(d,1H),7.38(s,1H),7.20-7.26(m,1H),7.06-7.11(m,1H),7.02-7.06(m,1H),6.95-7.03(m,1H),6.65(d,1H),6.00(d,1H),5.98(d,1H),5.91(br.s,1H),4.82-4.86(m,1H),4.74-4.78(m,1H),3.03(s,3H),2.86-2.90(m,1H),2.48-2.52(m,1H),1.76(s,3H)。

Compound I-533

To a mixture of intermediate 1(1 eq) and pyrrolidine-2, 5-dione (1.3 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water, extracted with ethyl acetate and washed with 1N sodium hydroxide solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 5-95% acetonitrile in water to afford the desired compound, compound I-533 as a white solid (3.8mg, 5% yield).

¹H-NMR(500MHz,CDCl₃)δ8.86(d,1H),8.47(d,1H),7.42(s,1H),7.20-7.24(m,1H),7.01-7.06(m,1H),6.96-7.00(m,1H),6.81-6.85(m,1H),6.59(d,1H),6.02(s,2H),3.02(s,4H)。

Compound I-534

To a mixture of intermediate 1(1 eq) and 5-oxopyrrolidine-2-carboxamide (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 24h, after which it was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 5-75% acetonitrile in water to afford the desired compound, compound I-534 as a white solid (0.6mg, 1% yield).

¹H-NMR(500MHz,CDCl₃)δ8.62(d,1H),8.50(d,1H),7.31(s,1H),6.99-7.07(m,3H),6.61(d,1H),6.01(d,1H),5.85(d,2H),5.29(s,2H),4.92-4.96(m,1H),2.87-2.93(m,1H),2.58-2.63(m,1H),2.43-2.55(m,2H)。

Compound I-590

To a mixture of intermediate 1(1 eq) and 5-oxopyrrolidine-3-carboxamide (1.3 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 100 ℃ for 16h, after which the reaction was diluted with water, extracted with ethyl acetate and washed with 1N hydrochloric acid solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 5-12% methanol gradient in dichloromethane to give the desired compound, compound I-590 as a tan solid (3.2mg, 3% yield).

¹H-NMR(500MHz,CD₃OD)δ8.76(d,1H),8.74(d,1H),7.53(s,1H),7.25-7.29(m,1H),7.07-7.11(m,1H),7.02-7.07(m,1H),6.91(d,1H),6.83-6.87(m,1H),5.97(s,2H),4.26-4.37(m,2H),3.45-3.49(m,1H),2.84-2.94(m,2H)。

Compound I-691

To a mixture of intermediate 1(1 eq) and ethyl 3-methyl-2-oxopyrrolidine-3-carboxylate (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq.) the reaction was heated to 75 ℃ for 16h, after which it was diluted with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 3-7% methanol gradient in dichloromethane to give the desired compound, compound I-691(377mg, 92% yield) as a white solid.

¹H-NMR(500MHz,CDCl₃)δ8.68(d,1H),8.48(d,1H),7.37(s,1H),7.19-7.25(m,1H),7.01-7.06(m,1H),6.96-7.01(m,1H),6.86-6.90(m,1H),6.60(d,1H),6.00(s,2H),4.26(q,2H),4.15-4.21(m,2H),2.75-2.80(m,1H),2.17-2.23(m,1H),1.59(s,3H),1.30(t,3H)。

Compound I-604

To a suspension of compound I-591(1 equivalent) in 1:1 tetrahydrofuran/water was added a 1M aqueous solution of sodium hydroxide (2 equivalents). The reaction was stirred at room temperature for 2h, after which the reaction was concentrated to about 50% of its volume, acidified by addition of 1M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired compound, compound I-604 as a white solid (154.6mg, 95% yield).

¹H-NMR(500MHz,CDCl₃) δ 8.77-8.80(m,2H,2 overlay shifts), 7.57(s,1H),7.28-7.32(m,1H),7.09-7.13(m,1H),7.04-7.09(m,1H),6.94(d,1H),6.86-6.90(m,1H),6.00(s,2H),4.26-4.31(m,1H),4.16-4.20(m,1H),2.75-2.79(m,1H),2.27-2.31(m,1H),1.54(s, 3H).

Compound I-605

To a-78 ℃ solution of compound I-604(1 equivalent) in dichloromethane was added oxalyl chloride (2M solution in dichloromethane, 2.5 equivalents). The reaction was stirred at-78 ℃ for 30min, then warmed to 0 ℃ and stirred at that temperature for 1 h. The reaction was then concentrated in vacuo, reconstituted in dichloromethane and cooled to-78 ℃. To this solution was added cyclopropylamine (5 eq), after which the reaction was allowed to warm to room temperature. After 20min, the reaction was concentrated in vacuo. The crude material was purified via silica gel chromatography with a 1-8% methanol gradient in dichloromethane to give the desired compound, compound I-604 as a white solid (14.5mg, 23% yield).

¹H-NMR(500MHz,CDCl₃) δ 8.70(d,1H),8.49(d,1H),7.36(s,1H),7.20-7.25(m,1H),7.01-7.08(m,1H),6.97-7.01(m,1H),6.86-6.90(m,1H),6.60(d,1H),6.00(s,2H),4.06-4.09(m,2H),3.00-3.06(m,1H),2.75-2.80(m,1H),2.14-2.29(m,1H),1.58(s,3H),0.78-0.82(m,2H),0.51-0.54(m, 2H); no 1N-H proton was observed.

Compound I-606

To a-78 ℃ solution of compound I-604(1 equivalent) in dichloromethane was added a solution of 2M oxalyl chloride in dichloromethane (2.5 equivalents). The reaction was stirred at-78 ℃ for 30min, then warmed to 0 ℃ and stirred at that temperature for 1 h. The reaction was then concentrated in vacuo, reconstituted in dichloromethane and cooled to-78 ℃. To this solution was added ammonium hydroxide solution (50 equivalents), after which the reaction was allowed to warm to room temperature. After 20 minutes, the reaction was diluted in water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired compound, compound I-619(43.3mg, 75% yield) as an off-white solid.

¹H-NMR(500MHz,CDCl₃) δ 8.71(d,1H),8.49(d,1H),7.37(s,1H),7.20-7.25(m,1H),7.03-7.07(m,1H),6.97-7.01(m,1H),6.86-6.91(m,1H),6.60(d,1H),6.00(s,2H),4.07-4.13(m,2H),2.97-3.03(m,1H),2.17-2.22(m,1H),1.65(s, 3H); no 2N-H protons were observed.

Compound I-612

A suspension of intermediate 1(1 equivalent) and potassium ((2-carboxylate ethyl) sulfonyl) amide (1.15 equivalents) in DMSO was stirred at room temperature for 72 h. The reaction was diluted in water, washed with dichloromethane, acidified by addition of 1M hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the acid intermediate. To the suspension of this acid intermediate in dichloromethane was added triethylamine (3 equivalents), followed by oxalyl chloride (2M solution in dichloromethane, 2 equivalents). After 15min, the reaction was concentrated in vacuo. The crude material was purified via reverse phase HPLC with a gradient of 5-75% acetonitrile in water to afford the desired compound, compound I-612 as a white solid (5.8mg, 12% yield).

¹H-NMR(500MHz,CDCl₃)δ8.86(d,1H),8.47(d,1H),7.43(s,1H),7.19-7.24(m,1H),7.01-7.06(m,1H),6.96-7.01(m,1H),6.83-6.88(m,1H),6.63(d,1H),6.02(s,2H),3.89(t,2H),3.35(t,2H)。

Compound I-615

To a mixture of intermediate 1(1 eq) and 3-hydroxypyrrolidin-2-one (1.2 eq) in 1, 4-dioxane was added cesium carbonate (1.5 eq). The reaction was heated to 70 ℃ for 12h, after which it was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired compound, compound I-615 as a white solid (59.7mg, 48% yield).

¹H-NMR(500MHz,CDCl₃) δ 8.48(d,1H),8.46(d,1H),7.32(s,1H),7.19-7.24(m,1H),7.02-7.07(m,1H),6.98-7.02(m,1H),6.89-6.94(m,1H),6.60(d,1H),5.97(s,2H),5.92-5.96(m,1H),3.60-3.65(m,1H),3.47-3.52(m,1H),2.82-2.86(m,1H),2.33-2.41(m, 1H); no 1O-H proton was observed.

Compound I-628

A solution of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine hydrochloride (produced in step 3 of general procedure a by using 1- (isoxazol-3-yl) ethanone in step 1 and 2-fluorobenzylhydrazine in step 2, 1 equivalent), methyl 4-oxotetrahydrothiophene-3-carboxylate (3 equivalents), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1 equivalent) in pyridine was heated to 80 ℃ for 12H. The reaction was concentrated in vacuo, slurried in methanol, concentrated in vacuo and slurried again in methanol. The precipitate was filtered and dried to give the desired cyclic sulfide intermediate as a pale tan solid (190mg, 45% yield). To a solution of this sulfide intermediate (1eq) in dichloromethane was added peracetic acid (2.3 eq). After 30min, the reaction was concentrated in vacuo, slurried in water and filtered to give the desired compound, compound I-628 as an off-white solid (148.8mg, 73% yield).

¹H-NMR(500MHz,CDCl₃)δ10.2(br.s,1H),8.56(s,1H),7.31-7.34(m,1H),7.30(s,1H),7.07-7.12(m,3H),6.64(m,1H),5.93(s,2H),4.36(s,2H),4.35(s,2H)。

Compound I-632

A suspension of compound I-628(1 eq) in phosphorus oxychloride (62 eq) was heated to 90 ℃ for 2h, after which the reaction mixture was concentrated in vacuo to give the desired chloropyrimidine intermediate (155mg, 100% yield) as a tan solid. To this suspension of intermediate (1eq) in dioxane was added ammonium hydroxide solution (440 eq). The reaction was stirred at 23 ℃ for 15h, then heated to 60 ℃ for 1h, after which the mixture was diluted in water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired compound, compound I-632(44.5mg, 60% yield) as a tan solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.09(d,1H),7.51(s,1H),7.31-7.35(m,1H),7.27(d,1H),7.21-7.24(m,1H),7.09-7.13(m,1H),6.83-6.87(m,1H),5.90(s,2H),4.49(s,2H),4.31(s,2H)。

Compounds I-497 and I-524

A solution of intermediate 2(1 eq), triethylamine (3.5 eq), DMAP (0.1 eq) and 2-chloro-2-oxoethyl acetate (2.2 eq) in dichloromethane was heated to 60 ℃ for 26 h. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-497 as a white solid (30mg, 23% yield) and byproducts, compound I-524 as a white solid (4.5mg, 4% yield).

Process for preparing compound I-497¹H-NMR(500MHz,DMSO-d₆)δppm 11.37(m,1H),9.11(d,1H),8.75(d,1H),7.94(m,1H),7.66(s,1H),7.35(m,1H),7.27(d,2H),7.11(m,1H),6.89(m,1H),5.93(s,2H),4.77(s,2H),2.12(s,3H)。

Of Compounds I-524¹H-NMR(500MHz,DMSO-d₆)δppm 11.13(m,1H),9.09(m,1H),8.72(m,1H),8.00(m,1H),7.65(s,1H),7.35(m,1H),7.26(s,2H),7.12(m,1H),6.88(m,1H),5.93(s,2H),2.15(s,3H)。

Compound I-499

To a slurry of compound I-497(1 eq) in methanol was added a solution of potassium carbonate (0.5 eq) in water. After stirring for 1h at 23 ℃, an additional 0.5 equivalents of potassium carbonate in water was added to the vessel along with THF (equal volume to the starting volume of methanol). The reaction was allowed to stir at 23 ℃ for an additional 1 h. The solvent was removed in vacuo, and the resulting crude material was purified via silica gel chromatography with a gradient of 0-5% methanol in dichloromethane to give the desired compound, compound I-499 as a white solid (10.5mg, 17% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 10.43(m,1H),9.11(m,1H),8.75(m,1H),8.01(m,1H),7.68(s,1H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.89(m,1H),5.93(s,2H),5.61(m,1H),4.11(m,2H)。

Compound I-525

The title compound was prepared as a library according to general procedure C except 4- (benzyloxy) tetrahydro-2H-pyran-4-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-525(9mg, 27% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.39(m,1H),8.91(m,1H),8.56(s,1H),8.36(m,1H),7.53(m,1H),7.38(m,5H),7.26(m,1H),7.07(s,3H),6.65(s,1H),6.02(s,2H),4.51(s,2H),3.96(m,2H),3.87(m,2H),2.28(m,2H),1.99(m,2H)。

Compound I-528

The title compound was prepared in library form following general procedure C, except 2-methoxyacetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-528 as a white solid (7mg, 58% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.18(m,1H),8.75(m,1H),8.47(m,1H),8.18(m,1H),7.50(m,1H),7.21(m,1H),7.05(m,1H),6.97(m,1H),6.83(m,1H),6.61(m,1H),6.05(m,2H),4.08(m,2H),3.52(s,3H)。

Compound I-532

The title compound was prepared in library form following general procedure C except oxazole-4-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-532 as a white solid (3.8mg, 15% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 10.39(m,1H),9.09(m,2H),8.82(m,1H),8.65(m,1H),8.11(m,1H),7.73(m,1H),7.29(m,3H),7.13(m,1H),6.88(m,1H),5.94(m,2H)。

Compound I-547

The title compound was prepared in library form following general procedure C, except 3-methoxypropionic acid was the acid reactant, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-547 as a white solid (4.9mg, 20% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.09(m,1H),9.09(m,1H),8.72(m,1H),8.02(m,1H),7.64(s,1H),7.34(m,1H),7.23(m,2H),7.12(m,1H),6.89(m,1H),5.92(s,2H),3.61(t,2H),3.23(s,3H),2.70(t,2H)。

Compound I-548

The title compound was prepared in library form following general procedure C, except tosylalanine was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-548(3.1mg, 9% yield) as a white solid.

Compound I-549

The title compound was prepared in library form following general procedure C, except thiazole-4-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-549(3.7mg, 14% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 10.20(m,1H),9.31(m,1H),9.09(m,1H),8.84(m,1H),8.72(m,1H),8.14(m,1H),7.73(m,1H),7.29(m,3H),7.13(m,1H),6.89(m,1H),5.94(m,2H)。

Compound I-550

The title compound was prepared in library form following general procedure C, except 1H-pyrrole-2-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-550(3.4mg, 13% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.84(m,1H),10.84(m,1H),9.09(m,1H),8.73(m,1H),8.16(m,1H),7.68(s,1H),7.36(m,2H),7.24(m,2H),7.13(m,1H),7.06(m,1H),6.88(m,1H),6.19(m,1H),5.94(s,2H)。

Compound I-551

The title compound was prepared in library form following general procedure C, except 1-cyanocyclopropane-1-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-551 as a white solid (3.3mg, 13% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.02(m,1H),9.09(m,1H),8.74(m,1H),7.88(m,1H),7.67(s,1H),7.33(m,1H),7.27(m,1H),7.23(m,1H),7.12(m,1H),6.89(m,1H),5.94(s,2H),1.74(m,4H)。

Compound I-552

The title compound was prepared in library form following general procedure C, except thiazole-5-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-552 as a white solid (2.3mg, 9% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.71(m,1H),9.35(m,1H),9.12(m,1H),8.96(m,1H),8.79(m,1H),8.08(m,1H),7.70(m,1H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.89(m,1H),5.95(m,2H)。

Compound I-553

The title compound was prepared in library form following general procedure C, except 6-oxo-1, 6-dihydropyridine-2-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-553 as a white solid (1.9mg, 7% yield).

Compound I-554

The title compound was prepared as a library form following general procedure C, except 3-methoxyisoxazole-5-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-554 as a white solid (4.6mg, 17% yield).

Compound I-555

The title compound was prepared in library form following general procedure C, except pyrimidine-4-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-555(1.6mg, 6% yield) as a white solid.

Compound I-556

The title compound was prepared in library form following general procedure C except oxazole-5-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-556 as a white solid (4.4mg, 17% yield).

Compound I-557

The title compound was prepared in library form following general procedure C except oxazole-4-carboxylic acid was the acid reactant and the crude material was purified by reverse phase HPLC to give the desired compound, compound I-557 as a white solid (4.4mg, 17% yield).

Compound I-558

The title compound was prepared in library form following general procedure C, except cyclopropanecarboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-558 as a white solid (5.1mg, 21% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.42(m,1H),9.11(m,1H),8.69(m,1H),8.01(m,1H),7.66(m,1H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.89(m,1H),5.93(m,2H),2.12(m,1H),0.87(d,4H)。

Compound I-559

The title compound was prepared as a library according to general procedure C, except that (S) -2-methoxy-2-phenylacetic acid was used as the acid reactant, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-559 as a white solid (6.8mg, 24% yield).

¹H-NMR(500MHz,DMSO-d₆)δ11.03(m,1H),9.09(m,1H),8.72(m,1H),7.96(m,1H),7.67(m,1H),7.51(m,2H),7.36(m,4H),7.23(m,2H),7.12(m,1H),6.87(m,1H),5.93(m,2H),5.12(m,1H),3.34(s,3H)。

Compound I-560

The title compound was prepared in library form following general procedure C, except furan-2-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-560 as a white solid (5.2mg, 20% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.10(m,1H),9.09(m,1H),8.75(m,1H),8.10(m,1H),8.00(m,1H),7.78(m,1H),7.69(m,1H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.89(m,1H),6.73(m,1H),5.94(s,2H)。

Compound I-561

The title compound was prepared in library form following general procedure C, except thiophene-2-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-561 as a white solid (3.9mg, 15% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.39(m,1H),9.10(m,1H),8.78(m,1H),8.36(m,1H),8.10(m,1H),7.95(m,1H),7.70(s,1H),7.34(m,1H),7.25(m,3H),7.12(m,1H),6.88(m,1H),5.95(m,2H)。

Compound I-562

The title compound was prepared in library form following general procedure C, except 2-ethoxyacetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-562 as a white solid (5.7mg, 23% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 10.70(m,1H),9.10(m,1H),8.73(m,1H),8.00(m,1H),7.66(m,1H),7.33(m,1H),7.23(m,2H),7.11(m,1H),6.89(m,1H),5.93(s,2H),4.17(s,2H),3.55(m,2H),1.17(m,3H)。

Compound I-563

The title compound was prepared in library form following general procedure C, except 2- (methylsulfonyl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-563(3mg, 11% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.53(m,1H),9.08(m,1H),8.78(m,1H),7.99(m,1H),7.66(m,1H),7.34(m,1H),7.23(m,2H),7.12(m,1H),6.91(m,1H),5.93(m,2H),4.46(m,2H),3.17(s,3H)。

Compound I-564

The title compound was prepared as a library form following general procedure C, except 3-cyclopropyl-1H-pyrazole-5-carboxylic acid as the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-564 as a white solid (1.2mg, 4% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.84(br s,1H),9.10(m,1H),8.77(m,1H),8.07(m,1H),7.72(m,1H),7.34(m,1H),7.28(m,1H),7.23(m,1H),7.12(m,1H),6.89(m,1H),6.61(m,1H),5.95(m,2H),1.96(m,1H),0.98(m,2H),0.76(m,2H)。

Compound I-565

The title compound was prepared in library form following general procedure C, except 2-acetoxy-2-phenylacetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-565(4.1mg, 14% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.60(m,1H),9.08(m,1H),8.72(m,1H),7.92(m,1H),7.65(m,1H),7.59(m,2H),7.41(m,3H),7.33(m,1H),7.23(m,2H),7.11(m,1H),6.88(m,1H),6.17(s,1H),5.92(s,2H),2.15(s,3H)。

Compound I-569

The title compound was prepared in library form following general procedure C, except 1-methylcyclopropane-1-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-569 as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.81(m,1H),8.69(m,1H),8.18(m,1H),7.59(m,1H),7.31(m,1H),7.10(m,2H),6.93(m,2H),6.01(m,2H),1.52(s,3H),1.32(m,2H),0.84(m,2H)。

Compound I-570

The title compound was prepared in library form following general procedure C, except tetrahydrofuran-2-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-570 as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.79(m,1H),8.72(m,1H),8.17(m,1H),7.55(m,1H),7.29(m,1H),7.09(m,2H),6.92(m,2H),5.99(m,2H),4.53(m,1H),4.13(m,1H),3.98(m,1H),2.39(m,1H),2.14(m,1H),2.01(m,2H)。

Compound I-571

The title compound was prepared in library form following general procedure C, except 2- (5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-571 as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.79(d,1H),8.69(d,1H),8.09(d,1H),7.54(s,1H),7.43(d,1H),7.32-7.25(m,1H),7.14-7.01(m,2H),6.96-6.89(m,1H),6.88(d,1H),5.98(s,2H),4.70(s,2H),1.91(d,3H)。

Compound I-572

The title compound was prepared in library form following general procedure C except 3,3, 3-trifluoro-2-methoxy-2-phenylpropionic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-572 as a white solid.

¹H-NMR(500MHz,CD₃OD)δ8.79(m,2H),8.19(m,1H),7.64(m,2H),7.57(m,1H),7.48(m,3H),7.30(m,1H),7.08(m,2H),6.92(m,2H),5.99(m,2H),3.63(d,3H)。

Compound I-574

The title compound was prepared as a library form following general procedure C, except tetrahydro-2H-pyran-4-carboxylic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-574, as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.81(d,1H),8.66(s,1H),8.20(d,1H),7.54(s,1H),7.30(m,1H),7.09(m,2H),6.93(m,1H),6.88(d,1H),5.98(s,2H),4.02(m,2H),3.52(m,2H),2.80(m,1H),1.85(d,4H)。

Compound I-577

The acetyl protected intermediate was prepared in the library form according to general procedure C, except that 2-acetoxybenzoic acid was the acid reactant. The crude material was purified via reverse phase HPLC to give the desired intermediate. The intermediate was then dissolved in a methanol: water mixture (8:1) and treated with lithium hydroxide (4.5 equivalents) and a small amount of THF (300 μ L). After completion of the reaction, the volatiles were removed in vacuo and the residue was treated with 1N HCl solution until pH was about 4. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The contents were dried over sodium sulfate, filtered and concentrated to give the desired compound, compound I-577(10mg, 33% yield over 2 steps) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.81(m,1H),11.12(m,1H),9.10(d,1H),8.79(m,1H),8.20(m,1H),8.00(m,1H),7.66(s,1H),7.51(m,1H),7.34(m,1H),7.28(d,1H),7.23(m,1H),7.08(m,3H),6.90(m,1H),5.96(s,2H)。

Compound I-579

A solution of 2-cyanoacetic acid (4 equivalents) in DMF was cooled to 0 ℃ and treated with oxalyl chloride (4.1 equivalents) as a solution in DMF. Gas evolution was observed and the contents were stirred at 0 ℃ for 30 min. Intermediate 2(1 eq) was added to the reaction and the contents were stirred for 18h while allowing it to warm to 23 ℃. The solvent was removed in vacuo, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-579(2.3mg, 10% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.47(m,1H),9.10(d,1H),8.78(m,1H),7.94(m,1H),7.65(s,1H),7.34(d,1H),7.24(m,2H),7.12(m,1H),6.91(t,1H),5.92(s,2H),4.05(s,2H)。

Compound I-594

The title compound was prepared in library form following general procedure C except 2-methyl-2, 3-dihydrobenzo [ b ] thiophene-2-carboxylic acid 1, 1-dioxide was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-594(7.4mg, 23% yield) as a yellow solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 10.96(m,1H),9.09(m,1H),8.77(m,1H),7.93(m,1H),7.79(m,1H),7.68(s,2H),7.57(m,2H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.89(m,1H),5.94(s,2H),4.11(m,1H),3.30(m,1H),1.89(s,3H)。

Compound I-596

The title compound was prepared in library form following general procedure C, except 2- (1, 3-dioxoisoindolin-2-yl) acetic acid was the acid reactant, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-596 as a white solid (17.4mg, 56% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.60(m,1H),9.09(m,1H),8.74(m,1H),7.91(m,5H),7.65(m,1H),7.35(m,1H),7.24(m,2H),7.12(m,1H),6.92(m,1H),5.93(m,2H),4.58(s,2H)。

Compound I-597

The title compound was prepared in library form following general procedure C, except (2-phenylacetyl) glycine was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-597(4.4mg, 15% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.83(m,1H),8.68(m,1H),8.24(m,1H),7.58(s,1H),7.34(m,5H),7.26(m,1H),7.10(m,2H),6.97(m,1H),6.90(m,1H),6.01(s,2H),4.17(s,2H),3.66(s,2H)。

Compound I-598

The title compound was prepared in library form following general procedure C except ((benzyloxy) carbonyl) glycine was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I598 as a white solid (4mg, 13% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.15(m,1H),9.10(d,1H),8.73(m,1H),7.98(m,1H),7.65(s,1H),7.57(m,1H),7.37(m,6H),7.23(m,2H),7.12(m,1H),6.90(m,1H),5.92(m,2H),5.05(s,2H),3.93(m,2H)。

Compound I-599

The title compound was prepared in library form following general procedure C, except 2- (1-oxoisoindolin-2-yl) acetic acid was the acid reactant, and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-599(11.7mg, 39% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.42(m,1H),9.10(m,1H),8.74(m,1H),7.95(m,1H),7.72(m,1H),7.66(m,1H),7.63(m,2H),7.52(m,1H),7.34(m,1H),7.24(m,2H),7.13(m,1H),6.92(m,1H),5.93(m,2H),4.55(m,4H)。

Compound I-610

The title compound was prepared in library form following general procedure C, except 2- (2-oxooxazolidin-3-yl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-610 as a white solid (11.4mg, 42% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.33(m,1H),9.10(m,1H),8.75(m,1H),7.96(m,1H),7.64(m,1H),7.35(m,1H),7.24(m,2H),7.12(m,1H),6.91(m,1H),5.93(m,2H),4.33(m,2H),4.15(s,2H),3.64(m,2H)。

Compound I-601

The title compound was prepared in library form following general procedure C, except 2- (4-oxoquinazolin-3 (4H) -yl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-601(3.3mg, 11% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.69(m,1H),9.10(m,1H),8.75(m,1H),8.37(s,1H),8.15(m,1H),7.90(m,2H),7.73(m,1H),7.67(s,1H),7.56(m,1H),7.34(m,1H),7.24(m,2H),7.13(m,1H),6.93(m,1H),5.94(s,2H),4.99(s,2H)。

Compound I-602

The title compound was prepared in library form following general procedure C, except that (2- (1, 3-dioxoisoindolin-2-yl) acetyl) glycine was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-602 as a white solid (1.2mg, 4% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.20(m,1H),9.09(m,1H),8.74(m,1H),8.62(m,1H),7.98(m,1H),7.91(s,2H),7.88(s,2H),7.64(s,1H),7.33(m,1H),7.24(d,1H),7.20(m,1H),7.11(m,1H),6.89(m,1H),5.92(m,2H),4.29(s,2H),4.05(m,2H)。

Compound I-603

The title compound was prepared in library form following general procedure C, except (methoxycarbonyl) glycine was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-603 as a white solid (2.2mg, 8% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 11.13(m,1H),9.09(m,1H),8.73(m,1H),7.97(m,1H),7.66(m,1H),7.42(m,1H),7.34(m,1H),7.23(m,2H),7.12(m,1H),6.90(m,1H),5.92(m,2H),3.90(m,2H),3.56(s,3H)。

Compound I-592

The title compound was prepared according to general procedure C, except 2- (phenylsulfonyl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-592(1.7mg, 5% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.44(m,1H),9.10(m,1H),8.75(m,1H),7.92(m,1H),7.91(m,1H),7.89(m,1H),7.88(m,1H),7.76(m,1H),7.65(m,2H),7.34(m,1H),7.26(m,1H),7.22(m,1H),7.12(m,1H),6.91(m,1H),5.92(m,2H),4.67(m,2H)。

Compound I-594

The title compound was prepared according to general procedure C, except 2- ((4-chlorophenyl) sulfonyl) acetic acid was the acid reactant and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-594(5.8mg, 15% yield) as a white solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.48(s,1H),9.10(d,1H),8.76(d,1H),7.92(m,2H),7.87(m,1H),7.76(m,2H),7.65(s,1H),7.34(m,1H),7.24(m,2H),7.12(m,1H),6.91(m,1H),5.93(s,2H),4.73(m,2H)。

Compound I-498

To a mixture of 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-amine (intermediate described in WO2012/3405 a 1; 1eq), triethylamine (6 eq) and N, N-dimethylpyridin-4-amine (0.01 eq) in dichloromethane was added 2-chloro-2-oxoethyl acetate (3eq) at 23 ℃. The contents were heated to 60 ℃ and stirred for 18 h. The solvent was removed in vacuo and the crude material was purified via reverse phase HPLC to give the desired compound, compound I-498(1.0mg, 2% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 11.21(m,1H),9.09(m,1H),8.84(m,1H),7.61(m,1H),7.34(m,1H),7.27(m,1H),7.22(m,1H),7.12(m,1H),6.94(m,1H),5.92(m,2H),4.91(s,2H),2.13(s,3H)。

Compound I-578

The title compound was prepared according to general procedure B, except tetrahydrofuran-3-amine was the amine reactant, 6 equivalents of triethylamine was used, and the contents were heated to 100 ℃ as a solution in dioxane/water (4:1) for 24 h. The mixture was cooled to 23 ℃ and the solvent was removed in vacuo. The solid was purified via reverse phase HPLC to give the desired compound, compound I-578 as a solid (12mg, 53% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(m,1H),8.58(m,1H),8.31(m,1H),7.61(m,1H),7.34(m,1H),7.24(m,2H),7.11(m,1H),6.89(m,1H),5.93(s,2H),4.76(m,1H),4.04(m,1H),3.89(m,1H),3.77(m,1H),3.64(m,1H),2.27(m,1H),2.04(s,1H)。

Compound I-613

A solution of intermediate 1(1 eq) in DMSO was treated with potassium benzenesulfonamide (2 eq). The resulting reaction mixture was stirred at 100 ℃ for 8 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-613(7mg, 26% yield) as a solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.82(m,1H),8.37(m,1H),8.26(m,2H),7.58(m,1H),7.47(m,2H),7.31(m,2H),7.11(m,2H),6.94(m,2H),5.98(m,2H)。

Compound I-614

A solution of intermediate 1(1 eq) in DMSO was treated with potassium 3, 4-dimethoxybenzenesulfonamide (2 eq). The resulting reaction mixture was stirred at 100 ℃ for 8 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-614(1.3mg, 5% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.12(m,1H),8.56(m,1H),7.90(m,1H),7.60(m,1H),7.38(m,2H),7.27(d,2H),7.12(m,1H),6.92(m,2H),5.94(s,2H),3.71(d,6H)。

Compound I-607

A solution of intermediate 1(1 eq) in DMSO was treated with potassium (4-fluorophenyl) methanesulfonamide (2 eq). The resulting reaction mixture was stirred at 60 ℃ for 0.5h, after which the reaction was diluted with water and 1N hydrochloric acid solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-5% methanol gradient in dichloromethane to give the desired compound, compound I-607(2.8mg, 6% yield) as a solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.79(m,1H),8.45(m,1H),7.52(m,1H),7.40(m,2H),7.26(m,1H),6.94(d,6H),5.98(s,2H),5.04(m,2H)。

Compound I-624

To a solution of 4-fluorobenzenesulfonamide (4 equivalents) in DMF was added bis (trimethylsilyl) amide (4 equivalents) at 23 ℃. After stirring for 15 minutes, intermediate 1(1 eq) was added and the reaction was stirred at 75 ℃ for 3 days. The product was purified by reverse phase HPLC without work-up to give the desired compound, compound I-624 as a solid (1.9mg, 7% yield).

¹H-NMR(500MHz,DMSO-d₆)δppm 9.13(m,1H),8.51(m,1H),8.30(m,2H),7.40(m,2H),7.27(m,2H),7.15(m,3H),6.95(m,1H),5.99(s,2H)。

Compound I-625

A solution of intermediate 1(1 eq) in DMSO was treated with potassium pyridine-3-sulfonamide (1eq) and potassium carbonate (0.5 eq). The resulting mixture was heated in a microwave at 150 ℃ for 10 min. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-625(4.4mg, 33% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.24(m,1H),9.14(m,1H),8.69(m,1H),8.59(m,1H),8.40(m,1H),7.42(m,1H),7.34(m,2H),7.24(m,2H),7.13(m,1H),6.96(m,1H),5.95(m,2H)。

Compound I-583

A solution of intermediate 2(1 eq) in DMF was treated with isocyanatobenzene (2 eq) and triethylamine (2 eq). The resulting reaction mixture was heated at 100 ℃ for 18 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-583(1.0mg, 4% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 10.20(m,1H),9.10(m,1H),8.62(m,1H),7.71(m,1H),7.63(m,2H),7.27(m,7H),7.09(m,1H),7.01(m,1H),6.88(m,1H),5.99(m,2H)。

Compound I-491

To a solution of intermediate 2(1 eq) in dichloromethane was added (4-fluorophenyl) methanesulfonyl chloride (1eq) followed by DBU (1 eq). The reaction was stirred at 90 ℃ for 18 h. The reaction mixture was diluted with water, extracted with dichloromethane (3 ×), washed with 1N hydrochloric acid solution (2 ×), dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-491(17.8mg, 17% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δppm 8.52(d,1H),8.28(br.s.,1H),7.38(br.s.,1H),7.30(dd,2H),7.25(br.s.,1H),7.14-6.97(m,4H),6.92-6.73(m,3H),6.63(d,1H),5.91(s,2H),4.54(br.s.,2H)。

Compound I-495

The title compound was prepared according to general procedure B, except that ethanol-1, 1,2,2-d 4-amine was the amine reactant and the contents were heated to 90 ℃ for 20 h. The contents were cooled to 23 ℃ and partitioned between a 1:1 mixture of dichloromethane and 1N HCl solution. The layers were separated and the aqueous layer was extracted with dichloromethane (× 2) and the organic portions were combined and washed with brine. The mixture was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-10% methanol gradient in dichloromethane to give the desired compound, compound I-495 as a solid (120mg, 74% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.09(d,1H),8.17(d,1H),7.61(s,1H),7.51(s,1H),7.33(d,1H),7.14-7.28(m,2H),7.10(t,1H),6.82(s,1H),5.90(s,2H),4.74(br.s.,1H)。

Compound I-505

5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate described in WO2012/3405 a 1; 1eq) was added to a suspension of NaH (1.2 eq) in anhydrous THF at 23 ℃. After stirring at 23 ℃ for 30min, a solution of propane-2-sulfonyl chloride (1eq) in THF was added to the reaction mixture. The contents were heated to 70 ℃ and stirred for a further 18 h. The reaction mixture was diluted with water, extracted with dichloromethane (3 ×), dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-505(2.9mg, 6% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δppm 11.59(br.s.,1H),9.13(d,1H),8.66(br.s.,1H),7.45(s,1H),7.38-7.31(m,1H),7.26(d,1H),7.24-7.17(m,1H),7.13(t,1H),7.08-7.02(m,1H),5.89(s,2H),4.24(br.s.,1H),1.35(d,6H)。

Compound I-510

To a suspension of intermediate 2(1 eq) in dichloromethane was added DBU (1eq) followed by methyl 2- (chlorosulfonyl) acetate (1 eq). The reaction was stirred at 90 ℃ for 18 h. The reaction mixture was diluted with water, extracted with dichloromethane (3 ×), washed with 1N hydrochloric acid solution (2 ×), dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-510(8.3mg, 12% yield) as a solid.

¹H NMR(500MHz,CDCl₃)δppm 8.52(d,1H),8.37(d,1H),7.40(s,1H),7.26-7.22(m,1H),7.08-6.99(m,4H),6.63(d,1H),5.93(s,2H),4.31(s,2H),3.71(s,3H)。

Compound I-521

The title compound was prepared according to general procedure B except 3-amino-2, 2-difluoropropan-1-ol (1.5 equivalents as the HCl salt) was the amine reactant, 1 equivalent of triethylamine was used, and the contents were heated to 60 ℃ for 20 h. The contents were cooled to 23 ℃ and partitioned between 1:1 of dichloromethane and 1N HCl solution. The layers were separated and the aqueous layer was extracted with dichloromethane (× 2) and the organic portions were combined and washed with brine. Through Na₂SO₄The mixture was dried, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-10% methanol gradient in dichloromethane to give the desired compound, compound I-521(36mg, 60% yield) as a solid.

¹H-NMR(500MHz,CDCl₃)δppm 8.48(d,1H),8.32(d,1H),7.42(s,1H),7.24-7.19(m,1H),7.04-6.97(m,3H),6.60(d,1H),6.05(br.s.,1H),5.93(s,2H),4.12(td,2H),3.74(t,2H)。

Compound I-539

To a solution of compound I-510(1 eq) in THF was added sodium borohydride (3eq) at 23 ℃. The reaction mixture was heated to 75 ℃, methanol (4 equivalents) was added dropwise via syringe, and the contents were stirred for 1 h. After cooling to 23 ℃, the reaction was concentrated in vacuo and the resulting crude material was purified via reverse phase HPLC to give the desired compound, compound I-539(1.5mg, 27% yield) as a solid.

¹H NMR(500MHz,CD₃OD)δppm 8.69(d,1H),8.35(d,1H),7.47(s,1H),7.19(d,1H),6.96(s,3H),6.89(d,1H),6.84-6.82(m,1H),5.89(s,2H),3.92(t,2H),3.66(t,2H)。

Compound I-610

A solution of intermediate 1(1 eq) in DMSO was treated with potassium (cyclopropylsulfonyl) amide (2 eq). The resulting reaction mixture was stirred at 23 ℃ for 16 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-610(34mg, 55% yield) as a solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.66(d,1H),8.35(d,1H),7.37(s,1H),7.23-7.11(m,1H),7.02-6.89(m,2H),6.86-6.74(m,2H),5.91-5.77(m,2H),3.36-3.26(m,1H),1.35-1.17(m,2H),1.08-0.89(m,2H)。

Compound I-611

A solution of intermediate 1(1 eq) in DMSO was treated with potassium (propylsulfonyl) amide (2 eq). The resulting reaction mixture was stirred at 23 ℃ for 16 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-611(50mg, 81% yield) as a solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.67(d,1H),8.36(d,1H),7.33(s,1H),7.23-7.13(m,1H),7.03-6.89(m,2H),6.87-6.81(m,1H),6.79(d,1H),5.91-5.68(m,2H),3.63(t,2H),1.93-1.74(m,2H),0.97(t,3H)。

Compound I-629

A solution of intermediate 1(1 eq) in DMSO was treated with potassium methyl (methylsulfonyl) amide (1 eq). The resulting reaction mixture was stirred at 23 ℃ for 16 h. The contents were filtered and the filtrate was directly purified via reverse phase HPLC to give the desired compound, compound I-629(8mg, 33% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.93(d,1H),7.62(s,1H),7.34(d,1H),7.28(d,1H),7.24-7.19(m,1H),7.12(td,1H),6.94(td,1H),5.92(s,2H),3.49(s,3H),3.37(d,3H)。

Compound I-475

The title compound was prepared according to general procedure C, except that (S) -2-acetoxy-3, 3, 3-trifluoropropionic acid was used as the acid reactant (3 equivalents), 7 equivalents of triethylamine were used, and 4 equivalents of T3P were used. The solution was heated to 50 ℃ for 10 minutes at which time the solution was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded the desired compound, compound I-475 as a white solid (98mg, quantitative yield).

¹H-NMR(500MHz,CDCl₃)δppm 8.81(d,1H),8.78(s,1H),8.50(d,1H),8.15(d,1H),7.51(s,1H),7.25-7.22(m,1H),7.09-7.05(m,1H),7.00(t,1H),6.85-6.82(m,1H),6.63(d,1H),6.06(s,2H),5.77(q,1H),2.39(s,3H)。

Compound I-485

The title compound was prepared according to general procedure B except 4-aminopyrrolidin-2-one was the amine reactant. After stirring at 90 ℃ for 16h, additional water was added to dissolve the reaction. After 5h, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-15% methanol gradient in dichloromethane) afforded the desired compound, compound I-485 as a white solid (11mg, 19% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.76(s,1H),8.11(d,1H),7.46(s,1H),7.27(q,1H),7.11-7.07(m,1H),7.03(t,1H),6.93(s,1H),6.83-6.80(m,1H),5.96(s,2H),5.11-5.06(m,1H),3.90(dd,1H),3.40(dd,1H),2.84(dd,1H),2.51(dd,1H)。

Compound I-500

A solution of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-ol (intermediate described in WO2012/003405 a 1; 1eq) and phosphorus oxychloride (20 eq) was heated to 60 ℃ for 1H, after which the phosphorus oxychloride was removed in vacuo. The resulting residue was dissolved in dioxane and water (2:1 ratio). 2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (3 equivalents) and triethylamine (10 equivalents) were added and the resulting solution was heated to 110 ℃ for 7 days. The solution was partitioned between 1N aqueous hydrochloric acid and dichloromethane. The aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-100% (7:1 ═ acetonitrile: methanol) gradient in dichloromethane) afforded the desired compound, compound I-500 as a yellow solid (16mg, 21% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.77(s,1H),8.20(d,1H),7.37(s,1H),7.29-7.24(m,1H),7.09-7.00(m,3H),6.85(s,1H),6.61(d,1H),5.95(s,2H),4.08(s,2H)。

Compound I-518

The title compound was prepared according to general procedure B except 3,3, 3-trifluoropropane-1, 2-diamine (9 equivalents) was the amine reactant and 30 equivalents of triethylamine were used. After stirring for 16h, the crude reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded the desired compound, compound I-518 as a white solid (10mg, 21% yield).

¹H-NMR(500MHz,CD₃OD)δppm 8.39(d,1H),8.11(d,1H),7.19(s,1H),7.14-7.10(m,1H),6.97-6.93(m,1H),6.89(t,1H),6.81-6.78(m,1H),6.52(d,1H),5.90(s,2H),5.57(brs,1H),4.17(ddd,1H),3.51-3.44(m,1H),3.34(ddd,1H)。

Compound I-540

A solution of compound I-403(1 eq) in dichloromethane was treated with diisopropylethylamine (2 eq), followed by HATU (1.5 eq). After stirring for 20min, ammonia (3 equivalents, 0.5M solution in dioxane) was added. After 22h, additional ammonia (3 equivalents) was added. After 4 hours, the solution was diluted with 1N aqueous hydrochloric acid and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-15% methanol gradient in dichloromethane) gave the desired compound, compound I-540(3mg, 13% yield) as a yellow film.

¹H-NMR(500MHz,CDCl₃)δppm 8.47(d,1H),8.27(d,1H),7.30(s,1H),7.24-7.20(m,1H),7.07-6.98(m,2H),6.91(m,1H),6.80(br s,1H),6.59(d,1H),6.10(d,1H),5.97(d,1H),5.92(d,1H),5.84(quint,1H),5.74(br s,1H)。

Compound I-568

A solution of compound I-418(1 eq), diphenylphosphorylazide (1.5 eq), and triethylamine (1.5 eq) in toluene was heated to 50 ℃ for 15 h. The solution was cooled to 23 ℃ and treated with sodium methoxide (3 equivalents, 0.5N solution in methanol). After stirring at 23 ℃ for 1h, saturated aqueous sodium bicarbonate solution was added and the resulting solution was stirred for another 1 h. The reaction was diluted with water and dichloromethane, and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the crude product. Purification via silica gel chromatography (0-15% (7:1 ═ acetonitrile: methanol) gradient in dichloromethane) afforded the desired compound, compound I-568(11mg, 52% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.76(d,1H),8.21(d,1H),7.49(s,1H),7.29-7.24(m,1H),7.12-7.06(m,1H),7.03(t,1H),6.94(d,1H),6.80(t,1H),5.97(s,2H),5.67-5.58(m,1H),3.73(dd,1H),3.51(s,3H),3.42(dd,1H)。

Compound I-576

The title compound was synthesized in 2 steps.

Step 1: synthesis of (S) -acetic acid 1- ((2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) amino) -1-oxoprop-2-yl ester

The intermediate was prepared according to general procedure C, except that (S) -2-acetoxypropionic acid was the acid reactant (3 equivalents), 10 equivalents of triethylamine was used and 4 equivalents of T3P were used. The solution was heated to 50 ℃ for 16h, at which time the solution was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded an impure intermediate which went to the next step without further manipulation.

Step 2: synthesis of Compound I-576

To a solution of (S) -acetic acid 1- ((2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) - -pyrimidin-4-yl) amino) -1-oxoprop-2-yl ester (1eq) in 4:1 ═ methanol: water was added a single portion of potassium carbonate (0.5 eq). After stirring for 10min, the reaction was acidified with 3N hydrochloric acid solution and diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol in dichloromethane) afforded the desired compound, compound I-576(4.5mg, 29% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.77(m,1H),8.71(d,1H),8.14(d,1H),7.54(s,1H),7.30-7.26(m,1H),7.11-7.03(m,2H),6.91-6.88(m,2H),5.98(s,2H),4.32(q,1H),1.45(d,3H)。

Compound I-580

The title compound was prepared following general procedure C, except 2-methyl-2- (methylsulfonyl) propionic acid was used as the acid reactant (3 equivalents), 10 equivalents of triethylamine was used, and 4 equivalents of T3P were used. The solution was heated to 70 ℃ for 3h, at which time the solution was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-100% ethyl acetate gradient in hexanes) afforded the desired compound, compound I-580(30mg, 42% yield) as a yellow foam.

¹H-NMR(500MHz,CDCl₃)δ9.13(br s,1H),8.78(d,1H),8.48(d,1H),8.06(d,1H),7.46(s,1H),7.24-7.19(m,1H),7.06-7.02(m,1H),7.00-6.97(m,1H),6.89-6.86(m,1H),6.63(d,1H),6.03(s,2H),3.00(s,3H),1.81(s,6H)。

Compound I-582

The title compound was prepared following general procedure C except that 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate described in the previous patent WO2012/003405 a 1; 1 equivalent) was used instead of intermediate 2, 2-methyl-2- (methylsulfonyl) propionic acid as the acid reactant (3 equivalents), 10 equivalents triethylamine was used, and 4 equivalents of propylphosphonic anhydride (T3P, 50 wt% in ethyl acetate) were used. After heating the mixture at 90 ℃ for 4 hours, the solution was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were washed with water, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (gradient in dichloromethane (7:1 acetonitrile: methanol)) afforded the desired compound, compound I-582 as a white solid (29mg, 41% yield).

¹H-NMR(500MHz,CDCl₃)δ9.10(br s,1H),8.67(d,1H),8.48(d,1H),7.42(s,1H),7.23-7.19(m,1H),7.06-7.02(m,1H),7.10-6.97(t,1H),6.86(t,1H),6.63(d,1H),6.02(s,2H),3.02(s,3H),1.82(s,6H)。

Compound I-587

The title compound was prepared following general procedure C, except 2- (methylsulfonyl) propionic acid was used as the acid reactant (3 equivalents), 10 equivalents of triethylamine were used, and 4 equivalents of T3P were used. After stirring at 70 ℃ for 1h, the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were washed with water, dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-5% methanol gradient in dichloromethane) afforded the desired compound, compound I-587(45mg, 64% yield) as a brown solid.

¹H-NMR(500MHz,CDCl₃)δ9.45(br s,1H),8.72(d,1H),8.48(d,1H),8.01(d,1H),7.34(s,1H),7.21-7.16(m,1H),7.04-7.01(m,1H),6.92(t,1H),6.80-6.77(m,1H),6.65(d,1H),6.00(s,2H),4.14(q,1H),3.02(s,3H),1.73(d,3H)。

Compound I-609

To a solution of potassium ((2,2, 2-trifluoroethyl) sulfonyl) amide (2 equivalents) in dimethylsulfoxide was added intermediate 1(1 equivalent). After stirring for 62h, the solution was diluted with ethyl acetate and 1N aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude residue was dissolved in methanol, and the resulting solid was filtered and washed with additional methanol. The residue was re-dissolved in methanol, and the resulting solid was filtered and washed with methanol to give the desired compound, compound I-609(24mg, 28% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δ9.14(d,1H),8.44(br s,1H),7.51(s,1H),7.37-7.31(m,1H),7.24-7.20(m,2H),7.12(t,1H),7.02-6.99(m,1H),5.92(s,2H),4.74(br s,2H)。

Compound I-627

A suspension of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-ol (intermediate described in WO 2012/003405A 1; 1 equivalent) in phosphorus oxychloride (20 equivalents) was heated to 60 ℃ for 2H. After evaporation to dryness in vacuo, the resulting residue and 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionamide (3 equivalents) were dissolved in a 2:1 mixture of dioxane: water and treated with triethylamine (10 equivalents). The solution was heated to 110 ℃ for 38 h. The solution was diluted with dichloromethane and 1N hydrochloric acid, the layers were separated, and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification via silica gel chromatography (0-65% (7:1 ═ acetonitrile: methanol) gradient in dichloromethane) afforded the contaminated product. The crude product was partitioned between water and dichloromethane. The layers were separated and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give the desired compound, compound I-627(1mg, 1% yield) as a clear film.

¹H-NMR(500MHz,CD₃OD)δ8.78(s,1H),8.17(d,1H),7.42(s,1H),7.30-7.26(m,1H),7.11-7.04(m,2H),7.01-6.98(m,1H),6.89(s,1H),6.59(d,1H),5.97(s,2H),4.10-4.02(m,2H)。

Compound I-634

The title compound was prepared according to general procedure B except 3-amino-1, 1, 1-trifluoro-2-methylpropan-2-ol (as the HCl salt, 2 equivalents) was the amine reactant and 4 equivalents triethylamine were used. After stirring at 90 ℃ for 21h, work up and purification via silica gel chromatography (0-70% ethyl acetate gradient in hexanes) gave the desired compound, compound I-634(33mg, 48% yield) as a white solid.

¹H-NMR(500MHz,CDCl₃)δppm 8.48(m,1H),8.22(d,1H),7.27(s,1H),7.24-7.19(m,1H),7.05-6.95(m,3H),6.61(m,1H),6.04-5.93(m,3H),5.74(br s,1H),4.00(dd,1H),3.81(dd,1H),1.44(s,3H)。

Compound I-631

The title compound was prepared according to general procedure B except 4,5,6, 7-tetrahydro-1H-pyrazolo [4,3-c ] pyridin-3 (2H) -one dihydrochloride (2 equivalents) was the amine reactant and 4 equivalents triethylamine were used. After stirring at 90 ℃ for 1.5h, work up and purification via silica gel chromatography (0-15% methanol gradient in dichloromethane) gave the desired compound, compound I-631(9mg, 14% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.79(d,1H),8.22(d,1H),7.50(s,1H),7.31-7.27(m,1H),7.13-7.09(m,1H),7.05(t,1H),6.94(m,1H),6.85-6.82(m,1H),5.98(s,2H),4.76(s,2H),4.17(t,2H),2.85(t,2H)。

Compound I-328

The title compound was prepared according to general procedure C except 1- (trifluoromethyl) cyclopropanecarboxylic acid (2 equivalents) was used as the acid reactant, 3 equivalents of triethylamine were used and 3 equivalents of T3P were used. The solution was stirred at 23 ℃ for 18h, at which time the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water (2 ×) and saturated aqueous sodium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate in hexanes) to give the desired compound, compound I-328(2mg, 14% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.73(d,1H),8.57(br s,1H),8.45(d,1H),8.02(d,1H),7.45(s,1H),7.19(m,1H),7.02(m,1H),6.96(m,1H),6.83(m,1H),6.60(d,1H),6.01(s,2H),1.40(m,4H)。

Compound I-415 the title compound was prepared following general procedure C except that 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (intermediate described in the previous patent WO2012/003405 a 1; 1 equivalent) was used as the acid reactant instead of intermediate 2, 1- (trifluoromethyl) cyclopropanecarboxylic acid (3 equivalents), 7 equivalents of triethylamine were used and 4 equivalents of T3P were used. After heating at 90 ℃ for 2 days, the vial was cooled to 23 ℃ and the contents were diluted with ethyl acetate. The contents were washed with water (3 ×), brine, then dried over sodium sulfate, filtered and concentrated via rotary evaporation. The residue was purified via silica gel chromatography (ethyl acetate in hexanes) to give the desired compound, compound I-415, as a white solid (42mg, 30% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.67(s,1H),8.49(s,1H),8.31(br s,1H),7.43(s,1H),7.23(m,1H),7.06(m,1H),6.99(m,1H),6.84(m,1H),6.63(s,1H),6.04(s,2H),1.64(m,2H),1.45(m,2H)。

Compound I-460 the title compound was prepared following general procedure C except that 5-fluoro-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-amine (described in the previous patent WO2012/003405 a 1; 1 equivalent) was used as the acid reactant instead of the intermediate 2, 1-cyanocyclopropanecarboxylic acid (3 equivalents), 7 equivalents of triethylamine were used and 4 equivalents of T3P were used. After heating at 50 ℃ for 18h, the vial was cooled to 23 ℃ and the contents diluted with ethyl acetate. The contents were washed with water (3 ×), brine, then dried over sodium sulfate, filtered and concentrated via rotary evaporation. The residue was purified via silica gel chromatography (ethyl acetate in hexanes) to give the desired compound, compound I-460(29mg, 23% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δppm 8.61(s,1H),8.50(br s,1H),8.41(s,1H),7.34(s,1H),7.14(m,1H),6.97(m,1H),6.91(m,1H),6.77(m,1H),6.54(s,1H),5.95(s,2H),1.80(m,2H),1.67(m,2H)。

Compound I-483

The title compound was synthesized in 2 steps.

Step 1: synthesis of 3- (3- (4-chloro-5-nitropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole

2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-nitropyrimidin-4-ol (intermediate described in the previous patent WO2012/003405 a 1; 1eq) was added to phosphorus oxychloride (22 eq) and the mixture was heated at 90 ℃ for 4H. The contents were concentrated in vacuo and the residue was dissolved in ethyl acetate and washed sequentially with 10% sodium bicarbonate solution (2 ×), water (2 ×) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the desired intermediate, 3- (3- (4-chloro-5-nitropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole as a tan solid (1.86g, 96% yield).

¹H-NMR(400MHz,CDCl₃)δppm 9.35(s,1H),8.53(d,1H),7.59(s,1H),7.25(m,1H),7.07(m,1H),7.02(m,1H),6.91(m,1H),6.65(d,1H),6.08(s,2H)。

Step 2: synthesis of Compound I-483

The title compound was prepared according to general procedure B except that 3- (3- (4-chloro-5-nitropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole was used instead of intermediate 1,2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (1.5 equivalents) as the amine reactant, 3 equivalents triethylamine was used and the contents were heated to 30 ℃ as a solution in dioxane: water (3:1) for 1H. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water (2 ×) and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography with a 0-100% ethyl acetate/hexanes gradient to give the desired compound, compound I-483 as a white solid (77mg, 73% yield).

¹H-NMR(400MHz,CDCl₃)δppm 9.36(s,1H),8.59(m,1H),8.55(d,1H),7.64(br s,1H),7.42(s,1H),7.28(m,1H),7.08(m,1H),7.06(m,1H),6.64(d,1H),5.98(s,2H),4.27,(d,2H)。

Compound I-484

A solution of compound I-483(1 equivalent) in methanol at 23 ℃ was treated with 10% palladium on charcoal (0.2 equivalent) and then placed in H₂An atmosphere, which is obtained via a hydrogen filled balloon attached to a needle. Subjecting the mixture to reaction under positive H₂Stirred under pressure for 1h and filtered through celite. The filter cake was washed with methanol and the combined washings were concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography using ethyl acetate in hexanes to give the desired compound, compound I-484(53mg, 66% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δppm 9.39(s,1H),7.92(br s,1H),7.19(m,1H),7.13(m,2H),7.98(m,1H),6.92(m,2H),6.52(s,1H),5.85(s,2H),4.01,(s,2H)。

Compound I-541

A mixture of 3- (3- (4-chloro-5-nitropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (as described in step 1 of the synthesis of compound I-483) (1 equivalent), methyl carbamate (5 equivalents), and cesium carbonate (5 equivalents) was heated at 90 ℃ for 18H. After cooling to 23 ℃, the mixture was diluted with ethyl acetate and washed with water (3 ×) and brine. The contents were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography using ethyl acetate/hexanes to give the desired compound, compound I-541 as a light yellow solid (35mg, 19% yield).

¹H-NMR(400MHz,CDCl₃)δppm 10.09(br s,1H),9.51(s,1H),8.50(d,1H),7.60(s,1H),7.24(m,1H),7.06(m,1H),7.02(m,1H),6.87(m,1H),6.67(d,1H),6.07(s,2H),3.95(s,3H)。

Compound I-542

A solution of compound I-541(1 eq) in methanol at 23 deg.C was treated with 10% palladium on charcoal (0.2 eq) and then placed in H₂An atmosphere, which is obtained via a hydrogen filled balloon attached to a needle. Subjecting the mixture to reaction under positive H₂Stirred under pressure for 1h and filtered through celite. The filter cake was washed with methanol and the combined washings were concentrated in vacuo. The resulting crude residue was purified via silica gel chromatography with an ethyl acetate gradient in hexanes to give the desired compound, compound I-542(26mg, 87% yield) as a solid.

¹H-NMR(400MHz,CDCl₃)δppm 8.43(d,1H),8.27(s,1H),7.52(s,1H),7.32(s,1H),7.18(m,1H),7.02(m,1H),6.99(m,1H),6.77(m,1H),6.57(d,1H),5.99(s,2H),4.61(br s,2H),3.81(s,3H)。

Compound I-488

The title compound was prepared according to general procedure B except 2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (2.3 equivalents) was the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2, 3-difluorobenzyl) -1H-pyrazol-5-yl) isoxazole (described in step 2 for the synthesis of compound I-235) was used in place of intermediate 1, and the contents were heated to 90 ℃ for 3 days. The contents were cooled to 23 ℃ and the mixture was diluted with ethyl acetate. The organic layer was washed with water (2 ×) and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography (ethyl acetate gradient in hexanes) to give the desired compound, compound I-488 as a white solid (62mg, 44% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.52(s,1H),8.39(s,1H),8.29(s,1H),7.25(s,1H),7.09(m,1H),6.98(m,1H),6.96(m,1H),6.64(s,1H),5.99(s,2H),5.58(br s,1H),4.14(d,2H)。

Compound I-489

The title compound was prepared according to general procedure B except 2- (aminomethyl) -3,3, 3-trifluoro-2-hydroxypropionic acid (1.3 equivalents) was used as the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (2, 3-difluorobenzyl) -1H-pyrazol-5-yl) isoxazole (described in step 2 for the synthesis of compound I-235) was used in place of intermediate 1, and the contents were heated to 90 ℃ for 3 days. The contents were cooled to 23 ℃ and the mixture was diluted with water and the pH was adjusted to 5 with 3N HCl solution. The mixture was filtered and the filter cake was washed with water (2 ×), and dried in vacuo. A portion of the residue was dissolved in dichloromethane/methanol (4mL, 1: 1). Filtration left 62mg of insoluble material. The insoluble fraction was subjected to silica gel chromatography using a dichloromethane/methanol gradient to give compound I-489(60mg) as a white solid. Analysis of the insoluble material remaining from filtration showed Compound I-489 (0.122 g total, 90% yield).

1H-NMR(400MHz,CD₃OD)δppm 8.77(d,1H),8.16(d,1H),7.51(s,1H),7.15(m,1H),7.01(m,1H),6.94(d,1H),6.71(m,1H),6.00(s,2H),4.43(d,1H),4.12(d,1H)。

Compound I-522

A solution of compound I-489(1 eq) in dichloromethane was treated with Hunig's base (3eq) and HATU (1.5 eq). The resulting solution was stirred for 2h, then a solution of ammonia (0.5M in dioxane, 8 equivalents) was added to the reaction. The contents were allowed to stir overnight at 23 ℃. The mixture was diluted with dichloromethane and washed with water (3 ×) and brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography with a dichloromethane/methanol gradient to afford the desired compound, compound I-522 as a white solid (5mg, 8% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.45(s,1H),8.14(s,1H),7.98(s,1H),7.18(s,1H),7.13(s,1H),7.01(m,1H),6.90(m,2H),6.56(s,1H),5.90(s,2H),5.65(br s,1H),5.53(brs,1H),4.12(d,2H)。

Compound I-507

The title compound was synthesized in 4 steps.

Step 1: synthesis of (3,3, 3-trifluoropropyl) hydrazine hydrochloride

3-bromo-1, 1, 1-trifluoropropane (1eq) and hydrazine hydrate (10 eq) were dissolved in absolute ethanol and heated at 80 ℃ for 18 h. The solution was cooled to 23 ℃ and concentrated in vacuo at 15 ℃. The viscous oil was diluted with water and dichloromethane, and solid potassium carbonate was added to saturate the aqueous layer. The phases were mixed and separated, then the aqueous phase was extracted with additional dichloromethane (2 ×). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. A small portion of the neutral hydrazine product was removed for characterization by NMR. The remaining portion was dissolved in ether and treated with hydrochloric acid (2.5M solution in ethanol) and the resulting mixture was concentrated in vacuo to give the desired intermediate, (3,3, 3-trifluoropropyl) hydrazine hydrochloride (2.02g, 43% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δppm 3.18(br s,4H),3.02(m,2H),2.36(m,2H)。

Step 2: synthesis of 3- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-5-carboxylic acid ethyl ester

With potassium carbonate (0.6 eq), followed by a solution of ethyl 4- (isoxazol-3-yl) -2- (methoxy (methyl) amino) -4-oxobut-2-enoate (2 eq, generated in step 1 of general procedure a by using 1- (isoxazol-3-yl) ethanone in step 1) (3,3, 3-trifluoropropyl) hydrazine hydrochloride (1eq) in a mixture of ethanol and water (9:1) at 23 ℃. The solution was stirred at 23 ℃ for 2 days, then 6N hydrochloric acid (1.5 equivalents) was added dropwise to the reaction. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed with water (5 ×), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography using an ethyl acetate gradient in dichloromethane to give the desired pyrazole ester, ethyl 3- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-5-carboxylate as a light yellow solid (1.34g, 36% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.55(d,1H),7.15(s,1H),6.63(d,1H),4.95(m,2H),4.46(q,2H),2.85(m,2H),1.44(t,3H)。

Step 3: synthesis of 5- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-3-carboxamidine

The desired amidine intermediate was generated according to the procedure described in step 3 of general procedure a, except that 3- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-5-carboxylic acid ethyl ester was used as starting ester and the mixture was heated at 110 ℃ for 4H. The reaction mixture was cooled in ice and then methanol (14 eq) and aqueous hydrochloric acid (17 eq) were added continuously over 5 min. The mixture was heated at 80 ℃ for 30min, then cooled in ice and filtered. The filter cake was washed with toluene (2 x) and air dried to give amidine hydrochloride. This material was stirred in saturated aqueous sodium carbonate solution and extracted with ethyl acetate/isopropyl alcohol (5:1 mixture). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the desired neutral amidine, 5- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-3-carboxamidine as a light yellow solid.

¹H-NMR(400MHz,CDCl₃)δppm 8.45(d,1H),6.99(s,1H),6.55(d,1H),5.61(br.s.,3H),4.83-4.74(m,2H),2.81-2.65(m,2H)。

Step 4: synthesis of Compound I-507

The title product was prepared according to general procedure a, step 4, except 5- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-3-carboxamidine was the starting amidine, 2.5 equivalents of sodium (Z) -3-ethoxy-2-fluoro-3-oxoprop-1-en-1-ol were used, and the mixture was heated at 90 ℃ for 2H. The reaction was cooled to 23 ℃ and the solvent was removed in vacuo. The residue was again dissolved in dichloromethane and treated with hydrochloric acid (2.5M in ethanol, 3 equivalents). The resulting solid was filtered, washed with dichloromethane (2 ×), and air dried to give the desired compound, compound I-507 as a white solid (0.43g, 110% yield).

¹H-NMR(400MHz,CD₃OD)δppm 8.84(d,1H),8.03(d,1H),7.40(s,1H),6.95(d,1H),4.96(t,2H),2.92(m,2H)。

Compound I-511

The title compound was synthesized in 2 steps.

Step 1: synthesis of 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole

A mixture of compound I-507(1 equivalent) in phosphorus oxychloride (28 equivalents) was heated at 90 ℃ for 2 h. The solvent was removed in vacuo and the residue was washed with dichloromethane (2 ×) to give the desired intermediate, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole as a tan solid (0.28g, 69% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.59(s,1H),8.47(d,1H),7.30(s,1H),6.60(d,1H),4.92(t,2H),2.81(m,2H)。

Step 2: synthesis of Compound I-511

The title compound was prepared according to general procedure B except 2-aminoacetamide (as the HCl salt, 2 equivalents) was the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole (described above) was used instead of intermediate 1, 5 equivalents triethylamine was used, and the contents were heated to 90 ℃ for 2H. The mixture was cooled to 23 ℃, diluted with water and brought to a pH of about 5 with 3N aqueous hydrochloric acid. The crude product was collected by filtration and then purified via silica gel chromatography using a methanol gradient in dichloromethane to give the desired compound, compound I-511(12mg, 45% yield) as a white solid.

¹H-NMR(400MHz,CD₃OD)δppm 8.81(s,1H),8.13(d,1H),7.34(s,1H),6.93(s,1H),4.91(m,2H),4.21(s,2H),2.89(m,2H)。

Compound I-513

3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole (described in step 1 of the synthesis of compound I-511) (1eq) and concentrated aqueous ammonium hydroxide solution (2.8 eq) in dioxane were sealed in screw-cap vials and heated at 95 ℃ for 2H. The mixture was cooled to 23 ℃, diluted with water and then filtered. The filter cake was washed with water (2 ×) and air dried to give the desired compound, compound I-513(0.14g, 76% yield) as a light tan powder.

¹H-NMR(400MHz,CDCl₃)δppm 8.51(d,1H),8.21(d,1H),7.26(s,1H),6.63(d,1H),5.26(s,2H),4.95(m,2H),2.85(m,2H)。

Compound I-516 and compound I-517

The title compound was prepared according to general procedure B except 2- (aminomethyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (2 equivalents) was used as the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole (described in step 1 of the synthesis of compound I-511) (1 equivalent) was used instead of intermediate 1,6 equivalents of triethylamine were used, and the contents were heated to 95 ℃ for 3 days. The mixture was cooled to 23 ℃ and diluted with ethyl acetate, then washed with water (2 ×) and brine. The contents were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. The residue was purified via silica gel chromatography with a hexane/ethyl acetate gradient to give two products, compound I-516(27mg, 37% yield) and compound I-517(9mg, 16% yield) as white solids.

Process for preparation of compound I-516¹H-NMR(400MHz,CDCl₃)δppm 8.56(s,1H),8.40(s,1H),8.31(d,1H),7.21(s,1H),6.67(s,1H),5.60(m,1H),4.95(m,2H),4.16(d,2H),2.93(m,2H)。

Process for preparation of compound I-517¹H-NMR(400MHz,CDCl₃)δppm 8.54(s,1H),8.15(d,1H),7.17(s,1H),6.68(s,1H),4.94(m,2H),3.69(q,4H),2.89(m,2H),1.31(t,6H)。

Compound I-523

The title compound was prepared according to general procedure B except that 1- ((methylamino) methyl) cyclopropanecarboxylic acid (as the HCl salt) was the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole (described in step 1 of the synthesis of compound I-511) (1 equivalent) was used instead of intermediate 1, 6.6 equivalents triethylamine was used, and the contents were heated to 90 ℃ for 18H. The reaction mixture was diluted with water and brought to pH 4 with 3N aqueous hydrochloric acid. The mixture was filtered and the filter cake was washed with water (2 ×) and air dried to give the desired compound, compound I-523 as a white solid (9mg, 60% yield).

1H-NMR(400MHz,CDCl₃)δppm 8.51(d,1H),8.16(d,1H),7.16(s,1H),6.64(s,1H),4.92(m,2H),4.10(s,2H),3.35(d,3H),2.87(m,2H),1.44(m,2H),1.13(m,2H)。

Compound I-573

The title compound was synthesized in 2 steps.

Step 1: synthesizing to obtain the 3- (methylsulfonyl) propionic acid

While adding an aqueous hydrogen peroxide solution (27%, 6 equivalents) at a certain rate, a solution of 3- (methylthio) propionic acid (1 equivalent) in glacial acetic acid was cooled in ice to keep the internal temperature at<At 50 ℃. The cooling bath was removed and stirring was continued at 23 ℃ for 18 h. The solvent was removed in vacuo to leave a white paste. The paste was mixed with dichloromethane and filtered. The filter cake was washed with additional dichloromethane (3 ×) and air dried to give the desired carboxylic acid, 3- (methylsulfonyl) propionic acid as a white solid (3.0g, 47% yield).¹H-NMR (400MHz, acetone-d)₆)δppm 10.2(br s,1H),3.38(t,2H),3.00(s,3H),2.85(t,2H)。

The title compound was prepared according to general procedure C, except that 3- (methylsulfonyl) propionic acid (2 equivalents) was used as the acid reactant, 6 equivalents of triethylamine was used, and 3 equivalents of propylphosphonic anhydride (T3P, 50 wt% in ethyl acetate) were used, and the solution was heated to 70 ℃ for 18 h. The contents were cooled to 23 ℃, diluted with ethyl acetate, then washed with water (3 ×) and brine. The contents were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography with a gradient of ethyl acetate in hexanes to give the desired compound, compound I-573(6mg, 8% yield) as a white solid.

¹H-NMR (400MHz, acetone-d)₆)δppm 8.77(d,1H),8.58(d,1H),7.92(d,1H),7.40(s,1H),7.20(m,1H),7.03(m,1H),6.98(m,1H),6.94(d,1H),6.83(m,1H),5.88(s,2H),3.38(t,2H),3.07(t,2H),2.88(s,3H)。

Compound I-588

The title compound was synthesized in 6 steps.

Step 1: synthesis of3- ((tert-Butoxycarbonyl) amino) -4,4, 4-trifluorobutanoic acid ethyl ester

Upon addition of triethylamine (2.2 equivalents) over 5min, a solution of ethyl 3-amino-4, 4, 4-trifluorobutanoate hydrochloride (1 equivalent) in THF was cooled in ice. Di-tert-butyl dicarbonate in THF (2 equivalents) was added to the vessel and the mixture was stirred at 23 ℃ for 2 days. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate, then washed sequentially with water, 10% aqueous sodium bicarbonate, water (3 ×), then brine. The contents were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography using an ethyl acetate gradient in hexanes to afford the desired Boc-protected amine, ethyl 3- ((tert-butoxycarbonyl) amino) -4,4, 4-trifluorobutyrate (1.9g, 74% yield) as a white solid.

¹H-NMR(400MHz,CDCl₃)δppm 5.25(br d,1H),4.68(m,1H),4.16(q,2H),2.74(dd,1H),2.57(dd,1H),1.43(s,9H),1.25(t,3H)。

Step 2: synthesis of tert-butyl (1,1, 1-trifluoro-4-hydroxybut-2-yl) carbamate

Upon addition of lithium aluminium hydride (2M in THF, 2.5 equivalents) over 5min, a solution of ethyl 3- ((tert-butoxycarbonyl) amino) -4,4, 4-trifluorobutyrate (1 equivalent) in THF was cooled down again in ice. The solution was stirred at 23 ℃ for 3h, then cooled again in ice and treated sequentially with water, 15% aqueous NaOH, and water. Stirring was continued at 23 ℃ for 15min, then the mixture was filtered through celite, and the filter cake was washed with ethyl acetate (4 ×). The combined organic filtrates were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired alcohol intermediate, tert-butyl (1,1, 1-trifluoro-4-hydroxybut-2-yl) carbamate as a white solid (0.26g, 98% yield).

¹H-NMR(400MHz,CDCl₃)δppm 4.79(br d,1H),4.44(m,1H),3.76(m,1H),3.68(m,1H),2.63(br s,1H),2.08(m,1H),1.55(m,1H),1.45(s,9H)。

Step 3: synthesis of 3- ((tert-butoxycarbonyl) amino) -4,4, 4-trifluorobutyl methanesulfonate

While methanesulfonyl chloride (1.7 equivalents) was added to the vessel, a solution of tert-butyl (1,1, 1-trifluoro-4-hydroxybut-2-yl) carbamate (1 equivalent) and triethylamine (2.5 equivalents) in dichloromethane was stirred at 23 ℃. The resulting solution was stirred at 23 ℃ for 2h, then diluted with ethyl acetate and washed with water (4 ×) and brine. The contents were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired methanesulfonyl-protected alcohol intermediate, 3- ((tert-butoxycarbonyl) amino) -4,4, 4-trifluorobutyl methanesulfonate as a colorless solid (0.29g, 89% yield).

¹H-NMR(400MHz,CDCl₃)δppm 4.67(br d,1H),4.45(m,1H),4.31(m,2H),3.05(s,3H),2.28(m,1H),1.84(m,1H),1.45(s,9H)。

Step 4: synthesis of tert-butyl (1,1, 1-trifluoro-4- (methylsulfonyl) butan-2-yl) carbamate

A solution of 3- ((tert-butoxycarbonyl) amino) -4,4, 4-trifluorobutyl methanesulfonate (1eq) in THF at 23 ℃ was treated with sodium thiomethoxide (10 eq) and the resulting solution was heated at 60 ℃ for 6 h. The reaction mixture was then cooled in ice while multiple portions of m-chloroperoxybenzoic acid (70% wt/wt, 12.5 equivalents) were added. The reaction was measured by LC/MS to confirm complete conversion to sulfone. The mixture was diluted with ethyl acetate and washed sequentially with 7:1 ═ 10% aqueous bicarbonate solution/3N aqueous sodium hydroxide solution (2 ×), 10% aqueous sodium bicarbonate solution (2 ×), water (4 ×), and then brine. The contents were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was purified via silica gel chromatography using an ethyl acetate gradient in hexanes to afford the desired sulfone intermediate, tert-butyl (1,1, 1-trifluoro-4- (methylsulfonyl) but-2-yl) carbamate as a white solid (0.18g, 72% yield).

¹H-NMR(400MHz,CDCl₃)δppm 4.75(br d,1H),4.36(m,1H),3.16(m,2H),2.99(s,3H),2.37(m,1H),2.07(m,1H),1.49(s,9H)。

Step 5: synthesis of 1,1, 1-trifluoro-4- (methylsulfonyl) butan-2-amine

Tert-butyl (1,1, 1-trifluoro-4- (methylsulfonyl) but-2-yl) carbamate (1eq) was dissolved in dichloromethane at 23 ℃ and then treated with trifluoroacetic acid (25 eq) and stirred at 23 ℃ for 3 h. The reaction was diluted with dichloromethane and 10% aqueous sodium bicarbonate and the phases were mixed well and separated. The aqueous phase was extracted with dichloromethane (3 ×) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired deprotected amine intermediate, 1,1, 1-trifluoro-4- (methylsulfonyl) butan-2-amine (18mg, 54% yield) as a colourless oil.

¹H-NMR(400MHz,CDCl₃)δppm 3.25(m,2H),3.15(m,1H),2.89(s,3H),2.23(m,1H),1.80(m,1H),1.36(br s,2H)。

Step 6: synthesis of Compound I-588

The title compound was prepared according to general procedure B except 1,1, 1-trifluoro-4- (methylsulfonyl) butan-2-amine (6 equivalents) was the amine reactant, 6 equivalents triethylamine was used, and the contents were heated via microwave to 215 ℃ for 2h as a solution in NMP. The resulting mixture was directly purified via silica gel chromatography using an ethyl acetate in hexane gradient to give an impure product. Further purification via reverse phase HPLC gave the desired compound, compound I-588(17mg, 16% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.40(d,1H),8.23(d,1H),7.29(s,1H),7.13(m,1H),6.97(m,1H),6.91(m,1H),6.81(m,1H),6.56(d,1H),5.93(d,1H),5.88(d,1H),5.35(m,1H),5.18,(br s,1H),3.19(m,1H),3.11(m,1H),2.86(s,3H),2.53(m,1H),2.21(m,1H)。

Compound I-626

The title compound was prepared according to general procedure B except that 1,1, 1-trifluoro-4- (methylsulfonyl) butan-2-amine (1.3 equivalents) was used as the amine reactant, 3- (3- (4-chloro-5-fluoropyrimidin-2-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazol-5-yl) isoxazole (described in step 1 of the synthesis of compound I-511) (1 equivalent) was used instead of intermediate 1, 1.3 equivalents triethylamine was used, and the contents were heated via microwave to 215 ℃ as a solution in NMP for 2.5H. The resulting mixture was directly purified via silica gel chromatography using an ethyl acetate in hexane gradient to give an impure product. Further purification via reverse phase HPLC afforded the desired compound, Compound I-626(1mg, 1% yield).

¹H-NMR(400MHz,CDCl₃)δppm 8.53(d,1H),8.32(d,1H),7.30(s,1H),6.71(d,1H),5.44(m,1H),5.27(br d,1H),4.94(m,2H),3.21(m,2H),2.95(s,3H),2.87(m,2H),2.61(m,1H),2.28(m,1H)。

Compound I-617

The title compound was prepared in 3 steps.

Step 1: synthesis of diethyl 2- (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-nitropyrimidin-4-yl) -2-methylmalonate

A mixture of 3- (3- (4-chloro-5-nitropyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazol-5-yl) isoxazole (described in step 1 for the synthesis of compound I-483 in step 1, 1.2 equivalents), diethyl 2-methylmalonate (1 equivalent), and potassium tert-butoxide (0.9 equivalent) in THF was stirred at room temperature for 15 min. The solution was diluted with saturated aqueous ammonium chloride and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified via silica gel chromatography (10-50% ethyl acetate gradient in hexanes) to give the desired intermediate, diethyl 2- (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-nitropyrimidin-4-yl) -2-methylmalonate as a yellow solid (94.5mg, 40% yield).

¹H NMR(500MHz,DMSO-d₆)δppm 9.56(s,1H),9.14(d,1H),7.69(s,1H),7.36(s,1H),7.30(d,1H),7.19-7.25(m,1H),7.12(t,1H),6.97-7.03(m,1H),5.95-5.97(m,2H),4.12-4.19(m,4H),1.94(s,3H),1.11(t,6H)。

Step 2: synthesis of diethyl 2- (5-amino-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-4-yl) -2-methylmalonate

A mixture of 2- (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-nitropyrimidin-4-yl) -2-methylmalonic acid diethyl ester (1eq) and 20% palladium on charcoal (0.5 eq) in ethanol and ethyl acetate (1:1) was stirred under hydrogen atmosphere at 23 ℃ for 18H. Then, the reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was taken to the next step without any further purification or characterization.

Step 3: synthesis of Compound I-617

A solution of diethyl 2- (5-amino-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidin-4-yl) -2-methylmalonate in ethanol and THF (2:1) was heated at 85 ℃ for 16H. The resulting solution was concentrated in vacuo and the residue was purified via reverse phase HPLC (20-60% acetonitrile gradient in water with 1% TFA) to give the desired compound, compound I-617(12mg, 20% yield) as a pale yellow solid.

¹H NMR(500MHz,DMSO-d₆)δppm 11.26(s,1H),9.07(d,1H),8.44(s,1H),7.57(s,1H),7.30(d,2H),7.17-7.25(m,1H),7.06-7.13(m,1H),6.80-6.88(m,1H),5.88-5.99(m,2H),4.01-4.20(m,2H),1.60(s,3H),1.05(s,3H)。

Compound I-618

The title compound was prepared in 2 steps.

Step 1: synthesis of diethyl 2- (dicyanomethyl) -2-methylmalonate

A mixture of diethyl 2-bromo-2-methylmalonate (1eq), malononitrile (1eq) and potassium tert-butoxide (1eq) in THF was heated to reflux for 15 h. The mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography using a 10-15% ethyl acetate gradient in hexanes to give the desired intermediate, diethyl 2- (dicyanomethyl) -2-methylmalonate (5.76g, 32% yield) as a colorless oil.

¹H NMR(500MHz,CDCl₃)δppm 4.53(s,1H),4.27-4.39(m,4H),1.81(s,3H),1.33(t,6H)。

Step 2: synthesis of Compound I-618

A mixture of 5- (isoxazol-3-yl) -1- (3,3, 3-trifluoropropyl) -1H-pyrazole-3-carboxamidine (generated in step 3 for the synthesis of compound I-507, 1eq), diethyl 2- (dicyanomethyl) -2-methylmalonate (1.15 eq) and potassium bicarbonate (2 eq) in t-BuOH was heated to reflux for 5H. The resulting solution was then concentrated in vacuo and the residue was purified via silica gel chromatography with a 0-5% methanol gradient in dichloromethane to give the desired compound, compound I-618(88.5mg, 51% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 11.31(s,1H),9.14(d,1H),7.34(s,1H),7.24(d,1H),6.57-6.71(m,2H),4.85(t,2H),4.11(t,2H),2.85-2.98(m,2H),1.61(s,3H),1.12(t,3H)。

Compound I-619

Ammonia (7.0M in MeOH, 200 equivalents) was added to compound I-618(1 equivalent). The reaction mixture was heated at 50 ℃ for 16 h. The resulting solution was then concentrated in vacuo and the residue was purified via reverse phase HPLC (20-40% acetonitrile gradient in water with 1% TFA) to give the desired compound, compound I-619(4.7mg, 31% yield) as a white solid.

¹H NMR(500MHz,DMSO-d₆)δppm 11.30(s,1H),9.14(d,1H),7.42-7.50(m,1H),7.36(s,1H),7.25(d,1H),7.17-7.22(m,1H),6.67-6.92(m,2H),4.83-4.89(m,2H),2.86-2.99(m,2H),1.56(s,3H)。

Compound I-620

The title compound was prepared in 3 steps:

step 1: synthesis of (E) -2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5- (phenyldiazenyl) pyrimidine-4, 6-diamine

A mixture of 1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazole-3-carboxamidine (formed in step 3 of the synthesis for compound I-507) (1 equivalent), (E) -2- (phenyldiazenyl) malononitrile (1.2 equivalents) and potassium bicarbonate (2 equivalents) in t-BuOH was heated to reflux for 18H. After cooling, the reaction mixture was concentrated in vacuo and taken to the next step without further purification.

Step 2: synthesis of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidine-4, 5, 6-triamine

A mixture of (E) -2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5- (phenyldiazenyl) pyrimidine-4, 6-diamine (1 equivalent) and 20% palladium on charcoal (0.5 equivalent) in DMF was stirred under hydrogen atmosphere at 23 ℃ for 18H. The reaction mixture was then filtered through celite and the residue was washed with DMF followed by a small portion of methanol. The filtrate was concentrated in vacuo, and the residue was suspended in ethyl acetate and one drop of methanol with vigorous stirring. The precipitate was filtered, washed with ethyl acetate, and dried in vacuo to give the desired triaminopyrimidine intermediate, 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -pyrimidine-4, 5, 6-triamine (278mg, 46% yield over 2 steps) as a dark yellow solid.

Step 3: synthesis of Compound I-620

A solution of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidine-4, 5, 6-triamine (1eq) in pyridine at 0 ℃ was treated with methyl chloroformate (1 eq). The reaction mixture was slowly warmed to 23 ℃ and stirred for 18 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and washed with water. The contents were dried over anhydrous sodium sulfate, filtered and concentrated to give a dark yellow solid. The crude material was purified via reverse phase HPLC (20-40% acetonitrile gradient in water with 1% TFA) to give the desired compound, compound I-620(15mg, 26% yield) as a light yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.82(d,1H),7.51(s,1H),7.27-7.35(m,1H),7.04-7.15(m,2H),6.92-6.99(m,1H),6.89(d,1H),6.00(s,2H),3.78(br.s.,3H),3.34-3.35(m,1H)。

Compound I-621

A solution of compound I-620(1 equivalent) and LiHMDS (1M in toluene, 6 equivalents) in THF at 0 deg.C was stirred for 20 min. Methyl iodide (12 equivalents) was added to the reaction vessel and the mixture was warmed to 23 ℃ and stirred for 1 h. The mixture was diluted with dichloromethane and saturated aqueous ammonium chloride solution, and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified via reverse phase HPLC (20-40% acetonitrile gradient in water with 1% TFA) to give the desired compound, compound I-621 as a yellow solid (1.6mg, 17% yield).

¹H NMR(500MHz,CD₃OD)δppm 8.83(d,1H),7.53(s,1H),7.27-7.35(m,1H),7.05-7.15(m,2H),6.96(t,1H),6.90(d,1H),6.00(s,2H),3.66-3.86(m,3H),3.13(d,3H)。

Compound I-623

The title compound was prepared in 2 steps:

step 1: synthesis of 4-amino-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [2,3-d]Pyrimidine-5-carbohydrazide

A mixture of compound I-420(1 eq), anhydrous hydrazine (325 eq), and water (11.2 eq) in methanol was heated at 50 ℃ for 2 h. The resulting solution was concentrated in vacuo. The hydrazine is azeotropically removed by treatment with methanol and dichloromethane to give the desired acylhydrazine intermediate, 4-amino-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine-5-carbohydrazide as a yellow solid. The material was used as such in the next reaction without further purification.

Step 2: synthesis of Compound I-623

A mixture of 4-amino-2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine-5-carbohydrazide (1eq) and N-acetylimidazole (4 eq) in THF was stirred at 23 ℃ for 16H. The resulting solution was concentrated in vacuo and the residue was purified via reverse phase HPLC (20-80% acetonitrile gradient in water with 1% TFA) to give the desired compound, compound I-623(71mg, 46% yield) as a yellow solid.

¹H NMR(500MHz,CD₃OD)δppm 8.80(d,1H),7.52(s,1H),7.25-7.32(m,1H),7.06-7.14(m,1H),7.01-7.06(m,1H),6.87-6.92(m,2H),5.98(s,2H),2.66(s,1H),2.00(s,3H),1.82(s,3H)。

Compound I-478

To a stirred solution of compound I-461(1 equivalent) in DMF and ethanol (3:2) was added 10% palladium on carbon (10 equivalents) and the reaction vessel was placed under a hydrogen atmosphere via a balloon and needle. The contents were stirred at 23 ℃ for 18h, and the mixture was filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-461(5mg, 19% yield) as a solid.

¹H-NMR(500MHz,DMSO-d₆)δppm 9.69(s,1H),9.11(d,1H),8.78(d,1H),8.00(d,1H),7.72(s,1H),7.31-7.38(m,1H),7.29(d,1H),7.21-7.26(m,1H),7.12(t,1H),6.86-6.94(m,2H),5.95(s,2H),1.22-1.28(m,2H),1.09-1.14(m,2H)。

Compound I-479

To a stirred solution of intermediate 2(1 eq) and 2-methoxyethanesulfonyl chloride (1eq) in dichloromethane was added DBU (1 eq). The reaction was heated to 60 ℃ for 24h and then cooled to 23 ℃. The contents were diluted in water and extracted with dichloromethane (3 ×). The combined organic layers were washed with 1N HCl solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via reverse phase HPLC to give the desired compound, compound I-479(8mg, 6% yield) as a solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.82(d,1H),8.50(d,1H),7.60(s,1H),7.27-7.35(m,1H),7.05-7.15(m,3H),6.94-6.98(m,2H),6.02(s,2H),3.86(s,4H),3.27(s,3H)。

Compound I-595

A solution of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-5-amine (this compound is described in the previous patent application WO2012003405 a 1) in dichloromethane/pyridine (2:1) was treated with 3,3, 3-trifluoropropan-1-sulfonyl chloride (1.8 equivalents). After 3h, 1N NaOH solution was added and the reaction was stirred for 1.5 h. Then, water was added and the resulting mixture was acidified to pH 3 with 1N HCl solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude material was purified via silica gel chromatography with a 0-10% methanol in dichloromethane gradient to give the desired compound, compound I-595(6.8mg, 15% yield) as a white solid.

¹H-NMR(500MHz,CD₃OD)δppm 8.77(d,1H),8.74(s,2H),7.52(s,1H),7.27(app.q,1H),7.09(m,1H),7.04(app.t,1H),6.90(d,1H),6.87(m,1H),5.97(s,2H),3.49(m,2H),2.77(m,2H)。

Compound I-530 and compound I-531

Chiral separation by SFC with a chiralcel AD-H50 mm × 250mm semi-preparative column using 15:85 ethanol + 0.5% diethylamine: CO₂Resolution of Compound I-405. Two peaks were collected and concentrated in vacuo to give compound I-530 as a pale orange solid (first peak eluted by analytical HPLC, Chiralcel AD-H4.6 mm x 250mm, 15:85 ethanol + 0.5% diethylamine: hexanes). The second eluting peak was collected and concentrated in vacuo to give compound I-531 as a light orange solid (the second peak was eluted by analytical HPLC, Chiralcel AD-H4.6 mm. times.250 mm, 15:85 ethanol + 0.5% diethylamine: hexanes).

Process for preparation of compound I-530¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.32(d,1H),7.93(t,1H),7.90(s,1H),7.78(br s,1H),7.69(br s,1H),7.51(s,1H),7.35-7.31(m,1H),7.22-7.19(m,2H),7.10(t,1H),7.00-6.97(m,1H),5.90(s,2H),4.02-3.94(m,2H)。

Of Compound I-531¹H-NMR(500MHz,DMSO-d₆)δppm 9.11(d,1H),8.33(d,1H),7.93(t,1H),7.90(s,1H),7.78(br s,1H),7.69(br s,1H),7.52(s,1H),7.35-7.31(m,1H),7.22-7.19(m,2H),7.10(t,1H),7.00-6.97(m,1H),5.90(s,2H),4.02-3.94(m,2H)。

Compound I-630

The title compound was synthesized in 2 steps:

step 1:synthesis of (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-5-yl) carbamic acid methyl ester

To a solution of 2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-5-amine (this compound is described in patent application publication WO2012003405 a 1) (1 equivalent) in anhydrous pyridine at 0 ℃ was added methyl chloroformate (1.2 equivalents). After stirring for 10min, the reaction mixture was allowed to warm to ambient temperature and was monitored closely by LC/MS. Additional portions of methyl chloroformate (3.2 equivalents) were added at 0 ℃. After stirring at ambient temperature for 20h, the crude mixture was diluted with water. The resulting tan solid was collected by filtration and used in the next step without further purification.

Step 2:synthesis of Compound I-630

A suspension of methyl (2- (1- (2-fluorobenzyl) -5- (isoxazol-3-yl) -1H-pyrazol-3-yl) pyrimidin-5-yl) carbamate (1eq) in DMF at 0 ℃ was treated with sodium hydride (60% w/w in mineral oil, 1.1 eq) and allowed to warm to ambient temperature. After 30min, the reaction mixture was cooled to 0 ℃ and iodomethane (1.1 eq) was added. After 25min, the crude reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude material was purified via silica gel chromatography with a gradient of 20% acetonitrile: methanol (7:1) in dichloromethane to give the desired compound, compound I-630, as a white solid (12mg, 21% yield over two steps).

¹H NMR(500MHz,CD₃OD)δppm 8.88(s,2H),8.77(d,1H),7.55(s,1H),7.28(app.q,1H),7.09(app.t,1H),7.04(app.t,1H),6.91(d,1H),6.88(app.t,1H),5.99(s,2H),3.79(s,3H),3.40(s,3H)。

Example 2A: measurement of biological Activity by sGC-HEK-cGMP assay (assay by SNP incubation)

Human embryonic kidney cells (HEK293) that endogenously express soluble guanylate cyclase (sGC) were used to assess the activity of the test compounds. Compounds that stimulate the sGC receptor should cause an increase in the intracellular concentration of cGMP. HEK293 cells at 1X 10⁵Density of cells/well 200 μ L volume of Dulbecco's serum supplemented with fetal bovine serum (final 10%) and L-glutamine (final 2mM) seeded in poly D-lysine coated 96-well flat-bottom platesKorea modified eagle's medium and grown overnight at 37 ℃. The medium was aspirated and the cells were washed with 1 × Hank buffered saline solution (200 μ L). Then, the cells were incubated with 200. mu.L of 0.5mM 3-isobutyl-1-methylxanthine (IBMX) solution at 37 ℃ for 15 minutes. Then, a test article and a sodium nitroprusside solution (concentration: X. mu.M for the test article solution; and concentration: 10. mu.M for the SNP solution; where x is one of the following concentrations: 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 0.03. mu.M, 0.01. mu.M, 0.003. mu.M, 0.001. mu.M, 0.0003. mu.M, or 0.0001. mu.M) were added to the assay mixtures (each 2. mu.L), and the resulting mixtures were incubated at 37 ℃ for 10 minutes. After 10min incubation, the assay mixture was aspirated and 0.1M HCl (200 μ L) was added to the cells. The plates were incubated in 0.1M HCl at 4 ℃ for 30 minutes to stop the reaction and to lyse the cells. The plate was then centrifuged at 1,200g for 5 minutes at room temperature. The supernatant was collected and transferred to a new flat bottom 96 well plate for analysis by HPLC-MS. Vehicle control was performed using DMSO (1%) solution. The known sGC stimulator BAY41-2272 was used as a positive control. The sample was diluted with an equal volume of 1M ammonium acetate (pH 7) to neutralize the sample for better chromatographic separation. A 2 xcgmp standard solution was prepared in 0.1M HCl and then diluted with an equal volume of 1M ammonium acetate to a final concentration (nM): 1024. 512, 256, 128, 64, 32, 16, 8, 4, 2, 1. The cGMP concentration of each sample in the test plate was determined using the LC/MS conditions shown in table 2 below, and a cGMP standard curve was calculated. EC was calculated from concentration-response curves generated by GraphPad Prism software₅₀The value is obtained. Data were normalized to high control using the following equation: 100 (sample-low control)/(high control-low control), where low control is the average of 6 samples treated with 1% DMSO and high control is the average of 8-12 samples treated with 10uM BAY 41-2272. Nonlinear regression, sigmoidal dose response, 3 parameter fitting were used to fit the data. The samples are typically run at n-1, but for samples run at n-2 (or greater), the results given herein correspond to the arithmetic mean of the various results obtained for each given compound. If the curve does not reach a plateau, it is limited to 100%. Not leading out 30%The least reactive compound was reported as ND and no EC50 value was determined. The biological activity of some compounds of formula I and formula I' as determined by sGC-HEK assay with SNP incubation is summarized in table 3.

TABLE 2(HPLC LC/MS experimental conditions)

Table 3 whole cell activity was detected by LC/MS in HEK assay.

⁺Code definition of sGC enzyme Activity value, expressed as E in the Presence of 10. mu.M SNP_max% (wherein E_max100% is the activity obtained in the HEK assay by 10 μ M positive control BAY41-2272 in the presence of 100 μ M SNP) which is:

a is 0 to < 10%

B is 10 to < 20%

C20 to < 40%

D-40 to <60

E60 or < 80%

F80 to < 100%

G is 100 to < 120%

H120% or higher

- - - (Y- -O) - -is not determined

⁺The same code definition applies for the unrestricted Emax, where this value is defined as the maximum activity value obtained from the complete concentration-response curve of the compound relative to the 100% positive control value obtained as above. Here, the term "without limitation" means that the upper part of the concentration-response curve is not fitted to 100% during the analysis of sGC enzyme activity data.

^#EC was obtained from the complete concentration-response curve according to two methods₅₀The value: the limiting EC50 refers to the value obtained when the upper part of the curve is fitted to 100% (where E is_max100% is the activity obtained in the HEK assay by 10 μ M positive control BAY41-2272 in the presence of 100 μ M SNP); unconfined ECs reported herein₅₀Refers to the value obtained from a complete concentration-response curve when the upper part of the curve is not fitted to 100%. EC50 code at micromolar concentrations (μ M) is defined as:

0.001≤EC50<0.1＝A

0.1≤EC50<0.5＝B

0.5≤EC50<1.0＝C

1.0≤EC50<5.0＝D

5.0≤EC50<10.0＝E

EC50≥10.0＝F

example 2B: measurement of biological Activity by sGC-HEK-cGMP assay (using HTRF detection) (assay by SNP incubation)

Human embryonic kidney cells (HEK293) that endogenously express soluble guanylate cyclase (sGC) were used to assess the activity of the test compounds. Compounds that stimulate the sGC enzyme should cause an increase in the intracellular concentration of cGMP. HEK293 cells at 1X 10⁵The density of individual cells/well was seeded in poly D-lysine coated 96-well flat-bottom plates in 200 μ L volumes of dulbecco's modified eagle's medium supplemented with fetal bovine serum (final 10%) and L-glutamine (final 2mM) and grown overnight at 37 ℃. The medium was aspirated and the cells were washed with 1 × Hank buffered saline solution (200 μ L). Then, the cells were incubated with 200. mu.L of 0.5mM 3-isobutyl-1-methylxanthine (IBMX) solution at 37 ℃ for 15 minutes. Then, the test article and sodium nitroprusside solution were added to the assay mixture (2 μ L each) and the resulting mixture was incubated at 37 ℃ for 10 minutes. After 10min incubation, the assay mixture was aspirated and 0.1M HCl (200 μ L) was added to the cells. The plates were incubated in 0.1M HCl at 4 ℃ for 30 minutes to stop the reaction and to lyse the cells. The plate was then centrifuged at 1,200g for 5 minutes at room temperature. GMP levels were determined using a cGMP HTRF assay (Cisbio product #62GM2 PEC). For each sample, 5uL HEK assay supernatant 1:5 was diluted in HTRF kit assay diluent and transferred to the wells of the assay plate and HTRF assay was performed according to the HTRF kit manufacturer's instructions. Sample calculations were performed using a high-low control, where the high control was the supernatant of a HEK assay performed in the presence of 10uM Bay41-2272 +100uM SNP, and the low control was the supernatant of a HEK assay performed in the presence of vehicle. cGMP standard solutions were prepared in 0.1M HCl and diluted to make cGMP standard curves using HTRF assay. Using the average ratio data of the HTRF measurements, the sample data was normalized according to the following equation: 100: (sample-low control)/(high)Control-low control). Data were fitted to 3-parameter log agonist dose responses (top: (% EMax); bottom: log EC50) using Graphpad (Prism software). The data in table 4 were obtained using a modified assay procedure. (for the test solution, the concentration: x. mu.M; and for the SNP solution, the concentration: 10. mu.M; where x is one of the following concentrations: 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 0.03. mu.M, 0.01. mu.M, 0.003. mu.M, 0.001. mu.M, 0.0003. mu.M, and 0.01 nM.

Table 4 whole cell activity was detected by HTRF in HEK assay.

⁺Code definition of sGC enzyme Activity value, expressed as E in the Presence of 10. mu.M SNP_max% (wherein E_max100% is the activity obtained in the HEK assay by 10 μ M positive control BAY41-2272 in the presence of 100 μ M SNP):

a is 0 to < 10%

B is 10 to < 20%

C20 to < 40%

D-40 to <60

E60 or < 80%

F80 to < 100%

G is 100 to < 120%

H120% or higher

- - - (Y- -O) - -is not determined

⁺The same code definition applies to the unrestricted Emax, where this value is defined relative to the 100% positive control value obtained as aboveMaximum activity value obtained from the complete concentration-response curve of the compound. Here, the term "without limitation" means that the upper part of the concentration-response curve is not fitted to 100% during the analysis of sGC enzyme activity data.

# obtaining EC from intact concentration-reactions₅₀The value:

these samples were not diluted.

0.001≤EC₅₀<0.1＝A

0.1≤EC₅₀<0.5＝B

0.5≤EC₅₀<1.0＝C

1.0≤EC₅₀<5.0＝D

5.0≤EC₅₀<10.0＝E

EC₅₀≥10.0＝F

Compounds I-306 to I-455 were tested in this assay, most of which exhibited EC₅₀A value of less than 5.0. mu.M, E_maxThe value is at least 80%.

Example 2C: measurement of biological Activity by sGC-HEK-cGMP assay, New protocol with LC/MS detection

Human embryonic kidney cells (HEK293) that endogenously express soluble guanylate cyclase (sGC) were used to assess the activity of the test compounds. Compounds that stimulate the sGC enzyme should cause an increase in the intracellular concentration of cGMP. HEK293 cells at 1.5X 10⁴Density of individual cells/well was seeded in 50 μ L volume of dulbecco's modified eagle's medium supplemented with fetal bovine serum (final 10%) and penicillin (100U/mL)/streptomycin (100 μ g/mL) in poly D-lysine coated 384-well flat-bottom plates. Cells were incubated at 37 ℃ with 5% CO₂Overnight in the humidified chamber. The medium was aspirated and the cells were washed with 1 × Hank buffered saline solution (50 μ Ι _). Then, the cells were washed with 50. mu.L of 0.5mM 3-isobutyl-1-methylyellow at 37 ℃Purine (IBMX) solution was incubated for 15 minutes. Then, the test article and a diethylenetriamine NONOate (DETA-NONOate) solution (concentration: x. mu.M for the test article solution; and 10. mu.M for the DETA-NONOate solution; where x is one of the following concentrations);

30000nM
	7500nM
1875nM
	468.75nM
117.19nM
	29.29nM
7.32nM
	1.83nM
0.46nM
	0.114nM
0.029nM

then added to the assay mixture and the resulting mixture incubated at 37 ℃ for 20 minutes. After 20min incubation, the assay mixture was aspirated and 10% acetic acid (50 μ L) containing 150ng/mL +3-cGMP (internal standard for LCMS) was added to the cells. The plates were incubated in acetic acid solution at 4 ℃ for 30 minutes to stop the reaction and to lyse the cells. The plate was then centrifuged at 1,000g for 3 minutes at 4 ℃ and the supernatant was transferred to a clean reaction plate for LCMS analysis.

cGMP concentrations were tested from each sample using the following LCMS conditions (table 5) and standard curves were calculated. A standard curve was made in 10% acetic acid with 150ng/mL +3cGMP (isotope-labeled cGMP 3 units higher in weight than wild-type), with the following final concentrations of cGMP (ng/mL): 1.5, 10, 50, 100, 250, 500, 1000, 2000.

Table 5: LC/MS conditions, example 2C

Data were normalized to high control using the following equation: 100 × (sample-low control)/(high control-low control), wherein low control is the average of 16 samples treated with 1% DMSO and high control is the average of 16 samples treated with 30 μ M I-329. Data were fitted using GraphPad Prism software v.5 version using a 4-parameter fit (log (agonist) contrast response-slope change). N-2 for all compounds. Interpolation of absolute EC from curve fitting₅₀And is defined as the concentration at which a given compound elicits 50% of the high control reaction. Compounds that failed to elicit a 50% minimal response were reported as>30 μ M. For compounds operating in two repetitions or n repetitions higher than two, the results given herein are geometric averages of several results obtained. Table 6 summarizes the results obtained in this assay for selected compounds of the invention.

TABLE 6 Whole cell Activity by LC/MS in HEK assay (latest assay conditions, example 2C)

Code definition of Activity value of ((to) sGC) expressed as Absolute EC₅₀Defined as the concentration of a given compound that elicits 50% of the high control reaction (I-329). Compounds that failed to elicit a 50% minimal response were reported as>30μM。EC50Abs<100nM＝A；101nM≤EC50Abs<1000nM＝B；1001nM≤EC50Abs＝C。

Example 3A: measurement of biological Activity by thoracic aortic Ring assay

The thoracic aortic annulus was dissected from male Sprague-Dawley rats, 75-299g weight anesthetized (isoflurane). The tissue was immediately transferred to ice-cold Krebs-Henseleit solution, which was treated with 95% O₂And 5% CO₂Aeration was carried out for 30 minutes. After removal of connective tissue, the aortic section was cut into 4 loops (about 2mm each) and hung on 2L-shaped hooks, one hook fixed to the bottom of a tissue bath (Schuler organ bath, Harvard Apparatus) and the other connected to a force sensor (F30 force sensor, Harvard Apparatus). The bath containing Krebs Henseleit solution (10mL) was heated to 37 ℃ and treated with 95% O₂And 5% CO₂And (6) ventilating. The ring was subjected to an initial tension of 0.3-0.5g and gradually increased to a static tension of 1.0g over 60 minutes. Using Krebs Henseleit solution (heated to 37 ℃ and 95% O₂And 5% CO₂Aeration) the loop was washed at 15 minute intervals until a stable baseline was obtained. The ring was considered stable after maintaining a static tension of 1.0g (for about 10 minutes) without adjustment. The ring was contracted with 100ng/mL phenylephrine by adding 100uL of a 10. mu.g/mL phenylephrine stock solution. Stable contracted tissue was then obtained in an additive dose-dependent manner by treatment with test compounds prepared in dimethyl sulfoxide (DMSO). In some cases, tissues were treated with Krebs-Heinsteleit solution (heated to 37 ℃ and with 95% O)₂And 5% CO₂Aeration) was washed 3 times over a 5 minute period, allowing it to stabilize at baseline, and then used to characterize the effects of other test articles or DMSO. All data were collected using HSE-ACAD software supplied by Harvard Apparatus. Percent relaxation was calculated in Microsoft Excel using the tensile values recorded for 100ng/mL phenylephrine treatment as 0% inhibition and 100. mu.M 3-isobutyl-1-methylxanthine treatment as 100% inhibition. EC was calculated from concentration-response curves generated by GraphPad Prism software₅₀The value is obtained.

Example 3B: measurement of biological Activity by thoracic aortic Ring assay (alternative method)

As an alternative thoracic aortic annulus determination, percent relaxation was calculated using the procedure of example 3, except that after treatment with 100ng/mL phenylephrine as 0% inhibition in Microsoft Excel and washing the tissue with buffer, the tension values recorded where the original resting tension of the tissue was used as 100% inhibition.

Example 4: blood pressure changes in Sprague-Dawley rats

Male rats (250-350g body weight, supplied by harlan laboratories) were anesthetized with ketamine/xylazine and a heparinized saline fluid-filled catheter was implanted in the right femoral artery. The catheter was removed from the abdomen between the scapulae, capped and the animals allowed to recover for at least 7 days post-surgery before any compound testing. Before testing, normal animal diets were maintained with free access to water under a 12 hour light-dark cycle.

On the day of the experiment, the catheter was uncapped and connected to a cable (Instech Labs) and pressure transducer (Harvard Apparatus) under inhaled isoflurane anesthesia. Blood pressure and heart rate were then captured and analyzed with a dedicated data capture system (PowerLab, instruments). The data sampling rate is set to 1 cycle/second. After ligation, each rat was allowed to recover from anesthesia and baseline blood pressure and heart rate levels were established in these conscious, freely moving animals. After establishing baseline, vehicle (0.5% methylcellulose or 100% PEG400) or test article was administered orally (PO, 10mg/kg) and effects on blood pressure and heart rate were monitored for up to 24 hours.

Data are reported as averages per hour and blood pressure changes are calculated by subtracting individual baselines on an hourly basis.

@ code definition of peak change from baseline in rat mean arterial pressure at 10mpk

A-10 < peak change from baseline at 10mpk <0

B-20 ≦ peak change from baseline at 10mpk ≦ 10

C-peak change from baseline at 10mpk < -20

Example 5: description of animal models:

lamb model using inhaled sGC stimulator pulmonary hemodynamics

("Inhaled Agents of solvent Guanylate Cyclease inductive variation", Oleg V. et al, American J of Resp and clinical Care Medicine, Vol. 176, 2007, p. 1138)

Following the published procedure, it was possible to test whether inhalation of the novel dry powder microparticle formulation containing sGC stimulator would produce selective pulmonary vasodilation in lambs with acute pulmonary hypertension. It is also possible to evaluate the combined administration of sGC stimulator microparticles and Inhaled Nitric Oxide (iNO) in this system. Finally, it is possible to check whether inhalation of sGC stimulator microparticles will produce pulmonary vasodilation when the response to iNO (inducible nitric oxide synthase) is impaired.

The scheme is as follows: spontaneous breathing lambs equipped with vascular catheters and tracheostomy cannula U-46619 were infused intravenously to increase mean pulmonary artery pressure to 35mm Hg while awake. Inhalation of microparticles consisting of BAY41-2272, BAY 41-8543 or BAY58-2667 and excipients (dipalmitoylphosphatidylcholine, albumin, lactose) produced dose-dependent pulmonary vasodilation and increased pulmonary cGMP release without significantly affecting mean arterial pressure. Inhalation of microparticles containing BAY 41-8543 or BAY58-2667 increases systemic arterial oxygenation. The size and duration of pulmonary vasodilation induced by iNO following inhalation of BAY 41-8543 microparticles increases. Intravenous administration of 1H- [1,2,4] oxadiazolo [4,3-a ] quinoxalin-1-One (ODQ), which oxidizes the heme prosthetic group of sGC, significantly reduces the pulmonary vasodilator effect of iNO. In contrast, pulmonary vasodilation and pulmonary cGMP release induced by inhalation of BAY58-2667 microparticles was greatly enhanced after treatment with ODQ. Thus, inhalation of microparticles containing agonists of sGC may provide an effective novel treatment for patients with pulmonary hypertension, particularly when responsiveness to iNO is impaired by sGC oxidation. Note that: BAY41-2272, BAY 41-8543 are sGC stimulators, while BAY58-2667 are sGC activators.

In vitro (ex vivo) model of guinea pig tracheal smooth muscle for evaluation of electric field stimulation of bronchorelaxation

It is possible to evaluate the bronchorelaxing effect of sGC stimulators by using the system described below. This system allows the determination of the efficacy, efficacy and duration of action of several sGC stimulators, as well as the evaluation of potential side effects such as blood pressure or heart rate changes.

Animals: dunkin Hartley guinea pigs, male, were kept in complete isolation and demonstrated no specific microorganisms upon receipt, the daily weight of the experiment was 525-. Guinea pigs 4 were housed in a controlled environment (air flow, temperature and humidity) solid bottom cage with gold bedding. Food (FD1, Special Diet Services) and water were freely provided.

Guinea pigs contracted tracheal smooth muscle in response to EFS. Compound efficacy and efficacy were evaluated:

on each experimental day, guinea pigs were sacrificed by exposure to increasing concentrations of CO2 and the trachea removed. The trachea is cleared of adherent tissue and cut longitudinally along a line opposite the muscle, unfolded and cut into strips 2-3 cartilaginous ring wide. A loop of cotton yarn is attached to one end of each tracheal tube and a length of cotton yarn is attached to the other end. The tracheal strip was then suspended between two platinum electrodes in a myopath system (World Precision Instruments Stevenage, UK) using a tissue holder. The loop was attached to a hook at the bottom of the tissue holder and the other end was attached to the wall of a FORT10 force sensor (worldwide Instruments Stevenage, UK) to ensure that the tissue was positioned between the two platinum electrodes. The whole assembly was then lowered into a 10ml tissue bath containing modified Kreb's-Henseleit buffer at 37 ℃ and bubbled with carbon alloy gas (Carbogen). 1g of tension was applied to each piece of tissue and the tissue was washed and then stabilized for a period of 1 hour. After allowing the tissue to stabilize, the device for electric field stimulation was set up to deliver stimulation with a frequency of 80Hz, a pulse width of 0.1ms, with gated unipolar pulses every 2 minutes using a DS 80008 channel digital stimulator (UK). Voltage response curves were performed at 2,4,6, 7, 8, 10, 12V for each tracheal tube, and then a sub-maximum voltage was selected for application to each tissue for the remainder of the experiment. Guinea Pig Tracheal Smooth Muscle (GPTSM) contraction was induced using sub-maximal Electric Field Stimulation (EFS) (it is also possible to induce contraction by using a spasmogen, such as methacholine or histamine as described in Coleman et al). Compounds were dissolved in 100% DMSO at 3x 10-2M and aliquots were stored at-200C. Separate aliquots were used for each experiment. Tissues were washed with Kreb buffer and stimulated for 1 hour using a previously determined sub-maximal voltage to establish a stable baseline contraction prior to evaluation of compound activity.

Cumulative Dose Response Curves (DRC) were then performed for each test substance and smooth muscle contraction changes were measured. The effect of each test substance in each experiment was expressed as a percentage inhibition of baseline contraction, normalized to the relevant vehicle control. Experiments were performed 3 times using tissues from 3 different animals. Data from all 3 experiments were pooled, DRCs were plotted, and potency and efficacy of the test substances were determined. The efficacy of ipratropium bromide was evaluated with the test compound and the IC50 was determined to be 0.86nM (95% Cl, 0.78-0.94), consistent with data previously generated in the system.

Novel and Versatile supercooled liquid infusion System (Novel and Versatile Superfusion System). It uses guinea pig isolated tracheal smooth muscle to evaluate the use of some spasmolytic and antispasmodic agents ", r.a. coleman et al, j.pharmacol.methods,21,71-86,1989.

Mouse model of diseases whose etiology involves altered CFTR function

These diseases include cystic fibrosis, pancreatic disorders, gastrointestinal disorders, hepatic disorders, cystic fibrosis related diabetes (CFRO), dry eye, dry mouth, and sjogren's syndrome.

By using transgenic mice expressing or not expressing the δ F508CFTR channel, it is possible to measure nasal potential differences and differences in salivary secretion in the presence of test sGC stimulators by using the literature protocol described below (see WO 2011095534).

Measurement of salivary secretion in delta (.6.)50S-CFTR mice

15 males and females were homozygous, heterozygous.6.50S-CFTR (backcrossed over 12 generations on an FVB genetic background, originally obtained from Erasmus University, Rotterdam; 10-14 weeks old, both sexes weighed 1S-36g) was used in this assay. Solutions of vardenafil at concentrations of 0.07, 0.14 and 0.42mg/kg BW were prepared in sterile saline (20), while sGC stimulant BAY41-2272 was dissolved to 0.01, 0.03, 0.1 and 0.3mg/kg BW in a solvent containing 50% ddH20, 40% PEG400 (polyethylene glycol 400) and 10% ethanol. The substance or appropriate vehicle was then administered to the mice via intraperitoneal injection (5ml/kg BW) 60min prior to the salivary secretion assay. After 60min, mice were anesthetized with a combination of (25) ketamine and diazepam (diazepam). The solution was prepared to contain 1ml of 5mg/ml diazepam and 1ml of 100mg/ml ketamine in 8ml of sterile saline. Anesthesia was induced by intraperitoneal injection of solution (10ml/kg BW). After anesthesia, mice were pretreated by subcutaneous injection of 1mM atropine (501-11) into the left cheek in order to avoid cross-stimulation of cholinergic receptors. A small Whatman filter (5) strip was placed in the buccal cavity of the previous injection for 4min to absorb any saliva secreted after the injection of atropine. This first piece of filter paper was removed and replaced with a pre-weighed second piece of filter paper. Thereafter, a solution of 501-11 containing 100I-IM isoproterenol and 1mM atropine was injected into the left cheek at the same site to induce salivation by an adrenergic mechanism. (10) The time for isoproterenol injection was taken to be 0 hours and the filter paper strips were replaced every 10 minutes for a total collection period of 30 minutes. Each piece of filter paper was immediately placed and sealed in a pre-weighed vial. After all samples had been collected, each vial was re-measured and the weight of all samples was recorded. The difference in total vial + paper weight measured before and after saliva collection (15) was taken as the net weight of saliva secreted during the collection period. The total amount of salivary secretion was calculated as the salivary weight divided by the number of minutes required for each collection and then normalized to mouse mass (grams). Results are expressed as mean percent increase in n mice compared to placebo treatment. Statistics were analyzed by ANOVA test (20) followed by post-hoc Bonferoni analysis; i/' means statistically significant, p values <0.05/<0.01/0.001 and n.s. means not significant.

These animal studies were performed with a number of sGC stimulators, sGC activators and PDE5 inhibitors. The results indicate that the compounds of the invention are useful in the treatment of cystic fibrosis, pancreatic disorders, gastrointestinal disorders, liver disorders, cystic fibrosis-associated diabetes (CFRO), dry eye, dry mouth, and sjogren's syndrome.

Neuromuscular disorders

It has previously been shown that neuronal nitric oxide synthase (nNOS) mis-localization from the sarcolemma to the sarcoplasmic muscle is observed in a wide range of non-dystrophic neuromuscular conditions associated with impaired motor status and catabolic stress. One tool for assessing muscle biopsies of patients with various genetic or acquired forms of neuromuscular pathologies is to evaluate the myofiber membrane localization of nNOS. nNOS levels at the sarcolemma were found to correlate with the runnability and functional status.

Similar evaluations can be used to determine nNOS localization in non-dystrophic myopathy animal models ("Loss of sarcolemmal nNOS is common in acquired and acquired neurous disorders"; E.L. Finager Hedderick et al, Neurology,2011,76(11), 960-.

nNOS mislocalization in acquired muscle atrophy mouse model

Two mouse models have been described that demonstrate muscle atrophy without impaired mobility, high dose corticosteroid therapy and short-term starvation.mice treated with steroids or starved for 48 hours show significant reductions in overall body weight and normalized wet skeletal muscle mass.morphometric analysis of skeletal muscle samples of both models demonstrates muscle atrophy as shown by immunofluorescence staining of dystrophin, α -myoglycan, and α -1-nutritive synthetic protein complex (syntrophin) as defined by a significant reduction in mean minimum Feret fiber diameter compared to age-matched controls (for each group n ═ 5), which indicates normal dystrophin localization, which indicates that DGC complexes are intact.

These murine models can be used to evaluate the effect of sGC stimulators (e.g., of the present invention) on the symptoms of muscle atrophy and related disease conditions.

Starved mice exhibited a 1-fold decrease in nNOS and iNOS transcript expression compared to wild-type mice (n ═ 9 for control; n ═ 7 for starvation). However, the protein levels of nNOS, iNOS and eNOS revealed no differences between control and starved mice (n ═ 4 for each group). These data demonstrate that abnormal localization of nNOS occurs in mice with severe muscle atrophy, even if overall motility is preserved, supporting the following notion: in addition to impaired motility, other triggers such as catabolic stress may be associated with nNOS sarcolemma loss.

Maintenance of skeletal muscle nNOS localization during hibernation (study with squirrel)

The effect of motility and catabolic stress on nNOS localization was evaluated in the context of maintaining muscle homeostasis and integrity using a 13-striped squirrel skeletal muscle specimen from hibernation. These animals are obligate hibernating mammals that protect against skeletal muscle atrophy during hibernation. The myofibrillar membrane expression of nNOS was preserved despite hibernation for 5 months with almost no exercise and no caloric intake. These data, together with patient and mouse data, indicate that biochemical control of nNOS localization is complex, and importantly, preservation of myofiber nNOS can be important in maintaining muscle homeostasis.

These results also indicate that targeting aberrant NO signaling (e.g., with sGC stimulators such as those described herein) may prove beneficial to a wide group of patients with neuromuscular conditions.

Mouse model of muscular dystrophy (BMD and DMD)

Becker Muscular Dystrophy (BMD), characterized by progressive skeletal muscle wasting, is caused by mutations in the dystrophin protein. In a human study, Martin et al (see "Tadalafil interleavities muscles in coatings with Becker Muscumular dynamics"; Elizabeth A. Martin et al, Sci. Transl. Med.4,162ra155 (2012); vacuum-targeted therapies for Duchennemmular dynamics "; Ennen et al, Skelet Muscle,2013,3:9) evaluated the attenuation of exercise-induced reflex sympathetic vasoconstriction in muscles of 10 BMD patients and 7 age-matched healthy male controls. This is a protective mechanism that optimizes skeletal muscle perfusion to meet the metabolic needs of exercise. Reflex vasoconstriction was induced by simulated freestanding stress and measured while the forearm muscles were resting or lightly exercising in a rhythmic hand grip. First, studies indicate that exercise-induced impaired reflex vasoconstriction is defective in 9 of 10 BMD patients, where common dystrophin mutations interfere with neuronal NO synthase (nNOS) targeting to the muscle sarcolemma. Then, in a double-blind randomized placebo-controlled crossover trial, the authors showed that normal blood flow regulation was restored in 8 of 9 patients by a single oral dose of 20mg of talanafil, a specific PDE5 inhibitor.

It is possible to evaluate the effect of drugs acting on the NO pathway by using a dystrophin deficient mdx mouse model of the associated disease Duchenne Muscular Dystrophy (DMD). This model also shows that inhibitors of phosphodiesterase 5(PDE5) reduce some of the features of the dystrophic phenotype, including skeletal muscle microvascular vasospasm which can lead to muscle damage and fatigue.

This protective mechanism, known as functional sympatholytic effect, is lost in mdx mice (BMD and DMD models), nNOS null mice, and boys with DMD, causing functional muscle ischemia.

In mdx mice, many characteristics of the dystrophic phenotype can be improved by a variety of strategies to enhance NO signaling, including transgenic expression of nNOS, restoring transgenic expression of dystrophin minigenes to sarcolemma nNOS (and thereby restoring functional sympatholytic effects), administration of the NOs substrate L-arginine (24, 25), treatment with NO donor drugs, and inhibition of phosphodiesterase 5A (PDE5A) with the drugs talnafil or sildenafil. These PDE5A inhibitors prolong the half-life of guanosine 3',5' -monophosphate (cGMP), a downstream target of NO in vascular smooth muscle, showing that after a brief bout of exercise, they reduce muscle ischemia as well as injury and fatigue in mdx mice. These drugs also showed improved cardiac dynamics and rescue of dystrophic skeletal muscle and prolonged survival of dystrophin deficient zebrafish in mdx mice.

These findings support the essential role of myofibrillar membrane nNOS in the regulation of sympathetic vasoconstriction in the exercise of human skeletal muscle, and suggest that targeting aberrant NO pathways (e.g., by using sGC stimulators of the invention) may be a useful therapeutic approach for the treatment of BMD and DMD in humans.

Sickle cell disease

Sickle Cell Disease (SCD) or Sickle Cell Anemia (SCA) or sickle cell disease is an inherited blood disorder characterized by abnormal, rigid sickle-shaped red blood cells. Sickling reduces the flexibility of the cell and leads to the risk of various complications. Sickling occurs due to a mutation in the hemoglobin gene. Individuals with one copy of the failure gene exhibit normal and abnormal hemoglobin. This is an example of co-dominance. In 1994, the mean life expectancy of people with this condition in the united states was estimated to be 42 years old for men and 48 years old for women, but today patients may live to 70 years or over due to better management of the disease.

Sickle cell anemia is a form of sickle cell disease in which there is homozygosity for mutations that cause HbS. Sickle cell anemia is also known as "HbSS," "SS disease," "hemoglobin S," or variations of these names. In heterozygous humans, i.e. having only one sickle-shaped baseOther, more rare forms of sickle cell disease are complex heterozygote conditions in which a human has only one copy of a mutation that causes HbS and one copy of another aberrant hemoglobin allele, including sickle hemoglobin C disease (HbSC), sickle β - + -thalassemia (HbS/β)⁺) And sickle β -0-thalassemia (HbS/β)⁰)。

Although Red Blood Cell (RBC) sickling and rheological abnormalities are central to the pathophysiology of sickle cell disease, vascular dysfunction caused by the complex interactions between sickled red blood cells (sRBC), endothelial cells, platelets, and leukocytes plays an equally important role. In sickle cell disease, endothelial activation is associated with sickle cell-mediated hypoxic reperfusion events (see, e.g., "Advances in understating of the pathogenesis of coronary vascular in cell anemia", P.connes et al, Br.J.Haematol.2013,161, 484-98). The sickling and attachment of red blood cells to the endothelium initiates vascular occlusion by impairing blood flow. Subsequent surges in inflammatory mediators and endothelial activation trigger a cascade of events leading to vascular injury. The pathophysiological response to intermittent hypoxia reperfusion of these vasoocclusive events is evidenced by increased cytokine production, leukocyte upregulation, and activation of procoagulant and adhesion molecules, coupled with inhibition by cytoprotective mediators.

Even at baseline, sickle cell disease patients exhibit elevated proinflammatory cytokines including C-reactive protein (CRP), Tumor Necrosis Factor (TNF), interleukin-1 (IL-1), and interleukin-8 (IL-8), in vitro studies have shown that sRBC promotes endothelial upregulation of TNF- α and IL-1- β -10, microarray studies of activated monocytes have shown differential expression of genes involved in inflammation, heme metabolism, cell cycle regulation, antioxidant responses, and angiogenesis.

In a transgenic mouse model (see "Novel therapeutics targeting the endo thelium inckible cell disaase", C.C Hoppe, Hemoglobin,35(5-6):530-546(2011) and references cited therein), sickling inducing oxidative stress has been shown to affect microvascular regulatory mechanisms leading to endothelial activation and exacerbated inflammatory and pro-adhesive responses. Oxidative stress occurs through the formation of Reactive Oxygen Species (ROS). NO depletion occurs through hemoglobin (Hb) mediated clearance, ROS-induced depletion, and arginase-mediated substrate depletion. In sickle cell disease, the clearance system that normally removes circulating free Hb is saturated. Free Hb depletes NO, resulting in endothelial dysfunction. Thus, the normal balance of vasoconstriction and vasodilation is biased towards vasoconstriction, endothelial activation, oxidative stress, and proliferative vasculopathy.

Therapies directed at restoring NO homeostasis have shown promise in preliminary studies in sickle cell disease patients. Previous in vitro studies and studies in other patient populations have shown down-regulation of NO-mediated expression of endothelial attachment molecules. Following these observations, the use of inhaled NO was studied in sickle cell disease children presenting VOE and the following associated trends were found: lower pain scores, reduced analgesic requirements, and shorter hospital stays.

These findings were reproduced in a recent randomized placebo-controlled trial evaluating inhaled NO for the treatment of acute VOE in adult sickle cell disease patients, showing that inhaled NO significantly reduces pain scores compared to placebo and correlates with a trend towards reduced use of parenteral morphine. The results of a completed phase II trial from adult sickle cell disease patients treated with inhaled NO for acute VOE are not yet available (clinicaltirials. gov NCT 00023296). Another phase II trial of inhaled NO for VOE treatment was expected to be done in children with sickle cell disease (clinicaltirials. gov NCT 00094887). The possible therapeutic effect of inhaled NO on ACS in sickle cell disease is currently being evaluated in children and adults in two separate French phase I/III trials comparing the use of inhaled NO with placebo or standard care in children with ACS (clinicaltralals. govc NCT01089439 and NCT 00748423).

Dietary supplementation of the NO synthase substrate L-arginine has been extensively studied in sickle cell disease as a means of increasing NO bioavailability. In sickle mice, high doses of oral L-arginine have been shown to reduce Gardos channel activity, dense cell formation and hemolysis, as well as functionally improve vascular reactivity.

Sildenafil, an agent aimed at amplifying the effects of endogenous NO by inhibiting PDE5 (a downstream mediator of NO), is widely used in the general population to treat primary PHT. Preliminary studies in sickle cell disease patients with severe PHT reported improved PAP and exercise capacity following treatment with sildenafil. Multicenter trials testing the safety and efficacy of sildenafil in sickle cell disease patients with Doppler-defined PHT (lung hypertension and sickle cell disease treated with sildenafil therapy, Walk-PHaSST) were prematurely discontinued due to a higher frequency of serious side effects including increased rates of VOE, headache, and visual disturbance in the treatment group.

Nitrite and nicotinic acid direct NO donor properties were also investigated. In a pilot phase I/II clinical trial, sodium nitrite infusion in adult sickle cell disease patients increased forearm blood flow consistent with NO donor mechanism of action. Larger phase I/II trials are now investigating whether nitrite infusion administered as adjuvant therapy during acute VOEs will improve microvascular blood flow and tissue oxygenation (clinicalrials. gov NCT 01033227). The effect of nicotinic acid on improving endothelium-dependent vasodilation was also evaluated in a phase II randomized control trial (clinicaltralals. gov NCT 00508989).

The above results indicate that targeting aberrant NO pathways in sickle cell disease (e.g., by using sGC stimulators of the invention) may be a useful therapy for treating the disease. Murine models of sickle cell anemia that can be used to evaluate the effects of sGC stimulators (e.g., the sGC stimulators of the invention) in this disease state are described in Blood,2001,98(5), 1577-84; clin. invest.2004,114(8), 1136-45; and br.j. haematol.,2004,124(3), 391-402.

Bladder dysfunction

The sGC Activator BAY 60-2770 has been shown to improve overactive bladder in obese mice (see "The simple guanyl Cyclerase Activator BAY 60-2770 animals over active bladderin organism mice", Luiz O Leiria et al, The Journal of Urology,2013, doi: 10.1016/j.j.j.ro.2013.09.020.). The animal models described in this disclosure can similarly be used to evaluate the effect of sGC stimulators (e.g., sGC stimulators of the invention) on overactive bladder.

The same group of researchers has described a rat bladder dysfunction model (NO deficient rats, F Z Monica et al, Neurology and Urodynamics,30,456-60,2011) and showed the protective role of BAY-2272(sGC activator) in this model. The animal models described in this disclosure can similarly be used to evaluate the effect of sGC stimulators (e.g., sGC stimulators of the invention) on bladder dysfunction associated with detrusor over activity.

A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.

Claims (20)

1. A compound represented by formula I, or a pharmaceutically acceptable salt thereof:

wherein:

X¹selected from N, CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl, and CF;

ring B is phenyl or a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms, or ring B is thiophene;

n is 0 or an integer selected from 1 to 3;

each J^BIndependently selected from halogen, -CN, C_1-6Aliphatic radical, -OR^BOr C_3-8A cycloaliphatic ring; wherein each of said C_1-6Aliphatic radical and each of said C_3-8The cycloaliphatic radical being optionally substituted with up to 3 halogens;

each R^BIndependently selected from hydrogen, C_1-6Aliphatic radicals or C_3-8A cycloaliphatic ring;

wherein is C_1-6Each of said R of the aliphatic radical^BAnd is C_3-8Each of said R of the cycloaliphatic ring^BOptionally substituted with up to 3 halogens;

J^Aselected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or-NR^aR^b(ii) a Wherein R is^aAnd R^bEach independently selected from hydrogen and C_1-6An alkyl or 3-6 cycloalkyl ring;

J^Dabsent or selected from halogen, -CN, -CF₃Methoxy, trifluoromethoxy, nitro, amino or methyl;

R¹and R²Taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein said 4-to 8-membered heterocyclic or 5-membered heteroaryl ring optionally contains up to 3 ring heteroatoms independently selected from N, O or S in addition to said nitrogen atom and is optionally substituted with up to 5R⁵Substitution; or

Or, R¹And R²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocycle, 5-or 6-membered heteroaryl or C_1-6alkyl-R^Y(ii) a Wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocyclic group, 5-or 6-membered heteroaryl group and said C_1-6alkyl-R^YC of (A)_1-6Each alkyl moiety is optionally and independently substituted with up to 5R^5aSubstitution; with the proviso that R¹And R²Never simultaneously hydrogen; wherein, when X¹Is CH, C (C)_1-4Alkyl group), C (C)_1-4Haloalkyl), CCl and CF, R¹Or R²One example of (a) is not pyridine or pyrimidine;

or, J^DAnd R¹Or R²Can form a 5-6 membered heterocyclic ring containing up to two heteroatoms selected from O, N and S and optionally being oxo or- (Y) -R for up to 3 times⁹Substitution;

wherein Y is absent or C_1-6A linkage in the form of an alkyl chain optionally substituted with up to 6 fluorines;

each R⁹Independently selected from hydrogen, fluorine, -CN, -OR¹⁰、COR¹⁰、-OC(O)R¹⁰、-C(O)OR¹⁰、-C(O)N(R¹⁰)₂、-C(O)N(R¹⁰)SO₂R¹⁰、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)C(O)N(R¹⁰)₂、-N(R¹⁰)₂、-SO₂R¹⁰、-SO₂N(R¹⁰)₂、-SO₂N(R¹⁰)COOR¹⁰、-SO₂N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)SO₂R¹⁰、-(C＝O)NHOR¹⁰、C_3-6A cycloalkyl ring, a 4-8 membered heterocyclic ring, or a 5-6 membered heteroaromatic aryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-6(iii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings and each of said 5-to 6-membered heteroaromatic rings are optionally substituted with up to 3R¹¹Substitution;

each R¹¹Independently selected from halogen, C_1-6Alkyl, -CN, -OR¹²、-COR¹²、-C(O)OR¹²、-C(O)N(R¹²)₂、-N(R¹²)C(O)R¹²、-N(R¹²)C(O)OR¹²、-N(R¹²)C(O)N(R¹²)₂、-N(R¹²)₂、-SO₂R¹²、-SO₂N(R¹²)₂and-N (R)¹²)SO₂R¹²(ii) a Wherein each of said C_1-6Alkyl is optionally and independently substituted with up to 3 fluoro or phenyl groups;

wherein each R¹⁰Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo; and is

Wherein each R¹²Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4(fluoroalkyl), -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Fluoroalkyl) or oxo;

R^Yis selected from C_3-8A cycloalkyl ring, a 4-to 8-membered heterocyclic ring, a phenyl or a 5-to 6-membered heteroaromatic ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-8A cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, eachSaid phenyl and each said 5-to 6-membered heteroaromatic ring being optionally substituted with up to 5R^5cSubstitution;

each R^5cIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6b、-SR^6b、-COR^6b、-OC(O)R^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-C(O)N(R^6b)SO₂R^6b、-N(R^6b)C(O)R^6b、-N(R^6b)C(O)OR^6b、-N(R^6b)C(O)N(R^6b)₂、-N(R^6b)₂、-SO₂R^6b、-SO₂N(R^6b)₂、-SO₂N(R^6b)COOR^6b、-SO₂N(R^6b)C(O)R^6b、-N(R^6b)SO₂R^6b、-(C＝O)NHOR^6b、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring and each said 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said C_3-8A cycloalkyl ring, each of said 4-to 7-membered heterocyclic rings, each of said 5-or 6-membered heteroaryl rings, each of said benzyl groups, and each of said phenyl groups are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic group contains in a fused or bridged relationship a first ring which is a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and a second ring which is a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl radical)、-O(C_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocycle, or a 5-or 6-membered heteroaryl ring, wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each of said 4-to 7-membered heterocyclic rings, and each of the 5-or 6-membered heteroaryl rings are optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

Is attached to R^YTwo instances of R of the same or different ring atoms^5cTogether with the ring atom or atoms may form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR "(CO) O (C)_1-4Alkyl), -OH or halogen, wherein R "is hydrogen or C_1-2An alkyl group;

each R^5aIndependently selected from halogen, -CN, C_1-6Alkyl, -OR^6a、-SR^6a、-COR^6a、-OC(O)R^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-C(O)N(R^6a)SO₂R^6a、-N(R^6a)C(O)R^6a、-N(R^6a)C(O)OR^6a、-N(R^6a)C(O)N(R^6a)₂、-N(R^6a)₂、-SO₂R^6a、-SO₂N(R^6a)₂、-SO₂N(R^6a)COOR^6a、-SO₂N(R^6a)C(O)R^6a、-N(R^6a)SO₂R^6a、-(C＝O)NHOR^6a、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, wherein C is_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic group contains a ring one and a ring two in a fused or bridged relationship, the ring one being a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the ring two being a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, or a 5-or 6-membered heteroaryl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-C(O)NH₂、-C(O)N(C_1-6Alkyl radical)₂、-C(O)NH(C_1-6Alkyl), -C (O) N (C)_1-6Haloalkyl)₂、-C(O)NH(C_1-6Haloalkyl), C (O) N (C)_1-6Alkyl) (C_1-6Haloalkyl), -COO (C)_1-6Alkyl), -COO (C)_1-6Haloalkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo, wherein the 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocycle each contains up to 4 ring heteroatoms independently selected from N, O and S; or

When R is¹Or R²Is one of up to 5 cases R^5aSubstituted C_3-8A cycloalkyl ring, a 4-to 8-membered heterocycle, or a 5-or 6-membered heteroaryl, to said R¹Or R²Of the same or different ring atoms^5aOptionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocycle, phenyl, or a 5-or 6-membered heterocycle to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4-to 6-membered heterocycle or the 5-or 6-membered heteroaryl ring contains up to 2 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, phenyl or a 5-or 6-membered heterocyclic ring optionally substituted with up to 2 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, oxo, - (CO) O (C)_1-4Alkyl), -NR' (CO) O (C)_1-4Alkyl) or halogen, wherein R' is hydrogen or C_1-2An alkyl group;

each R⁵Independently selected from halogen, -CN, C_1-6Alkyl, -OR⁶、-SR⁶、-COR⁶、-OC(O)R⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-C(O)N(R⁶)SO₂R⁶、-N(R⁶)C(O)R⁶、-N(R⁶)C(O)OR⁶、-N(R⁶)C(O)N(R⁶)₂、-N(R⁶)₂、-SO₂R⁶、-SO₂N(R⁶)₂、-SO₂N(R⁶)COOR⁶、-SO₂N(R⁶)C(O)R⁶、-N(R⁶)SO₂R⁶、-(C＝O)NHOR⁶、C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, phenyl, benzyl, oxo, or a bicyclic group; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl radical, C_3-8A cycloalkyl ring, a 4-to 7-membered heterocyclic ring, a 5-or 6-membered heteroaryl ring, benzyl or phenyl each optionally and independently substituted with up to 3 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; wherein the bicyclic group contains a ring one and a ring two in a fused or bridged relationship, the ring one being a 4 to 7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and the ring two being a phenyl ring or a 5 or 6 membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to 6 of the following groups: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo;

each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl, C_3-8A cycloalkyl ring, or a 4-to 7-membered heterocyclic ring, 5-or 6-membered heteroaryl ring; wherein each said 5-or 6-membered heteroaryl ring or 4-to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl, each of said C_3-8Cycloalkyl, each said 4-to 7-membered heterocycle and each said 5-or 6-membered heteroaryl ring are optionally and independently substituted with up to 3 of: halogen, C_1-4Alkyl, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、-COOH、-COO(C_1-4Alkyl), -O (C)_1-4Alkyl), -O (C)_1-4Haloalkyl) or oxo; or

R when attached to the nitrogen atom¹And R²Form up to 5 cases of R⁵When said 4-to 8-membered heterocyclic ring or 5-or 6-membered heteroaryl ring is substituted, these radicals R attached to the same or different atoms of said ring⁵Optionally form C together with said one or more atoms_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

p is an integer selected from 0, 1 or 2;

ring C is a monocyclic 5-membered heteroaryl ring containing up to 4 ring heteroatoms selected from N, O or S, wherein the monocyclic 5-membered heteroaryl ring is not a1, 3, 5-triazinyl ring;

each J^CIndependently selected from halogen or C_1-4An aliphatic group optionally and independently substituted with up to 3 of the following groups: c_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -OH, or halogen; wherein, the C_1-4Haloalkoxy contains up to 3 halogen atoms.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 1 or 2 and wherein each J is^BIndependently selected from halogen, C_1-4Alkyl OR-OR^B。

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each J is^BIndependently selected from fluorine or chlorine.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-membered heteroaryl ring or a thiophene ring.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring B is a pyridyl ring.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein ring B is a pyrimidinyl ring.

8. The compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein J^DFluorine, chlorine or absent.

9. The compound of any one of claims 1-3 and 6-7, or a pharmaceutically acceptable salt thereof, wherein J^AIs hydrogen.

10. The compound of any one of claims 1-3 and 6-7, or a pharmaceutically acceptable salt thereof, wherein ring C is a monocyclic 5-membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, O or S.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein ring C is an oxazole or isoxazole ring.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein ring C is unsubstituted.

13. The compound of any one of claims 1-3, 6-7, and 11-12, or a pharmaceutically acceptable salt thereof, wherein X¹Is CH, C (C)_1-4Alkyl) or CF.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formulae IIIa to IIIb:

wherein J^BIs halogen and ring C is an unsubstituted oxazole or isoxazole ring;

R¹and R²Taken together with the nitrogen atom to which they are attached to form a 4-to 8-membered heterocyclic or 5-membered heteroaryl ring; wherein the 4-to 8-membered heterocyclic or 5-membered heteroaryl ring is R-deleted¹And R²Optionally containing up to 3 ring heteroatoms independently selected from N, O or S in addition to the nitrogen atom attached and optionally substituted with up to 5R^5eSubstitution;

each R^5eIndependently selected from halogen, -CN, C_1-6Alkyl radical, C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR⁶、-SR⁶、-OCOR⁶、-COR⁶、-C(O)OR⁶、-C(O)N(R⁶)₂、-N(R⁶)C(O)R⁶、-N(R⁶)₂、-SO₂R⁶、-SO₂N(R⁶)COR⁶、-SO₂N(R⁶)₂、-N(R⁶)SO₂R⁶Benzyl, phenyl or oxo groups; wherein each said phenyl ring and each said benzyl group are optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、C_1-4Alkyl radical, C_1-4Haloalkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_1-6Alkyl, said- (C)_1-4Alkyl) -R⁶Each C of the moiety_1-4Alkyl moieties and each of said C_3-8The cycloalkyl ring is optionally and independently substituted with up to 3 halogens, wherein

Each R⁶Independently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

attached to R¹、R²And R¹And R²Two instances R of the same or different atoms of the ring formed by the nitrogen atom to which they are attached^5eOptionally together with said one or more atoms may form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system, wherein the two rings of the bicyclic ring system are in spiro, fused or bridged relationship, wherein the 4 to 6 membered heterocyclic ring or the 5 or 6 membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR (CO) O (C)_1-4Alkyl), -OH or halogen; wherein R is hydrogen or C_1-2An alkyl group;

or, R¹And R²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-8Cycloalkyl ring, 4-to 8-membered heterocycle, 5-or 6-membered heteroaryl or C_1-6alkyl-R^Y(ii) a Wherein each said 4-to 8-membered heterocyclic ring and each said 5-or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein said C_1-6Alkyl, each of said C_1-6alkyl-R^YPart C_1-6Alkyl moiety, C_3-8Cycloalkyl ring, 4-to 8-membered heterocyclyl, 5-or 6-membered heteroaryl and C_1-6alkyl-R^YEach optionally and independently of the other up to 5R^5fSubstitution; with the proviso that R¹Or R²One of them cannot be pyridine or pyrimidine; and, with the proviso that R¹And R²Not both may be hydrogen;

R^Yis selected from C_3-8A cycloalkyl ring, a 4-to 8-membered heterocyclic ring, phenyl, or a 5-to 6-membered heteroaryl ring; wherein each said 4-to 8-membered heterocyclic or 5-to 6-membered heteroaromatic ring contains 1 and 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C_3-8(ii) a cycloalkyl ring, each of said 4-to 8-membered heterocyclic rings, each of said phenyl groups, and each of said 5-to 6-membered heteroaryl rings are optionally substituted with up to 5 instances of R^5gSubstitution;

each R^5fIndependently selected from halogen, -CN, C_1-6Alkyl radical, C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR^6a、-SR^6a、-OCOR^6a、-COR^6a、-C(O)OR^6a、-C(O)N(R^6a)₂、-N(R^6a)C(O)R^6a、-N(R^6a)₂、-SO₂R^6a、-SO₂N(R^6a)₂、-N(R^6a)SO₂R^6a、-SO₂N(R^6a)COR^6aPhenyl or oxo; wherein each said phenyl is optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、C_1-4Alkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_1-6Alkyl and each of said C_3-8Cycloalkyl is optionally and independently substituted with 3 halogen;

each R^6aIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl and each of said C_3-8Cycloalkyl is optionally and independently substituted withUp to 3 halogen substitutions;

when R is¹Or R²Is one of up to 5 cases R^5fSubstituted C_3-8A cycloalkyl ring, a 4-to 8-membered heterocycle, or a 5-or 6-membered heteroaryl, to said R¹Or R²Of the same or different ring atoms^5fAre taken together with said atom or atoms to form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocycle, phenyl, or a 5-or 6-membered heterocycle to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship, wherein the 4-to 6-membered heterocycle or the 5-or 6-membered heteroaryl ring contains up to 2 ring heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, phenyl or a 5-or 6-membered heterocyclic ring optionally substituted with up to 2 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, oxo, - (CO) O (C)_1-4Alkyl), -NR' (CO) O (C)_1-4Alkyl) or halogen, wherein R' is hydrogen or C_1-2An alkyl group;

each R^5gIndependently selected from halogen, -CN, C_1-6Alkyl, benzyl, C_3-8Cycloalkyl ring, C_1-4Cyanoalkyl, -OR^6b、-SR^6b、-OCOR^6b、-COR^6b、-C(O)OR^6b、-C(O)N(R^6b)₂、-N(R^6b)C(O)R^6b、-N(R^6b)₂、-SO₂R^6b、-SO₂N(R^6b)₂、-N(R^6b)SO₂R^6b、-SO₂N(R^6b)COR^6bPhenyl or oxo; wherein each said phenyl and each said benzyl is optionally and independently substituted with up to 3 of the following groups: halogen, -OH, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-CN、C_1-4Alkyl, -O (C)_1-4Alkyl) or-O (C)_1-4Haloalkyl); and wherein each of said C_1-6Alkyl, each of (C)_1-4Alkyl) -R^6bPart C_1-4Alkyl moieties and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

each R^6bIndependently selected from hydrogen, C_1-6Alkyl, phenyl, benzyl or C_3-8A cycloalkyl ring; wherein each of said C_1-6Alkyl, each of said phenyl, each of said benzyl and each of said C_3-8Cycloalkyl is optionally and independently substituted with up to 3 halogens;

or to R^YTwo instances of R of the same or different ring atoms^5gTaken together with said one or more ring atoms to form C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring; phenyl or a 5 or 6 membered heteroaryl ring, to give a bicyclic ring system wherein the two rings are in spiro, fused or bridged relationship; wherein the 4-to 6-membered heterocyclic ring or the 5-or 6-membered heteroaryl ring contains up to 3 heteroatoms independently selected from N, O or S; and wherein said C_3-8A cycloalkyl ring, a 4-to 6-membered heterocyclic ring, a phenyl or a 5-or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 of the following groups: c_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, oxo, -C (O) O (C)_1-4Alkyl), -C (O) OH, -NR "(CO) O (C)_1-4Alkyl), -OH or halogen; and is

R' is hydrogen or C_1-2An alkyl group.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, having formula XIa or formula XIb:

wherein J^BIs halogen;

R¹is hydrogen or C_1-6An alkyl group;

R²is C_1-6Alkyl optionally and independently substituted with up to 3R^5fAnd (4) substitution.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R²Is C_1-3Alkyl, which is optionally substituted withIndependently up to 3 cases of R^5fSubstituted, in which each instance R^5fIndependently selected from hydroxy, C_1-2Haloalkyl or-CONH₂。

17. The compound of claim 1 selected from those depicted in table IA or table 1B or table IC or table ID, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and one or more excipients.

19. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease, health condition, or disorder in a subject in need thereof, wherein the disease, health condition, or disorder is selected from the group consisting of:

(1) a peripheral, pulmonary, hepatic, renal, cardiac or cerebrovascular/endothelial disorder or condition or disease associated with other modes of circulation selected from the group consisting of:

a disorder related to: hypertension and reduced coronary vascular flow; acute and chronic coronary blood pressure increases; arterial hypertension; vascular disorders resulting from cardiac and renal complications, heart disease, stroke, cerebral ischemia, or renal failure; refractory hypertension; diabetic hypertension; congestive heart failure; diastolic or systolic dysfunction; coronary insufficiency; cardiac arrhythmia; a reduction in ventricular preload; cardiac hypertrophy; heart failure/cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage;

thromboembolic disorders and ischemia; myocardial infarction; stroke; transient Ischemic Attack (TIA); obstructive thrombotic vasculitis; stable or unstable angina; coronary artery spasm; variant angina pectoris; prinzmitos angina; restenosis resulting from thrombolytic therapy; thrombotic disorders;

alzheimer's disease; parkinson's disease; dementia; vascular cognitive disorders; cerebral vasospasm; traumatic brain injury;

peripheral arterial disease; peripheral obstructive arterial disease; peripheral vascular disease; the pressure is too high; raynaud's syndrome or phenomenon; critical limb ischemia; vasculitis; a peripheral plug; intermittent claudication; vascular occlusion crisis; duchenne muscular dystrophy; becker muscular dystrophy; a microcirculation abnormality; vascular leakage or permeability problems;

shock; septicemia; cardiogenic shock; controlling leukocyte activation; inhibiting or modulating platelet aggregation;

lung/respiratory conditions; pulmonary hypertension; pulmonary arterial hypertension and associated pulmonary vascular remodeling; local thrombosis and right heart hypertrophy; excessive lung pressure; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic pulmonary hypertension, pre-capillary pulmonary hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary artery disease; plexogenic pulmonary artery disease; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory distress syndrome; pulmonary fibrosis; lung transplantation;

pulmonary hypertension associated with or related to: left ventricular dysfunction, hypoxemia, WHO I, II, III, IV and V group hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary venous malformation drainage, pulmonary vein obstructive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, interstitial lung disease, sleep disordered breathing, sleep apnea, alveolar hypoventilation conditions, chronic altitude sickness, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease; blood coagulation disorders; chronic thromboembolism, pulmonary embolism due to tumor, parasite or exogenous material, connective tissue disease, lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangioma; histiocytosis X, lymphangiomatosis and pulmonary vascular compression due to adenosis, tumors or fibrositis;

an arteriosclerotic disease or condition; atherosclerosis; atherosclerosis associated with: endothelial injury, platelet and monocyte attachment and accumulation, smooth muscle proliferation and migration; restenosis; thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA), and restenosis that develops after bypass; inflammation;

cardiovascular diseases associated with: metabolic syndrome, obesity, dyslipidemia, diabetes, hypertension; lipid-related disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis; pre-eclampsia; polycystic kidney disease progression; subcutaneous fat accumulation;

cirrhosis of the liver; cirrhosis associated with: chronic liver disease; hepatic fibrosis, hepatic stellate cell activation, hepatic fibrocollagen; total collagen accumulation; a fatal inflammatory and/or immunogenic liver disease;

a genitourinary disorder; renal fibrosis; renal failure due to chronic kidney disease or insufficiency; renal failure due to accumulation/deposition and tissue damage, progressive sclerosis, and glomerulonephritis; prostatic hyperplasia;

systemic sclerosis;

cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy;

(2) ischemia, reperfusion injury; ischemia/reperfusion associated with: organ transplantation, lung transplantation (lung transplantation), lung transplantation (pulmony transplantation) or heart transplantation; preserving blood substitutes in trauma patients;

(3) sexual, gynecological and urological disorders selected from erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal disorder; hypofunction sexual excitation disorder; vaginal atrophy; the sexual feeling is not quick; atrophic vaginitis; benign Prostatic Hypertrophy (BPH) or overgrowth or enlargement; bladder outlet obstruction; bladder Pain Syndrome (BPS); interstitial Cystitis (IC); overactive bladder, neurogenic bladder and incontinence; diabetic nephropathy;

(4) an ocular disease or disorder selected from glaucoma, retinopathy, diabetic retinopathy, blepharitis, dry eye syndrome, sjogren's syndrome;

(5) a hearing disease or disorder selected from hearing impairment; partial or total hearing loss; partial or complete deafness; tinnitus; noise-induced hearing loss;

(6) a topical or dermal disorder or condition selected from dermal fibrosis, scleroderma, dermal fibrosis;

(7) healing of the wound; wound healing in diabetes; improvement in microvascular perfusion; post-injury microvascular perfusion improvement to counter inflammatory reactions in perioperative care; anal fissure; diabetic ulcers; and

(8) other diseases or conditions selected from cancer metastasis; osteoporosis, gastroparesis; functional dyspepsia; diabetic complications; diseases associated with endothelial dysfunction and neurological disorders associated with reduced nitric oxide production.

20. The use of claim 19, wherein the compound is used in combination with one or more other therapeutic agents.