CN112574235B - A RET inhibitor, its pharmaceutical composition and its use - Google Patents

Abstract

The invention belongs to the field of medicines, and relates to a RET inhibitor, a pharmaceutical composition thereof and application thereof. In particular, the present invention relates to a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound of formula (I), to pharmaceutical compositions comprising said compounds, and to the use of said compounds and pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of diseases and disorders associated with useful RET, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

Description

A RET inhibitor, its pharmaceutical composition and use thereof

Technical Field

The present invention belongs to the field of medicine. Specifically, the present invention relates to new compounds that exhibit inhibition of rearranged during transfection (RET) kinase, pharmaceutical compositions comprising the compounds, and use of the compounds or their pharmaceutical compositions in the preparation of drugs, which are particularly useful for treating and preventing RET-related diseases and conditions, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

Background Art

Re-arranged during transfection (RET) is a receptor tyrosine kinase belonging to the cadherin superfamily that activates multiple downstream pathways involved in cell proliferation and survival.

It is reported that the results of abnormal RET gene production (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) involve cancerization. RET fusion protein is associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer. The identification of RET fusion protein as a driver of certain cancers has promoted the use of multikinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion protein. It is reported that multikinase inhibitors such as sorafenib, sunitinib, vandetanib, and ponatinib show cell proliferation inhibition effects on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012, suppl; Abstract no: 7510). In addition, it is reported that the multikinase inhibitor cabozantinib showed partial efficacy in two patients with RET fusion gene-positive non-small cell lung cancer (Cancer Discov, 3 (6), Jun 2013, p. 630-5). However, these drugs cannot always be administered at levels sufficient to inhibit RET due to toxicity caused by inhibition of targets other than RET. In addition, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Reactivation of kinases via mutations is a common mechanism of drug resistance. When resistance occurs, patients' treatment options are usually very limited, and in most cases cancer progression is not inhibited. WO 2017011776 discloses a single-target RET kinase inhibitor that has a good preventive or therapeutic effect on cancers related to RET and its mutations. There is still a need to further develop compounds that inhibit RET and its resistance mutants to deal with cancers related to RET gene abnormalities.

Summary of the invention

The present invention provides a novel compound exhibiting inhibition of rearranged during transfection (RET) kinase, wherein the compound has a good inhibitory effect on RET wild type and RET gene mutants, and has good inhibitory selectivity for RET wild type and RET gene mutants.

The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can lead to the reduction of side effects, the expansion of therapeutic index or the improvement of tolerability.

In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

in,

X ¹ , X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ or N;

Y is O, NH or S;

T is a bond, alkylene, alkylene-O-, alkylene-O-alkylene or alkylene-NH-, and said T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, OH, F, Cl, Br, I, CN, _NH2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino;

Ring G is a bridged carbocyclic group or a bridged heterocyclic group;

q is 0, 1, 2, 3, or 4;

^Ra is D, OH, _NH2 , F, Cl, Br, I, CN, ^{NR5R6 , OR7} , ^-NR6C (=O) ^R7 , -S(=O ^{) 2R7} , -S(=O) ^R7 , -C(=O) _R7 , -C(=O) ^OR7 , oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl;

E is a bond, -NR ⁶ - or -O-;

Ring A is a bridging cyclylene, a paracyclylene or a spirocyclylene, and is optionally substituted by ¹ , 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, ^NR5R6 , ^R5 (C=O) ^NR6- , aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene and heterocycloalkylene;

Q is a bond, -(CR ² R ³ ) _t O-, -(CR ² R ³ ) _f -, -(CR ² R ³ ) _t -NR ⁶ -, -(C＝O)(CR ² R ³ ) _t -, -(C＝O)(CR ² R ³ ) _t -(S＝O) ₂ (CR ² R ³ ) _f -, -(C＝O)(CR ² R ³ ) _t -NR ⁶ ( CR ² R ³ ) _f -, -(C＝O)(CR ² R ³ ) _t -O(CR ² R ³ ) _f -, -(C＝O)NR ⁶ O(CR ² R ³ ) _f -, -(S＝O) ₂ -NR ⁶ -(CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(C＝O)-, -(CR ² R ³ ) _t -(C＝O)-NR ⁶ -(CR ² R ³ ) _t -, -(S＝O) ₂ (CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(S＝O) ₂ (CR ² R ³ ) _t -, -(S＝O) ₂ O-, -O(C＝O)-, -(C＝O)NR ⁶ -or -NR ⁶ (C＝O)-;

Each f is independently 1, 2, 3 or 4;

Each t is independently 0, 1, 2, 3 or 4;

M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, ^NR5R6 , ^{OR7 ,} alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and cycloalkyl;

R ¹ is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;

Or, R ² , R ³ and the same C atom to which they are connected form a carbocyclic ring or a heterocyclic ring;

R ⁴ is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;

R ⁶ is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

^R7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

In some embodiments, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O-, C _1-6 alkylene-OC _1-6 alkylene, or C _1-6 alkylene-NH-, and T is optionally substituted with 1, 2, 3, or 4 substituents selected from D, OH, F, Cl, Br, I, CN, NH ₂ , C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _6-10 aryl, 5-12 membered heteroaryl, and C _1-6 alkylamino.

In some embodiments, T is a bond, _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -( _CH2 ) _4- , -( _CH2 ) _5- , -( _CH2 ) _6- , -( _CH2 ) ₂ -O-, -( _CH2 ) ₂ -O-CH2-, or -( _CH2 ) ₂ -NH-, and is optionally substituted with 1, 2, ₃ , or 4 substituents selected from D, OH, F, Cl, Br, I, CN, _NH2 , _CF3 , _CHF2 , _CHCl2 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.

In some embodiments,

Ring G is a 6-12 membered bridged carbocyclic group or a 6-12 membered bridged heterocyclic group;

^Ra is D, OH, _NH2 , F, Cl, Br, I, ^CN , ^{NR5R6 , OR7} , ^-NR6C (=O) ^R7 , -S(=O) ^2R7 , -S(=O) ^{R7, -C(=O)R7} _, -C(=O) _OR7 , ^oxo , _C1-6alkyl , _C1-6alkoxy , _{C3-7cycloalkyl} , _{C1-6haloalkyl} , _{C1-6alkoxyC1-6alkyl} or _{C1-6hydroxyalkyl} ;

R ⁵ is H, D, C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein said C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , C _1-6 alkylamino, C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl;

R ⁶ is H, D, C _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxyC _1-6 alkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

^R7 is OH, _C1-6 alkyl, _C3-6 cycloalkyl, 3-12 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl.

In some embodiments, Ring G is of the following substructure:

in,

each Z ¹ is independently CH or N; and

Each Z ² is independently CH ₂ , C═O, NH, O, S, S═(O) or S═(O) ₂ -.

In some embodiments, Ring G is of the following substructure:

^Ra is D, OH, _NH2 , F, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , _Cl , Br, I, CN, _NH2 , _NHCH3 , N( _CH3 ) ₂ , -NHC(=O) _CH3 , -S(=O) _2CH3 , -S(=O) _CH3 , -C(=O _{) CH3} , -C(=O)OH, -C(=O)OC( _CH3 ) ₃ , oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl;

R ⁵ is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl or pyrazolyl; wherein the methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , methyl, -S(=O) ₂ CH ₃ , methoxy, ethoxy and phenyl;

R ⁶ is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

R ⁷ is OH, methyl, ethyl, NH ₂ , N(CH ₃ ) ₂ , methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.

In some embodiments, ring A is a 5-12 membered cyclylene, a 5-12 membered paracyclylene, or a 5-12 membered spirocyclylene, and ring A is optionally substituted with 1, 2, ³ , or 4 substituents selected from F, Cl, _Br , OH, oxo, ^NR5R6 , ^R5 (C=O) ^NR6- , aminoC1-6alkyl, _C1-6alkyl , _C1-6alkoxy , _{C1-6haloalkyl} , _{C1-6hydroxyalkyl} , _3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC1-6alkyl, _{C1-6alkoxyC1-6alkyl} , _{C3-6cycloalkylene} , and _3-6 membered heterocycloalkylene.

In some embodiments, Ring A is of the following sub-structure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

each Z ^3a and Z ^7a is independently CH or N;

Z ^4a is O, S or NH;

each Z ^5a and Z ^6a is independently CH ₂ , O, S, S(═O), S(═O) ₂ , C(═O) or NH;

Each m and t is independently 0, 1 or 2;

Each n and t1 is independently 0 or 1;

wherein each subformula of ring A is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, ^oxo , ^NR5R6 , ^R5 (C=O) ^NR6- , _{aminoC1-4alkyl} , C1-4alkyl, _C1-4alkoxy , _{C1-4haloalkyl} , _{C1-4hydroxyalkyl} , _{3-12 -} membered carbocyclyl, _3-12 -membered heterocyclyl, 3-12-membered heterocyclylC1-4alkyl, _{C1-4alkoxyC1-4alkyl} , C3-6cycloalkylene and _3-6 -membered heterocycloalkylene.

In some embodiments, Ring A is of the following sub-structure:

wherein each subformula of Ring A is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In some embodiments, M is H, D, 5-10 membered heteroaryl, C _6-10 aryl, C _3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxyC _1-6 alkyl, oxo, C _1-6 alkylacyl, 3-7 membered heterocyclyl, and C _3-7 cycloalkyl.

In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridinyl, 7-azabicyclo[2.2.1]heptanyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexanyl, octahydropyrrolo[1,2-a]pyrazinyl, or 5-azaspiro[2.4]heptanyl; and M is optionally substituted by 1, 2, 3, or 4 of D, F, Cl, CN, OH, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , _NH2 , _{NHCH 3} , N( _CH3 ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl;

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

^R4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and _NO2 .

In some embodiments, each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , C _1-6 hydroxyalkyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _3-7 cycloalkylC _1-6 alkyl, C _6-10 aryl, or 5-10 membered heteroaryl;

Or, R ² , R ³ and the same carbon atom to which they are attached form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.

In some embodiments, each R ² and R ³ is independently OH, F, CF ₃ , CHCl ₂ , CHF ₂ , H, D, CN, Cl, Br, NH ₂ , hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N(CH ₃ ) ₂ , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl, or pyrazinyl;

Or, R ² , R ³ and the same carbon atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

In some embodiments, Q is a bond, -O-, -( _CH2 ) _2O- , _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -CH2CH(CH3)CH2-, -CH2CH _(CH3 ) _CH2NHCH2- , -(C= _{O )} OC(CH3) _{2CH2- , -(C=O)(CH2)2 ( S =} O) _2CH2- , -(C=O ₎ CH _{( OH} )-, -(C=O)CH(OH) _CH2- , -(C ₌ O)-, -(S=O) _2- , -(C=O) _CH2CH (OH)-, -(C=O) _CH2- , -(C=O)CH( _CH2OH )-, -(C=O)C( _CH3 ) _2- , -(C=O)CH ₂ NHC(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ CH(N(CH ₃ ) ₂ )-, -(C＝O)(CH ₂ ) ₂ N(CH ₃ )CH ₂ -, -(C＝O)C(CH ₃ ) ₂ CH ₂ -, -(C＝O)C(OH)(CH ₃ )CH ₂ -, -(C＝O)CH ₂ OCH ₂ -, -(C＝O)( CH ₂ ) ₃ -, -(C＝O)CH(NH ₂ )-, -(C＝O)(CH ₂ ) ₃ N(CH ₃ )CH ₂ -, -(C＝O)(CH ₂ ) ₂ -, -(C＝O)CH ₂ CH(OH)CH ₂ -, -(C＝O)CF ₂ CH ₂ -, -(C＝O)CH(OH)C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ C(CH ₃ )(OH)CH ₂ -, -(S＝O) ₂ CH ₂ -, -(S＝O) ₂ CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH(OCH ₃ )-, -(C＝O)NHCH(CH ₂ OH)(CH ₂ ) ₂ -, -(C＝O)NH-, -(C＝O)N(CH ₃ )-, -(C＝O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -(C＝O)N(CH ₂ CH ₃ )(CH ₂ ) ₂ -, -(C＝O)NHC(CH ₃ ) ₂ CH ₂ -, -(C＝O)N(CH ₃ )(CH ₂ ) ₂ -, -(C＝O)NHCH ₂ CH(CH ₃ )CH ₂ -, -(C＝O)NHCH ₂ -, -(C＝O)NH(CH ₂ ) ₂ OCH ₂ -, -(C＝O)N(CH ₃ )(CH ₂ ) ₂ OCH ₂ -, -(S＝O) ₂ NHC(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH(OH)C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(OH)-, -CH ₂ (C＝O)NHCH(CH ₃ )CH ₂ -, -CH ₂ (C＝O)-, -(CH ₂ ) ₂ (C＝O)N(CH ₃ )CH ₂ -, -CH ₂ CH(OH)-, -CH ₂ CH(OH)CH ₂ -, -CH ₂ CH(OH)CH(CH ₃ )CH ₂ -, -(C＝O)CH(N(CH ₃ ) ₂ )-, -(C＝O)C(CH ₃ ) ₂ CH ₂ OCH ₂ -, -(C＝O)C(OCH ₃ )(CF ₃ )-, -(CH ₂ ) ₃ S(＝O) ₂ CH(CH ₃ )CH ₂ -, -(C＝O)N(CH ₂ CH ₂ OCH ₃ )CH ₂ CH(OCH ₃ )-, -CH ₂ CH(OCF ₃ )-, -CH ₂ CH(OCH(CH ₃ ) ₂ )-, -CH ₂ CH(OC(CH ₃ ) ₃ )-, -CH ₂ CF ₂ -, -CH(CH ₃ )-, -CH ₂ CH(OCH ₃ )C(CH ₃ ) ₂ -, -CH ₂ CH(N(CH ₃ ) ₂ )-, -NH-, -(C＝O)NHOCH ₂ -, -(C＝O)NHOCH ₂ (CHOH)-, -(S＝O) ₂ (CH ₂ CH ₃ )-, -(S＝O) ₂ O-, -(S＝O) ₂ -NHC(CH ₃ ) ₂ -, -(CH ₂ ) ₂ (S＝O) ₂ -,

In some embodiments, the compound described in the present invention has the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-1),

in,

Ring A1 is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

and each sub-formula of Ring A1 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C＝O)NR ⁶ -, aminoC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC 1-4 alkyl, C _1-4 alkoxyC _1-4 alkyl, _{C 3-6} cycloalkylene and 3-6 membered heterocycloalkylene.

In some embodiments, Ring A1 is of the substructure formula:

wherein each subformula of Ring A1 is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In some embodiments, the compound described in the present invention has a structure of formula (I-3) or (I-4), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-3) or (I-4).

wherein each of Z ¹ , Z ² , Z ^3a and Z ^7a is independently CH or N;

Each m and t is independently 0, 1 or 2;

Each n and t1 is independently 0 or 1;

Among them and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, ^NR5R6 , ^R5 (C= _O ) ^NR6- , aminoC1-4alkyl, _C1-4alkyl , C1-4alkoxy, _{C1-4haloalkyl} , _{C1-4hydroxyalkyl} , _3-12 membered carbocyclyl, _3-12 membered heterocyclyl, _3-12 membered heterocyclylC1-4alkyl, _{C1-4alkoxyC1-4alkyl} , ^{C3-6cycloalkylene} and 3-6 _membered heterocycloalkylene.

In some embodiments, The substructure is as follows:

The substructure is as follows:

in Each subformula of is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

On the other hand, the present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

On the other hand, the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing or treating RET-related diseases.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

On the other hand, the present invention also provides a method for preventing or treating RET-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

In another aspect, the present invention relates to an intermediate for preparing a compound represented by formula (I), (I-1), (I-2) or (I-3).

In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds represented by formula (I), (I-1), (I-2) or (I-3).

On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable adjuvant thereof. In some embodiments, the adjuvant of the present invention includes, but is not limited to, a carrier, an excipient, a diluent, a solvent, or a combination thereof. In some embodiments, the pharmaceutical composition can be a liquid, solid, semisolid, gel or spray formulation.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.

The salts of the compounds of the present invention also include intermediates used to prepare or purify compounds represented by formula (I), (I-1), (I-2) or (I-3) or salts of separated enantiomers of compounds represented by formula (I), (I-1), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.

Detailed description of the present invention

Definitions and general terms

Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

"Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.

The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

Unless otherwise indicated, the structural formulae and compounds described herein include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, compounds of single stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention also fall within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include one or more different isotopically enriched atoms.

As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "independently optionally substituted with..." can be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted with one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner.

In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C _1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

The term "alkyl" means a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

When alkyl is a linking group and "alkyl" is listed for the Markush group definition, "alkyl" means the linking alkylene group.

The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon group by removing two hydrogen atoms. Examples of _alkylene groups include, but are not limited to, _-CH2- , _-CH2CH2- , -CH( _CH3 ) _CH2- , and the like.

The term "alkylene-O-" means an alkylene group attached to the rest of the molecule through an oxygen atom, wherein the alkylene group has the definition as described herein.

The term "alkylene-NH-" means that an alkylene group is attached to the rest of the molecule through an NH group, wherein the alkylene group has the definition as described herein.

The term "oxo", ie, =O, refers to the situation where two hydrogen atoms on a carbon atom are replaced by =O, that is, _-CH2- is replaced by =O to become -C(=O)-.

The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 hydroxyalkyl group, i.e., a C _1-6 alkyl group substituted by 1 or more hydroxyl groups. Preferably, C _1-6 hydroxyalkyl refers to a C _1-6 alkyl group substituted by ₁ hydroxyl group. In some embodiments, hydroxyalkyl refers to a C _1-4 hydroxyalkyl group. In some embodiments, hydroxyalkyl refers to a C _1-3 hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, OHCH ₂ -, CH ₂ OHCH ₂ CH ₂ CH ₂ -, CH ₂ OHCH ₂ -, CH ₂ OHCH ₂ CHOHCH ₂ -, CH(CH ₃ )OHCH ₂ CHOHCH ₂ -, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n-propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n-butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, —OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (—OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (—OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (—OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (—OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (—OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (—OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein. In some embodiments, alkoxyalkyl refers to C _1-6 alkoxy C _1-6 alkyl; in other embodiments, alkoxyalkyl refers to C _1-4 alkoxy C _1-4 alkyl; in other embodiments, alkoxyalkyl refers to C _1-4 alkoxy C _1-3 alkyl; in some embodiments, alkoxyalkyl refers to C _1-3 alkoxy C _1-3 alkyl. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.

The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms. In some embodiments, haloalkyl means C _1-6 haloalkyl, i.e., C _1-6 alkyl is substituted with one or more halogens. In some embodiments, haloalkyl means C _1-4 haloalkyl. In some embodiments, haloalkyl means C _1-3 haloalkyl. Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

The term "cycloalkyl" refers to a monovalent saturated monocyclic carbon ring system. The -CH ₂ - group in the cycloalkyl group may be optionally replaced by -C(=O)-. In some embodiments, the cycloalkyl group contains 3-7 ring carbon atoms, i.e., C _3-7 cycloalkyl. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, i.e., C _3-6 cycloalkyl; in another embodiment, the cycloalkyl group contains 3-5 carbon atoms, i.e., C _3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of carbocyclic rings in which the -CH ₂ - group may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc. The cycloalkyl group may be independently and optionally substituted by one or more substituents described herein.

The term "cycloalkylene" refers to a divalent saturated monocyclic carbon ring system. The -CH ₂ - group in the cycloalkylene may be optionally replaced by -C(=O)-. In some embodiments, the cycloalkylene contains 3-7 ring carbon atoms, i.e., C _{3-7 cycloalkylene. In one embodiment, the cycloalkylene contains 3-6 carbon atoms, i.e., C 3-6 cycloalkylene} ; in another embodiment, the cycloalkylene contains 3-5 carbon atoms, i.e., C _3-5 cycloalkylene, examples of cycloalkylene include, but are not limited to, 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,3-cyclopentylene, etc. The cycloalkylene group may be independently and optionally substituted by one or more substituents described herein.

The term "monocyclic" refers to a saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein carbocyclic and heterocyclic rings have the definitions as described herein, wherein a monocyclic carbocyclic ring system is a carbomonocyclic ring, and a monocyclic heterocyclic ring system is a heteromonocyclic ring.

The term "monocyclic group" refers to a monovalent saturated or unsaturated monocyclic carbocyclic ring or monocyclic heterocyclic ring system, wherein carbocyclic ring and heterocyclic ring have the definitions as described in the present invention. The -CH ₂ - group in the monocyclic group can be optionally replaced by -C(＝O)-. In some embodiments, the monocyclic group contains 3-7 ring atoms, that is, the monocyclic group is a 3-7-membered monocyclic group; in other embodiments, the monocyclic group contains 3-6 ring atoms, that is, the monocyclic group is a 3-6-membered monocyclic group. Examples of monocyclic groups include, but are not limited to: cyclopropyl, cyclopentyl, cyclohexyl, 1,2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furanyl, etc. Preferably, the monocyclic group described in the present invention is a monovalent saturated monocyclic carbocyclic ring or monocyclic heterocyclic ring system. The monocyclic group can be independently and optionally substituted by one or more substituents described in the present invention.

The term "monocyclylene" refers to a divalent saturated or unsaturated monocyclic carbocyclic ring or monocyclic heterocyclic ring system, wherein carbocyclic ring and heterocyclic ring have the definitions as described in the present invention. The -CH ₂ - group in the monocyclylene can be optionally replaced by -C(=O)-. In some embodiments, the monocyclylene contains 3-7 ring atoms, that is, the monocyclylene is a 3-7-membered monocyclylene; in other embodiments, the monocyclylene contains 3-6 ring atoms, that is, the monocyclylene is a 3-6-membered monocyclylene. Preferably, the monocyclylene described in the present invention is a divalent saturated monocyclic carbocyclic ring or monocyclic heterocyclic ring system. Examples of monocyclylene include, but are not limited to, cyclopropylene, cyclopentylene, cyclohexylene, 1,2-cyclopentadienylene, pyrrolidinylene, etc. The monocyclylene can be independently and optionally substituted by one or more substituents described in the present invention.

The term "monoheterocyclylene" refers to a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocycle has the definition as described in the present invention. The -CH ₂ - group in the monoheterocyclylene may be optionally replaced by -C(=O)-. In some embodiments, the monoheterocyclylene contains 3-7 ring atoms, i.e., the monoheterocyclylene is a 3-7-membered monoheterocyclylene; in other embodiments, the monoheterocyclylene contains 3-6 ring atoms, i.e., the monoheterocyclylene is a 3-6-membered monoheterocyclylene. Preferably, the monoheterocyclylene described in the present invention is a divalent saturated monocyclic heterocyclic ring system.

The term "heterocycloalkylene" refers to a divalent saturated monocyclic heterocyclic ring system. The -CH ₂ - group in the heterocycloalkylene may be optionally replaced by -C(=O)-. In some embodiments, the heterocycloalkylene contains 3-7 ring atoms, i.e., the heterocycloalkylene is a 3-7-membered heterocycloalkylene; in other embodiments, the heterocycloalkylene contains 3-6 ring atoms, i.e., the heterocycloalkylene is a 3-6-membered heterocycloalkylene. Examples of heterocycloalkylene include, but are not limited to, piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and the like.

The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein heterocyclyl and alkyl have the definitions described herein. In some embodiments, heterocyclylalkyl is a 3-12 membered heterocyclylC _1-6 alkyl group; in other embodiments, heterocyclylalkyl is a 3-6 membered heterocyclylC _1-6 alkyl group; in some embodiments, heterocyclylalkyl is a 3-6 membered heterocyclylC _1-4 alkyl group. Examples of heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, and the like.

The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogen atoms, wherein halogen and alkoxy have the definitions as described herein. In some embodiments, haloalkoxy refers to C _1-6 haloalkoxy, i.e., C _1-6 alkoxy substituted by one or more halogens. In some embodiments, haloalkoxy refers to C _1-4 haloalkoxy. In some embodiments, haloalkoxy refers to C _1-3 haloalkoxy. Such examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, monochloroethoxy, and the like.

The term "alkylacyl" means an alkyl group connected to the rest of the molecule through a carbonyl group, wherein alkyl has the definition as described herein, and carbonyl represents -C(=O)-. In some embodiments, alkylacyl represents C _1-6 alkylacyl; in other embodiments, alkylacyl represents C _1-4 alkylacyl. Examples of alkylacyl include, but are not limited to, formyl, acetyl, and the like.

The term "cycloalkylalkyl" refers to an alkyl group substituted by a cycloalkyl group. Cycloalkyl and alkyl are defined as described herein. In some embodiments, cycloalkylalkyl refers to C _3-7 cycloalkylC _1-6 alkyl; in other embodiments, cycloalkylalkyl refers to C _3-6 cycloalkylC _1-6 alkyl; in other embodiments, cycloalkylalkyl refers to C _3-6 cycloalkylC _1-4 alkyl. Examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.

The term "aryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl and anthracene. When aryl is a linking group, and "aryl" is listed for the Markush group definition, then "aryl" refers to a linked arylene group. The term "arylene" refers to a divalent aromatic ring group formed by removing two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of arylene groups represented as links may include phenylene, naphthylene and anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10-atom heteroaryl or 5-10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" refers to a heteroaromatic ring group or a 5-membered heteroaryl group containing 5 ring atoms, wherein 1, 2, 3 or 4 heteroatoms independently selected from O, S and N are contained. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, 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, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like. When heteroaryl is a linking group, and heteroaryl is listed for the Markush group definition, heteroaryl represents a linked heteroarylene. The term "heteroarylene" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from a ring atom of a heteroaryl. The heteroaryl may be independently optionally substituted with one or more substituents described herein.

The term "sub-bridged cyclyl" refers to a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more non-adjacent ring atoms, including sub-bridged carbocyclyl and sub-bridged heterocyclyl. In some embodiments, the sub-bridged cyclyl is a 5-12 membered sub-bridged cyclyl. The sub-bridged cyclyl can be independently optionally substituted with one or more substituents described herein.

The term "cyclohexylene" refers to a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two adjacent ring atoms, including cyclohexylene and cycloheterocyclohexylene. In some embodiments, the cyclohexylene is a 5-12 membered cyclohexylene. The cyclohexylene may be independently and optionally substituted with one or more substituents described herein.

The term "spirocyclyl" refers to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system formed by two rings sharing a carbon atom, including spirocarbocyclyl and spiroheterocyclyl. In some embodiments, spirocyclyl is a 5-12 membered spirocyclyl. The spirocyclyl can be independently and optionally substituted by one or more substituents described herein.

The terms "carbocyclyl" and "carbocycle" are used interchangeably to refer to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system in which all ring atoms are carbon atoms, including monocarbocyclyl, bridged carbocyclyl, paracarbocyclyl and spirocarbocyclyl.

The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and both refer to non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring systems that share two or more non-adjacent ring carbon atoms, and the ring atoms are carbon atoms. The -CH ₂ - group in the bridged carbocycle may be optionally replaced by -C(=O)-. In some embodiments, the bridged carbocycle contains 6-12 ring carbon atoms, i.e., a 6-12-membered bridged carbocycle; in other embodiments, the bridged carbocycle contains 6-10 ring carbon atoms, i.e., a 6-10-membered bridged carbocycle. Examples of bridged carbocycles include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, octahydro-1H-indene, and the like. When a bridged carbocycle or bridged carbocyclyl is a linking group, and a bridged carbocycle or bridged carbocyclyl is listed for the Markush group definition, the bridged carbocycle or bridged carbocyclyl represents a subbridged carbocyclyl of the linking group. The term "subbridged carbocyclyl" means a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged carbocycle. The bridged carbocycle or bridged carbocyclyl may be independently and optionally substituted with one or more substituents described herein.

The terms "spirocarbocycle" and "spirocarbocyclyl" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system formed by two carbocyclic rings sharing one carbon atom. The _-CH2- group in the spirocarbocycle may be optionally replaced by -C(=O)-. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, i.e., a 7-12-membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, i.e., a 7-10-membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to, spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, etc. When a spirocarbocycle or spirocarbocyclyl is a linking group, and a spirocarbocycle or spirocarbocyclyl is listed for the Markush group definition, then the spirocarbocycle or spirocarbocyclyl refers to a linked spirocarbocyclyl. The term "spirocarbocyclyl" refers to a divalent spirocarbocyclic group formed by removing two hydrogen atoms from the ring atoms of the spirocarbocycle. The spirocarbocycle or spirocarbocyclic group may be independently optionally substituted with one or more substituents described herein.

The terms "heterocycle" or "heterocyclyl" are used interchangeably and refer to a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having 3 to 12 ring atoms, and containing at least 1 carbon atom and 1, 2 or 3 heteroatoms selected from O, N and S. Unless otherwise specified, the heterocyclyl group may be a carbon group or a nitrogen group, and the _-CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide, and the nitrogen atom of the ring may be optionally oxidized to N-oxide. In some embodiments, the heterocyclyl contains 4-7 ring atoms, that is, it represents a 4-7 membered heterocyclyl; examples of heterocyclyl include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholine, and the like. Examples of heterocyclic groups in which the -CH ₂ - group is replaced by -C(＝O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, and 3,5-dioxopiperidinyl. Examples of heterocyclic groups in which the nitrogen atom is oxidized to form an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine. When a heterocyclic ring or heterocyclic group is a linking group, and a heterocyclic ring or heterocyclic group is listed for the Markush group definition, the heterocyclic ring or heterocyclic group represents a linked heterocyclic group. The term "heterocyclic group" means a divalent heterocyclic group formed by removing two hydrogen atoms from a ring atom of a heterocyclic ring. The heterocyclic ring or heterocyclic group may be independently and optionally substituted with one or more substituents described herein.

The terms "bridged heterocycle" or "bridged heterocyclyl" are used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more non-adjacent ring atoms, and the system contains at least one carbon atom and one, two or three heteroatoms selected from O, N, and S. The _-CH2- group in the bridged heterocycle may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide, and the nitrogen atom of the ring may be optionally oxidized to N-oxide. In some embodiments, the bridged heterocycle contains 6-12 ring atoms, i.e., a 6-12-membered bridged heterocycle; in other embodiments, the bridged heterocycle contains 6-10 ring atoms, i.e., a 6-10-membered bridged heterocycle. Examples of bridged heterocycles include, but are not limited to, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-diazabicyclo[2.2.2]octane, etc. When a bridged heterocycle or bridged heterocyclic group is a linking group, and a bridged heterocycle or bridged heterocyclic group is listed for the Markush group definition, the bridged heterocycle or bridged heterocyclic group represents a subbridged heterocyclic group that is connected. The term "subbridged heterocyclic group" means a divalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged heterocycle. The bridged heterocycle or bridged heterocyclic group may be independently optionally substituted with one or more substituents described herein.

The terms "spiroheterocycle" or "spiroheterocyclyl" can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing a carbon atom, and the system contains 1, 2 or 3 heteroatoms selected from O, N, and S. The _-CH2- group in the spiroheterocycle can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide, and the nitrogen atom of the ring can be optionally oxidized to N-oxide. In some embodiments, the spiroheterocycle contains 7-12 ring atoms, that is, it represents a 7-12-membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, that is, it represents a 7-10-membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to, 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane-1-one, etc. When a spiroheterocycle or spiroheterocyclyl is a linking group, and a spiroheterocycle or spiroheterocyclyl is listed for the Markush group definition, the spiroheterocycle or spiroheterocyclyl represents a linked spiroheterocyclyl. The term "spiroheterocyclyl" refers to a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of the spiroheterocycle. The spiroheterocycle or spiroheterocyclyl may be independently and optionally substituted with one or more substituents described herein.

The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" refers to an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" refers to an aminoC _1-6 alkyl group. In other embodiments, the term "aminoalkyl" refers to an aminoC _1-4 alkyl group. In other embodiments, the term "aminoalkyl" refers to an aminoC _1-3 alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, aminoisopropyl, aminoisobutyl, amino-tert-butyl, 1,2-diaminoethyl, and the like.

The term "alkylamino" refers to an amino group substituted by one or two alkyl groups. In some embodiments, the term "alkylamino" refers to a C _1-6 alkylamino group, i.e., an amino group substituted by one or two C _1-6 alkyl groups. In other embodiments, the term "alkylamino" refers to a C _1-4 alkylamino group. In other embodiments, the term "alkylamino" refers to a C _1-3 alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, and the like.

The term "alkylsulfonyl" refers to alkyl-S(=O) ₂ -, i.e., the alkyl group is connected to the rest of the molecule through -S(=O) ₂ -. In some embodiments, alkylsulfonyl refers to C _1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl refers to C _1-4 alkylsulfonyl; in other embodiments, alkylsulfonyl refers to C _1-4 alkylsulfonyl. Examples of alkylsulfonyl include, but are not limited to, methylmethylsulfonyl, ethylmethylsulfonyl, n-propylmethylsulfonyl, isopropylmethylsulfonyl, n-butylmethylsulfonyl, and the like.

In the general formula (I) of the compound of the present invention, the left end of Q is connected to the ring A, and the right end of Q is connected to M. For example, when Q is -(S=O) ₂ NR ⁶ -, then express Similarly, the left end of ring A is connected to E, and the right end of A is connected to Q.

In the general formula (I) of the compound of the present invention, when T is alkylene-O- or alkylene-NH-, express

As described herein, unless otherwise specified, the ring substituents can be connected to the rest of the molecule via any connectable position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.

As described in the present invention, if there are two attachment points on a ring connected to the rest of the molecule, the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged. For example, the substructure a1 of ring A represents that any two possible positions on the ring can be used as connection points (i.e., attachment points), and the two ends of the connection points can be interchanged. Preferably, if there are two attachment points on a ring connected to the rest of the molecule, the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two attachment points are attached to two different ring atoms on the ring.

Preferably, in the present invention, if a ring is a cyclic ring or a spirocyclic ring formed by two sub-rings, and the two attachment points on the ring are respectively located on the two sub-rings, then the two attachment points are connected to the rest of the molecule at any connectable positions on the two sub-rings, and the two ends of the connection can be interchanged. For example, the sub-structural formula a2 of ring A preferably indicates that the two attachment points on the ring are connected to the rest of the molecule on the H1 ring and the H2 ring, respectively, and the two ends of the connection can be interchanged; the sub-structural formula a3 of ring A preferably indicates that the two attachment points on the ring are connected to the rest of the molecule on the H1' ring and the H2' ring, respectively, and the two ends of the connection can be interchanged.

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect a particular functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that is used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. " _Carboxyl protecting group" refers to a _carboxyl substituent used to block or protect the functionality of the carboxyl group. Common carboxyl protecting groups include _-CH2CH2SO2Ph , cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ ( _C1-4alkyl ) ₄ salts. The present invention also contemplates quaternary ammonium salts formed by compounds of any N-containing group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and aromatic sulfonates.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can be found in some other suitable salt lists.

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by a solvent molecule that is water.

"Nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

The term "RET-related cancer" as used herein refers to a cancer associated with or having a disorder of the expression or activity or level of the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any one of them. Non-limiting examples of RET-related cancers are described herein. The disorder of the expression or activity or level of the RET gene, RET kinase, or any one of them is one or more point mutations in the RET gene.

The phrase "dysregulated expression or activity or level of the RET gene, RET kinase, or any of them" refers to a gene mutation (e.g., a RET gene translocation resulting in expression of a fusion protein, a deletion in the RET gene resulting in expression of a RET protein comprising at least one amino acid deletion compared to the wild-type RET protein, or a mutation in the RET gene resulting in expression of a RET protein having one or more point mutations, or an alternative splicing form of RET mRNA resulting in at least one amino acid deletion in the RET protein compared to the wild-type RET protein), or RET gene amplification, the gene amplification resulting in overexpression of the RET protein or autocrine activity resulting from overexpression of the cellular RET gene, resulting in a pathogenic increase in the activity of the kinase domain of the RET protein in the cell (e.g., constitutive activation of the kinase domain of the RET protein). As another example, dysregulated expression or activity or level of the RET gene, RET kinase, or any of them may be a mutation in a RET gene encoding a RET protein, the RET protein being constitutively active or having increased activity compared to a protein encoded by a RET gene that does not contain the mutation. For example, RET gene, RET kinase or any one thereof, expression or activity or level dysregulation can be the result of a gene or chromosomal translocation, which results in the expression of a fusion protein comprising a first RET portion comprising a functional kinase domain and a second portion of a partner protein (i.e., not RET). In some examples, RET gene, RET protein or expression or activity dysregulation can be the result of gene translation of one RET gene with another RET gene.

The disorder of expression or activity or level of RET kinase, RET gene or any (e.g., one or more) thereof may contribute to tumorigenesis. For example, disorder of RET kinase, RET gene or disorder of expression or activity or level of any one thereof may be translocation, overexpression, activation, amplification or mutation of RET kinase, RET gene or RET kinase domain. Translocation may include translocation involving RET kinase domain, mutation may include mutation involving RET ligand binding site, and amplification may be RET gene. Other disorders may include RET mRNA splice variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.

In some embodiments, the RET gene, RET kinase, or any one thereof, expression or activity or level disorder comprises one or more deletions (e.g., a deletion of amino acid 4), insertions, or point mutations in the RET kinase. In some embodiments, the RET gene, RET kinase, or any one thereof, expression or activity or level disorder comprises a deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.

The term "irritable bowel syndrome" includes diarrhea-predominant, constipation-predominant or alternating bowel patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, etc.

Any structural formula given by the present invention is also intended to represent the isotopically unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure described by the general formula given by the present invention, except that one or more atoms are replaced by atoms with selected atomic weights or mass numbers. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, those compounds in which radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically enriched compounds may be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiotherapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) may be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein using a suitable isotopically labeled reagent in place of the unlabeled reagent originally used.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages resulting from greater metabolic stability. For example, an increased in vivo half-life or reduced dosage requirements or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of a compound of formula (I), (I-1), (I-2), (I-3) or (I-4). The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example _D2O , acetone- _d6 , DMSO- _d6 .

Description of the compounds of the present invention

The present invention provides a novel compound showing inhibition of rearranged during transfection (RET) kinase, which has good inhibitory effect on RET wild type and RET gene mutant, and has good inhibitory selectivity for RET wild type and RET gene mutant.

In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, A, Q, M, T, Y, G, ^Ra and q have the same definitions as described in the present invention.

In some embodiments, X ¹ , X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ or N.

In some embodiments, Y is O, NH, or S.

In some embodiments, T is a bond, alkylene, alkylene-O-, alkylene-O-alkylene, or alkylene-NH-, and said T is optionally substituted with 1, 2, 3, or 4 substituents selected from D, OH, F, Cl, Br, I, CN, _NH2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino.

In some embodiments, Ring G is a bridged carbocyclyl or a bridged heterocyclyl.

In some embodiments, q is 0, 1, 2, 3, or 4.

In some embodiments, ^Ra is D, OH, _NH2 , F, Cl, Br, I, ^CN , ^NR5R6 , ^OR7 , ^-NR6C (=O) ^R7 , -S(=O) ^2R7 , -S(=O) ^R7 , -C(=O) ^R7 , -C( ₌ O) ^OR7 , oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl, or hydroxyalkyl.

In some embodiments, E is a bond, -NR ⁶ -, or -O-.

In some embodiments, Ring A is an oxocyclic group, an oxocyclic group, or a spirocyclic group, and Ring A is optionally substituted with 1, 2, 3, or 4 substituents selected from F, Cl, Br, OH, oxo, ^NR5R6 , ^R5 (C=O) ^NR6- , aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl ^, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and heterocycloalkylene.

In some embodiments, Q is a bond, -(CR ² R ³ ) _t O -, -(CR ² R ³ ) _f -, -(CR ² R ³ ) _t -NR ⁶ -, -(C=O )(CR ² R ³ ) _t -, -(C＝O)(CR ² R ³ ) _t -(S＝O) ₂ (CR ² R ³ ) _f -, -(C＝O)(CR ² R ³ ) _t -NR ⁶ (CR ² R ³ ) _f -, -(C＝O)(CR ² R ³ ) _t -O(CR ² R ³ ) _f -, -(C＝O)NR ⁶ O(CR ² R ³ ) _f -, -(S＝O) ₂ -NR ⁶ -(CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(C＝O)-, -(CR ² R ³ ) _t -(C＝O)-NR ⁶ -(CR ² R ³ ) _t -, -(S＝O) ₂ (CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(S＝O ) ₂ (CR ² R ³ ) _t -, -(S＝O) ₂ O-, -O(C＝O)-, -(C＝O)NR ⁶ -or -NR ⁶ (C＝O)-;

Each f is independently 1, 2, 3 or 4;

Each t is independently 0, 1, 2, 3 or 4.

In some embodiments, M is H, D, heteroaryl, aryl, cycloalkyl, or heterocyclyl, and M is optionally substituted with 1, 2, 3, or 4 substituents selected from D, ^F , Cl, CN, OH, ^NR5R6 , ^OR7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl, and cycloalkyl.

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl, or heteroaryl;

Or, R ² , R ³ and the same carbon atom to which they are attached form a carbocyclic ring or a heterocyclic ring;

In some embodiments, R ⁴ is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl.

In some embodiments, R ⁶ is H, D, alkyl, or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH, and NO ₂ .

In some embodiments, R ⁷ is OH, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O—, C _1-6 alkylene-OC _1-6 alkylene, or C _1-6 alkylene-NH—, and T is optionally substituted with 1, 2, 3, or 4 substituents selected from D, OH, F, Cl, Br, I, CN, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _6-10 aryl, 5-12 membered heteroaryl, and C _1-6 alkylamino.

In some embodiments, T is a bond, _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -( _CH2 ) _4- , -( _CH2 ) _5- , -( _CH2 ) _6- , -( _CH2 ) ₂ -O-, -( _CH2 ) ₂ -O-CH2-, or -( _CH2 ) ₂ -NH-, and is optionally substituted with 1, 2, ₃ , or 4 substituents selected from D, OH, F, Cl, Br, I, CN, _NH2 , _CF3 , _CHF2 , _CHCl2 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.

In some embodiments, Ring G is a 6-12 membered bridged carbocyclyl or a 6-12 membered bridged heterocyclyl.

In some embodiments, ^Ra is D, OH, _NH2 , F, Cl, Br, I, ^CN , ^NR5R6 , ^OR7 , ^-NR6C (=O) ^R7 , -S(=O) ^2R7 , -S(=O) ^R7 , -C(=O) ^R7 , -C(=O) ^OR7 , oxo, _{C1-6 alkyl} , _C1-6 alkoxy, _C3-7 cycloalkyl, _C1-6 haloalkyl, _{C1-6 alkoxyC1-6} alkyl, or _C1-6 hydroxyalkyl.

In some embodiments, R ⁵ is H, D, C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , C _1-6 alkylamino, C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl.

In some embodiments, R ⁶ is H, D, C _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxyC _1-6 alkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, R ⁷ is OH, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl.

In some embodiments, Ring G is of the following substructure:

in,

each Z ¹ is independently CH or N; and

Each Z ² is independently CH ₂ , C═O, NH, O, S, S═(O) or S═(O) ₂ .

In some embodiments, Ring G is of the following substructure:

In some embodiments, ^Ra is D, OH, F, _CF3 , _CHCl2 , _CHF2 , _{CH2F, CF3CH2 ,} Cl, Br, I, CN, _NH2 , _NHCH3 , N( _CH3 ) ₂ , -NHC(=O) _CH3 , -S(=O) _2CH3 , _-S (=O) _CH3 , -C(=O) _CH3 , -C(=O)OH, -C(=O)OC( _CH3 ) ₃ , _oxo , methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl.

In some embodiments, R ⁵ is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl or pyrazolyl; wherein the methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , methyl, -S(═O) ₂ CH ₃ , methoxy, ethoxy and phenyl.

In some embodiments, ^R6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and _NO2 .

In some embodiments, R ⁷ is OH, methyl, ethyl, NH ₂ , N(CH ₃ ) ₂ , methyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.

In some embodiments, ring A is a 5-12 membered cyclylene, a 5-12 membered paracyclylene, or a 5-12 membered spirocyclylene, and ring A is optionally substituted with 1, 2, ³ , or 4 substituents selected from F, Cl, _Br , OH, oxo, ^NR5R6 , ^R5 (C=O) ^NR6- , aminoC1-6alkyl, _C1-6alkyl , _C1-6alkoxy , _{C1-6haloalkyl} , _{C1-6hydroxyalkyl} , _3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC1-6alkyl, _{C1-6alkoxyC1-6alkyl} , _{C3-6cycloalkylene} , and _3-6 membered heterocycloalkylene.

In some embodiments, Ring A is of the following sub-structure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

each Z ^3a and Z ^7a is independently CH or N;

Z ^4a is O, S or NH;

each Z ^5a and Z ^6a is independently CH ₂ , O, S, S(═O), S(═O) ₂ , C(═O) or NH;

Each m and t is independently 0, 1 or 2;

Each n and t1 is independently 0 or 1;

wherein each subformula of ring A is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, ^oxo , ^NR5R6 , ^R5 (C=O) ^NR6- , _{aminoC1-4alkyl} , C1-4alkyl, _C1-4alkoxy , _{C1-4haloalkyl} , _{C1-4hydroxyalkyl} , _{3-12 -} membered carbocyclyl, _3-12 -membered heterocyclyl, 3-12-membered heterocyclylC1-4alkyl, _{C1-4alkoxyC1-4alkyl} , C3-6cycloalkylene and _3-6 -membered heterocycloalkylene.

In some embodiments, Ring A is of the following sub-structure:

wherein each subformula of Ring A is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In some embodiments, M is H, D, 5-10 membered heteroaryl, C _6-10 aryl, C _3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxyC _1-6 alkyl, oxo, C _1-6 alkylacyl, 3-7 membered heterocyclyl, and C _3-7 cycloalkyl.

In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridinyl, 7-azabicyclo[2.2.1]heptanyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexanyl, octahydropyrrolo[1,2-a]pyrazinyl, or 5-azaspiro[2.4]heptanyl; and M is optionally substituted by 1, 2, 3, or 4 of D, F, Cl, CN, OH, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , _NH2 , _{NHCH 3} , N( _CH3 ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl substituents.

In some embodiments, M is phenyl, and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, _CF3 , _NH2 , _NHCH3 , N( _CH3 ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.

In some embodiments, M is

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , C _1-6 hydroxyalkyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _3-7 cycloalkylC _1-6 alkyl, C _6-10 aryl, or 5-10 membered heteroaryl;

Or, R ² , R ³ and the same carbon atom to which they are connected form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.

In some embodiments, each R ² and R ³ is independently OH, F, CF ₃ , CHCl ₂ , CHF ₂ , H, D, CN, Cl, Br, NH ₂ , hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N(CH ₃ ) ₂ , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl, or pyrazinyl;

Or, R ² , R ³ and the same carbon atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

In some embodiments, Q is a bond, -O-, -( _CH2 ) _2O- , _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -CH2CH(CH3)CH2-, -CH2CH _(CH3 ) _CH2NHCH2- , -(C= _{O )} OC(CH3) _{2CH2- , -(C=O)(CH2)2 ( S =} O) _2CH2- , -(C=O ₎ CH _{( OH} )-, -(C=O)CH(OH) _CH2- , -(C ₌ O)-, -(S=O) _2- , -(C=O) _CH2CH (OH)-, -(C=O) _CH2- , -(C=O)CH( _CH2OH )-, -(C=O)C( _CH3 ) _2- , -(C=O)CH ₂ NHC(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ CH(N(CH ₃ ) ₂ )-, -(C＝O)(CH ₂ ) ₂ N(CH ₃ )CH ₂ -, -(C＝O)C(CH ₃ ) ₂ CH ₂ -, -(C＝O)C(OH)(CH ₃ )CH ₂ -, -(C＝O)CH ₂ OCH ₂ -, -(C＝O)( CH ₂ ) ₃ -, -(C＝O)CH(NH ₂ )-, -(C＝O)(CH ₂ ) ₃ N(CH ₃ )CH ₂ -, -(C＝O)(CH ₂ ) ₂ -, -(C＝O)CH ₂ CH(OH)CH ₂ -, -(C＝O)CF ₂ CH ₂ -, -(C＝O)CH(OH)C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH ₂ C(CH ₃ )(OH)CH ₂ -, -(S＝O) ₂ CH ₂ -, -(S＝O) ₂ CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C＝O)CH(OCH ₃ )-, -(C＝O)NHCH(CH ₂ OH)(CH ₂ ) ₂ -, -(C＝O)NH-, -(C＝O)N(CH ₃ )-, -(C＝O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -(C＝O)N(CH ₂ CH ₃ )(CH ₂ ) ₂ -, -(C＝O)NHC(CH ₃ ) ₂ CH ₂ -, -(C＝O)N(CH ₃ )(CH ₂ ) ₂ -, -(C＝O)NHCH ₂ CH(CH ₃ )CH ₂ -, -(C＝O)NHCH ₂ -, -(C＝O)NH(CH ₂ ) ₂ OCH ₂ -, -(C＝O)N(CH ₃ )(CH ₂ ) ₂ OCH ₂ -, -(S＝O) ₂ NHC(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH(OH)C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(OH)-, -CH ₂ (C＝O)NHCH(CH ₃ )CH ₂ -, -CH ₂ (C＝O)-, -(CH ₂ ) ₂ (C＝O)N(CH ₃ )CH ₂ -, -CH ₂ CH(OH)-, -CH ₂ CH(OH)CH ₂ -, -CH ₂ CH(OH)CH(CH ₃ )CH ₂ -, -(C＝O)CH(N(CH ₃ ) ₂ )-, -(C＝O)C(CH ₃ ) ₂ CH ₂ OCH ₂ -, -(C＝O)C(OCH ₃ )(CF ₃ )-, -(CH ₂ ) ₃ S(＝O) ₂ CH(CH ₃ )CH ₂ -, -(C＝O)N(CH ₂ CH ₂ OCH ₃ )CH ₂ CH(OCH ₃ )-, -CH ₂ CH(OCF ₃ )-, -CH ₂ CH(OCH(CH ₃ ) ₂ )-, -CH ₂ CH(OC(CH ₃ ) ₃ )-, -CH ₂ CF ₂ -, -CH(CH ₃ )-, -CH ₂ CH(OCH ₃ )C(CH ₃ ) ₂ -, -CH ₂ CH(N(CH ₃ ) ₂ )-, -NH-, -(C＝O)NHOCH ₂ -, -(C＝O)NHOCH ₂ (CHOH)-, -(S＝O) ₂ (CH ₂ CH ₃ )-, -(S＝O) ₂ O-, -(S＝O) ₂ -NHC(CH ₃ ) ₂ -, -(CH ₂ ) ₂ (S＝O) ₂ -,

In some embodiments, the compounds described herein have the structure of Formula (IA), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of Formula (IA),

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, A, Q, M, T, G, ^Ra and q have the same definitions as described in the present invention.

In some embodiments, the compound described in the present invention has the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-1),

wherein R ¹ , X ¹ , X ^{2 , X 3 ,} X ⁴ , X ⁵ , E, Q, M, T, G, ^Ra , and q have the definitions described in the present invention;

Ring A1 is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

and each sub-formula of Ring A1 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C＝O)NR ⁶ -, aminoC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC 1-4 alkyl, C _1-4 alkoxyC _1-4 alkyl, _{C 3-6} cycloalkylene and 3-6 membered heterocycloalkylene.

In some embodiments, Ring A1 is of the substructure formula:

wherein each subformula of Ring A1 is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In some embodiments, the compound described in the present invention has a structure of Formula (IA1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of Formula (IA1),

wherein R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , A, T, G, ^Ra , and q have the definitions described in the present invention;

Wherein, ^M1 is heteroaryl or aryl.

In some embodiments, M ¹ is 5-10 membered heteroaryl or C _6-10 aryl; and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxyC _1-6 alkyl, oxo, C _1-6 alkylacyl, 3-7 membered heterocyclyl and C _3-7 cycloalkyl.

In some embodiments, M ¹ is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl; pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl.

In some embodiments, ^M1 is

In some embodiments, the compounds described herein have a structure of formula (I-1aa), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-1aa).

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , T, G, ^Ra , q, A1 and ^M1 have the same definitions as described in the present invention.

In some embodiments, the compound described in the present invention has a structure of formula (I-2) or (I-3), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-2) or (I-3),

wherein R ¹ , X ¹ , X ^{2 , X 3 ,} X ⁴ , X ⁵ , E, Q, M, T, G, ^Ra , and q have the definitions described in the present invention;

each of Z ¹ , Z ² , Z ^3a and Z ^7a is independently CH or N;

Each m and t is independently 0, 1 or 2;

Each n and t1 is independently 0 or 1;

Among them and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, ^NR5R6 , ^R5 (C= _O ) ^NR6- , aminoC1-4alkyl, _C1-4alkyl , C1-4alkoxy, _{C1-4haloalkyl} , _{C1-4hydroxyalkyl} , _3-12 membered carbocyclyl, _3-12 membered heterocyclyl, _3-12 membered heterocyclylC1-4alkyl, _{C1-4alkoxyC1-4alkyl} , ^{C3-6cycloalkylene} and 3-6 _membered heterocycloalkylene.

In some embodiments, The substructure is as follows:

The substructure is as follows:

in Each subformula of is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.

In some embodiments, the compounds described herein have one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

On the other hand, the present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

On the other hand, the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing or treating RET-related diseases.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

On the other hand, the present invention also provides a method for preventing or treating RET-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

On the other hand, the present invention relates to intermediates for preparing compounds represented by structures of formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3).

On the other hand, the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3).

On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable adjuvant thereof. In some embodiments, the adjuvant of the present invention includes, but is not limited to, a carrier, an excipient, a diluent, a solvent, or a combination thereof. In some embodiments, the pharmaceutical composition can be a liquid, solid, semisolid, gel or spray formulation.

Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutical composition thereof.

Also provided herein are methods of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

The present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating irritable bowel syndrome (IBS) and/or pain associated with IBS.

The present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing or treating irritable bowel syndrome (IBS) and/or pain associated with IBS.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.

The salts of the compounds of the present invention also include intermediates used in the preparation or purification of compounds represented by formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3), or salts of separated enantiomers of compounds represented by formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as ammonia (primary, secondary, tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, and cyclic amines, such as piperidine, morpholine and piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compounds of the present invention and pharmaceutical compositions, preparations and administration thereof

The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, for example, RET mutants that are resistant to current standard of care treatments ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, thereby resulting in reduced toxicity associated with inhibiting other kinases.

The pharmaceutical composition of the present invention includes a compound represented by formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3), a compound listed in the present invention, or a compound of the examples. The amount of the compound in the composition of the present invention is effective to treat or alleviate a RET-related disease or condition in a patient, including RET-related cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which, as used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

When preparing the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted by the excipient or encapsulated in such a vehicle in the form of, for example, a capsule, a sachet, paper or other container. If an excipient is used as a diluent, it can be a solid, semisolid or liquid material, which is used as a vehicle, carrier or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Therefore, the composition can be a tablet, a pill, a powder, a lozenge, a capsule, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (solid form or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, a soft and hard gelatin capsule, a suppository, a sterile injection solution and a sterile packaged powder. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated into a tablet or a capsule.

When used in therapy, a therapeutically effective amount of a compound of the invention, particularly a compound of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and a pharmaceutically acceptable salt thereof, may be administered as a crude chemical or as an active ingredient in a pharmaceutical composition. Thus, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, particularly a compound of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents or excipients, etc. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit (e.g., a reduction in cancer cells). When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of the active ingredients that results in a therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of the present invention, in particular the compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the recipient thereof. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, which comprises mixing the compounds of the present invention, in particular the compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) or their pharmaceutically acceptable salts with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or other problems and complications commensurate with a reasonable benefit/risk ratio within the scope of reasonable medical judgment, and are effective for the intended use.

The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending on the host being treated and the particular route of administration. The amount of active ingredient that a compound of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) is mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the duration of treatment, and the age, sex, weight and condition of the patient. A preferred unit dosage form is a unit dosage form containing a daily dose or divided dose of the active ingredient as described herein above, or a suitable fraction thereof. Treatment may be initiated with a small dose that is significantly less than the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the optimum effect is achieved under the circumstances. In general, the compound is most desirably administered at a concentration level that generally provides effective results in terms of anti-tumor effects without causing any harmful or toxic side effects.

Compositions containing the compounds of the present invention can be formulated in unit dosage form, each dose containing about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or other patients, each unit containing a predetermined amount of active material (i.e., a compound of Formula I as provided herein) and a suitable pharmaceutical excipient, the predetermined amount being calculated to produce the desired therapeutic effect.

In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient. It will be understood by those of ordinary skill in the art that this embodies a compound or composition comprising about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg or about 45 mg to about 50 mg of active ingredient.

In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient.

In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a compound or composition comprising about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

The pharmaceutical composition is suitable for administration by any suitable route, for example, by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such preparations can be prepared by any known method in the field of pharmacy, for example, by mixing the active ingredient with a carrier or excipient. Oral administration or injection is preferred.

The present invention also provides a method of treating an individual suffering from a RET-related cancer, the method comprising administering a compound of the present invention before, during, or after administration of another anti-cancer agent (eg, not a compound of the present invention).

The present invention provides methods for treating cancer in a patient in need thereof, the methods comprising: (a) determining whether the cancer in the patient is a RET-related cancer (e.g., a RET-related cancer including a RET-related cancer having one or more RET inhibitor resistance mutations) (e.g., using a regulatory agency-approved, e.g., FDA-approved, kit to identify a disorder in the expression or activity or level of a RET gene, RET kinase, or any of them in a patient or in a biopsy sample of the patient, or by performing any non-limiting example of an assay described herein); and (b) if the cancer is determined to be a RET-related cancer, administering to the patient a therapeutically effective amount of a compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anticancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor that is not a compound of the present invention). In some embodiments, the subject was previously treated with a RET inhibitor that was not a compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or was previously treated with other anti-cancer agents (e.g., after tumor resection or radiation therapy).

In some embodiments of any of the methods described herein, a compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapeutic or treatment (e.g., chemotherapeutic) agents.

Non-limiting examples of other therapeutic agents include: other RET targeted therapeutics (i.e., other RET kinase inhibitors: RET inhibitors that are not compounds described herein), receptor tyrosine kinase targeted therapeutics, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., Obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapeutics, immune targeted agents, and radiation therapy.

In some embodiments, the additional RET targeted therapeutic is a multi-kinase inhibitor that exhibits RET inhibitory activity.

Non-limiting examples of RET-targeted therapeutics include alatinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib, motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516), sunitinib, sorafenib, vatalanib, vandetanib, AUY-922 (5-(2,4-dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, NVP-AST487 (1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methyl)piperidinib]-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methyl)piperidinib]-1-yl)methyl]-3-[trifluoromethyl]phenyl]-3-[4-[6-(methyl)piperidinib]-1-yl)methyl]- =1-(3-(6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) and TG101209 (N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide).

Other therapeutic agents include RET inhibitors, such as those described in, for example, U.S. Pat. Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157; 2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; International Publication Nos. WO 2014/184069; WO 2014/072220; WO 2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO 2005/044835; and J. Med. Chem. 2012, 55(10), 4872-4876, all of which are incorporated herein by reference in their entirety.

Also provided herein is a method for treating cancer, comprising administering to a patient in need thereof a drug combination for treating cancer, which comprises (a) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agent are jointly effective in treating cancer.

Compounds and compositions described herein can be used alone or in combination with other compounds (including other RET regulating compounds) or other therapeutic agents. In some embodiments, the compound or composition of the present invention can be used in combination with one or more selected from the following compounds: cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR), sunitinib (SUTENT), regorafenib (STAVARGA), ponatinib (ICLUSIG), bevacizumab (Avastin), crizotinib (XALKORI) or gefitinib (IRESSA). The compound or composition of the present invention can be used simultaneously or successively with other therapeutic agents by the same or different routes of administration. The compound of the present invention can be included in a single preparation or in a separate preparation together with other therapeutic agents.

In some embodiments, the compounds of the present invention can be used to treat irritable bowel syndrome (IBS) in combination with one or more other therapeutic agents or therapies that act by the same or different mechanisms of action and are effective in the treatment of irritable bowel syndrome. According to standard pharmaceutical practices known to those skilled in the art, the at least one other therapeutic agent can be administered as part of the same or separate dosage form, via the same or different routes of administration, and according to the same or different administration schedules with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Non-limiting examples of other therapeutic agents used to treat irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g., psyllium, methylcellulose), antidiarrheals (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergics and antispasmodics (e.g., scopolamine, dicyclomine), antidepressants (e.g., tricyclic antidepressants such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine or paroxetine), antibiotics (e.g., rifaximin), alosetron, and lubiprostone.

Uses of the compounds and pharmaceutical compositions of the present invention

The present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases or conditions, wherein the RET-related diseases or conditions include RET-related cancers, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, for example, RET mutants that are resistant to current standard of care treatments ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, thereby resulting in reduced toxicity associated with inhibiting other kinases.

The present invention provides use of the compounds of the present invention or their pharmaceutical compositions for inhibiting wild-type RET and RET mutants in the preparation of drugs for preventing or treating diseases or conditions associated with wild-type RET and RET mutants.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar lung cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, cranial cancer, Pharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesia neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell Histiocytosis, Laryngeal cancer, Leukemia, Lip and oral cavity cancer, Liver cancer, Lung cancer, Lymphoma, Macroglobulinemia, Malignant fibrous histiocytoma of bone, Bone cancer, Melanoma, Merkel cell carcinoma, Mesothelioma, Metastatic squamous neck cancer, Midline carcinoma, Oral cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma, Fungal disease mycosis fungoides, Myelodysplastic syndrome, Myelodysplastic/myeloproliferative neoplasms, Myeloid leukemia, Myeloid leukemia, Multiple myeloma, Myeloproliferative neoplasms, Nasal cavity and sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Non-Hodgkin lymphoma, Non-small cell lung cancer, Mouth cancer, Oral cancer, Lip cancer, Oropharyngeal cancer, Osteosarcoma, Ovarian cancer, Pancreatic cancer, Papillomatosis , paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilm's tumor.

In some embodiments, the RET-related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma and cervical cancer. In some embodiments, the RET-related cancer is RET fusion lung cancer or medullary thyroid cancer.

In some embodiments, compounds of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof can be used to treat patients with cancers that have RET inhibitor resistance mutations that increase resistance to compounds that are not Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates thereof, such as substitutions at amino acid position 804, such as V804M, V804L or V804E, by co-administration or as a follow-up to existing drug therapy (e.g., other RET kinase inhibitors that are not compounds of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates thereof). Exemplary RET kinase inhibitors are described herein (e.g., other RET kinase inhibitors that are not a compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the RET kinase inhibitor can be selected from cabozantinib, vandetanib, alatinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

In some embodiments of any of the methods or uses described herein, the irritable bowel syndrome (IBS) includes diarrhea-predominant, constipation-predominant or alternating types, functional bloating, functional constipation, functional diarrhea, unspecified functional intestinal disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

According to the method of the present invention, the compounds and compositions can be any dosage and any administration route to effectively treat or alleviate the severity of the disease. The exact amount required will vary according to the patient's condition, depending on race, age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compound or composition can be used in combination with one or more other therapeutic agents, as discussed in the present invention.

General Synthesis Methods of Compounds of the Invention

Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3). The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise indicated, reagents can be purchased from commercial suppliers such as Lingkai Pharmaceutical, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and are not further purified when used, unless otherwise indicated. Common reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran is obtained by drying under reflux over sodium metal. Anhydrous dichloromethane and chloroform are obtained by drying under reflux over calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether are dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The NMR spectra were CDC1 ₃ or DMSO-d ₆ as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL/min; the HPLC peak was recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B).

Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1×30 mm, 4 μm, 10 min, a flow rate of 0.6 mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.

The following abbreviations are used throughout this invention:

DMAC,DMA N,N-2-methylacetamide

PdCl ₂ (dppf)CH ₂ Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex

_H2 Hydrogen

Pd/C Palladium Carbon

NaOH Sodium hydroxide

NH ₄ Cl Ammonium chloride

K ₂ CO ₃ Potassium carbonate

MeOH, CH ₃ OH Methanol

PE Petroleum Ether

EA Ethyl acetate

DCM Dichloromethane

L Liter

mg milligram

ml,mL milliliters

min

KI Potassium iodide

DMF N,N-Dimethylformamide

HCl/EA Hydrogen chloride in ethyl acetate

DMSO Dimethyl sulfoxide

TLC Thin layer chromatography

CH ₃ CN Acetonitrile

The following synthetic schemes describe the procedures for preparing the compounds disclosed herein. Unless otherwise stated, ^R1 , ^X1 , ^X2 , ^X3 , X4, ^X5 , E, A, Q, M, T, ^Ra , q have the ^definitions as described herein.

Synthesis Scheme 1

Intermediate (IA-1a) Synthesis Scheme:

The intermediate compound of formula (IA-1a) can be obtained by referring to the synthesis steps of the intermediate synthesis scheme above. Wherein ring A is the following substructure formula: Hal ¹ and Hal ² are each independently F, Cl, Br, I, preferably Cl, Br; Pg ¹ is an amino protecting group, such as Boc, etc.; Pg ² is a hydroxy protecting group, such as benzyl, etc. The compound of formula (IA-1a-1) and the compound of formula (IA-1a-2) undergo coupling reaction under suitable coupling agent conditions (such as palladium coupling agent, preferably PdCl ₂ (dppf)CH ₂ Cl ₂ ) in a suitable solvent (such as dioxane, etc.) to obtain the compound of formula (IA-1a-3); the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) undergo coupling reaction under suitable coupling agent conditions (such as palladium coupling agent, preferably PdCl ₂ (dppf)CH ₂ Cl ₂ ) in a suitable solvent (such as toluene, etc.) to obtain a compound of formula (IA-1a-5); the compound of formula (IA-1a-5) is reacted under suitable reaction conditions (such as in the presence of sodium hydroxide and hydrogen peroxide in tetrahydrofuran solvent) to obtain a compound of formula (IA-1a-6); the compound of formula (IA-1a-6) and the compound of formula (IA-1a-7) are subjected to coupling reaction to obtain a compound of formula (IA-1a-8); the compound of formula (IA-1a-8) and the compound of formula (IA-1a-9) are reacted under alkaline conditions to obtain a compound of formula (IA-1a-10); the compound of formula (IA-1a-10) is deaminated under acidic conditions to obtain a compound of formula (IA-1a-11); the compound of formula (IA-1a-11) and the compound of formula (IA-1a-12) are reacted under alkaline conditions to obtain a compound of formula (IA-1a-13); the compound of formula (IA-1a-13) is reacted under suitable conditions (such as H ₂ , Pd/C) to obtain the compound of formula (IA-1a).

Intermediate (IA-3) synthesis scheme:

Intermediate (IA-3) can be prepared by the above synthesis scheme, wherein Hal and Hal ² are F, Cl, Br, I, preferably Cl, Br. The compound of formula (IA-1a-6) reacts with the compound of formula (IA-2) under alkaline conditions (such as the base is K ₂ CO ₃ ) in a suitable solvent (such as N,N-dimethylformamide or DMSO) to obtain the compound of formula (IA-3).

Synthesis Scheme 1:

The compound of formula (IA) can be obtained by referring to the synthesis steps of synthesis scheme 1. Wherein, Hal is F, Cl, Br, I, preferably Cl, Br. The compound of formula (IA-1) reacts with the compound of formula (IA-2) under suitable conditions (such as alkaline conditions, the base is K ₂ CO ₃ ) in a suitable solvent (such as N,N-dimethylacetamide or N,N-dimethylformamide) to obtain the compound of formula (IA).

Synthesis Scheme 2:

The compound of formula (IAa) can be obtained by referring to the synthesis steps of Synthesis Scheme 2. The compound of formula (IA-3) and the compound of formula (IA-4) or a salt of the compound of formula (IA-4) are reacted under basic conditions (such as the base is K ₂ CO ₃ ) in a suitable solvent (such as DMSO) to obtain compound (IAa).

Specific embodiments

Intermediate 1: 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

At room temperature, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol), water (16.5mL, 916mmol), sodium hydroxide (16.03g, 396.8mmol), DMA (500mL) were added in sequence in a 1L single-mouth bottle. After stirring at room temperature for 5min, the mixture was transferred to 0℃ and dodecanethiol (97mL, 397mmol) was slowly added. After the addition was completed, the reaction was transferred to 45℃ overnight. The reaction solution was poured into 3L ice water, and saturated citric acid water was slowly added to adjust the pH to 5. After stirring for half an hour, it was allowed to stand and filtered. The filter cake was washed with water and petroleum ether several times, and dried at 60℃ to obtain 44.1g of yellow solid, which was the target product (yield 93.4%). Rf＝0.35(PE/EA＝3:1); LC-MS: m/z＝239.05[M+H] ⁺ .

Step 2: 3-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1 g, 185 mmol), pyridine (45 mL, 559 mmol), and DCM (800 mL) were added to a 1L single-mouth bottle. The temperature was lowered to below -10°C, and trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added. After stirring for 1 hour, the mixture was naturally warmed to room temperature and reacted overnight. DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL × 3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and purified by silica gel column chromatography (eluent PE/EA = 50:1-25:1) to obtain 61.5 g of off-yellow solid, which was the target product, with a yield of 89.7%. Rf = 0.45 (PE/EA = 5:1).

Step 3: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Under nitrogen protection, 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5 g, 166 mmol), 2-fluoropyridine-5-boronate (44.5 g, 200 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.8 g, 8.3 mmol), and 1,4-dioxane (850 mL) were added into a 1L three-necked flask. The temperature was lowered to -10°C, and potassium acetate solution (115 mL, 345 mmol, 3 mol/L) was slowly added. The mixture was stirred at this temperature for 1 h and then naturally returned to room temperature and the reaction was continued overnight. Filter, wash the filter cake with EA (500 mL × 3), wash the organic phase with water (500 mL), wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, purify by silica gel column chromatography (eluent PE/DCM=2:1-0:1), collect the target spot, spin-dry to obtain 49 g of white solid, which is the target product, with a yield of 93.0%. Rf=0.50 (PE/EA=1:1). LC-MS: m/z=318.10[M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H ).

Step 4: 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 250mL single-necked bottle, 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8 g, 25.23 mmol), biboronic acid pinacol ester (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), and redistilled toluene (150 mL) were added in sequence under nitrogen protection. After nitrogen replacement and bubbling for 10 minutes, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2.1 g, 2.6 mmol) was added. After nitrogen replacement and bubbling for 10 minutes, the reaction was heated at 120°C overnight. Filter with diatomaceous earth, wash the filter cake with EA (50 mL×3), wash the organic phase with water (250 mL), wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin dry, and chromatograph on a silica gel column (eluent PE/DCM＝2:1-0:1). Collect and spin dry to obtain 8.5 g of an orange-yellow solid, which is the target product (yield 93.0%). Rf＝0.15(DCM). ¹ H NMR(400MHz,CDCl ₃ )δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H).

Step 5: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

In a 250mL single-mouth bottle, add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol) and tetrahydrofuran (120mL) in sequence. In an ice bath, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol/L) and hydrogen peroxide (14mL, 140mmol, 30mass%) and stir at low temperature. After the reaction is complete, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol/L). After returning to room temperature, add water (250mL), extract with EA (250mL×2), and combine the organic phases and wash with 0.1M NaOH solution (500mL×2). Combine all aqueous phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 min, and filter to obtain a wet cake. Extract the mother liquor with EA (250 mL × 3), combine all organic phases, dry over anhydrous sodium sulfate, filter, spin dry, and chromatograph on a silica gel column (eluent DCM\MeOH=100:0-100:1) to obtain a light yellow solid. Combine all solids and dry at 50°C to obtain 5.1 g of a light yellow solid, which is the target product (yield 86.0%). Rf=0.25 (DCM\MeOH=100:1). LCMS: m/z=255.10[M+H] ⁺ .

Step 6: 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl ester carboxylic acid

In a 30mL microwave tube, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.5g, 5.9mmol), 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2.3g, 12mmol), N,N-diisopropylethylamine (2.0mL, 12mmol), dimethyl sulfoxide (15mL) were added in sequence, sealed, and reacted at 80℃ for 8h. Under low temperature conditions, water (50mL) was added for dilution, EA was extracted (100mL×5), the organic phases were combined, washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified on a silica gel chromatography column (eluent PE/EA＝5:1-1;1.5), and 1.9g of a yellow product was collected, which was the target product (yield 74.0%). Rf=0.5 (PE/EA=1:1.5). LC-MS: m/z=433.10[M+H] ⁺ .

Step 7: Ethyl 3-(5-(6-(benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-tert-butyl ester-6-carboxylate

3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carboxylate (1 g, 2.312 mmol), benzyl bromide (0.302 mL, 2.54 mmol), potassium carbonate (0.9683 g, 6.936 mmol), N,N-dimethylformamide (10 mL) were added to a 25 mL single-mouth bottle in sequence, and stirred at 80°C overnight. Saturated ammonium chloride (100 mL) was added to quench the mixture at room temperature, and the mixture was extracted with DCM (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin drying on a silica gel chromatography column (eluent PE/EA=5:1-2:1) to obtain 1.06 g of a yellow solid, which was the target product (yield 87.7%). Rf=0.7 (PE/EA=1:1). LC-MS: m/z=523.30[M+H]. ¹ H NMR (400MHz, CDCl ₃ ) δ8.37 (s, 1H), 8.19 (s, 1H), 8.17 (d, J = 1.9Hz, 1H), 7.74 (d, J = 8.7Hz, 2H), 7.42 (dt, J = 11.9, 7.4Hz, 5H), 7.18 (d, J = 2.0Hz, 1H), 5.13 (s ,2H),4.31(d,J＝4.0Hz,2H),4.16(dd,J＝8.7,4.4Hz,2H),3.55(dd,J＝8.1,3.1Hz,2H),2.24–2.20(m,1H),2.01(d,J＝5.5Hz,1H),1.38(s,9H).

Step 8: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride

3-(5-(6-(Benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-tert-butyl ester-6-carboxylic acid ethyl ester (1.06g, 2.03mmol), hydrochloric acid ethyl acetate solution (5mL, 20mmol, 4mol/L), react at room temperature overnight. The reaction solution was spin-dried to obtain a yellow viscous substance, which was dried at 60°C to obtain 1.0g of a yellow solid, which was the target product (yield 100%). LC-MS: m/z=423.30[M-2HCl+H] ⁺ .

Step 9: (6-methoxypyridin-3-yl)methanol

At 0℃, 6-methoxy-3-pyridinecarboxaldehyde (0.4g, 3mmol), lithium aluminum tetrahydride (0.06g, 2mmol), and tetrahydrofuran (10mL) were added to a 25mL single-mouth bottle in sequence, and the reaction was allowed to react overnight at this temperature. EA (50mL) was added, and the reaction mixture was diluted with water (50mL). After extraction and separation, the organic layer was washed with saturated NH ₄ Cl (50mL) solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Purification was performed on a silica gel chromatography column (eluent DCM/EA=4:1) to obtain 0.38g of a light yellow liquid, which was the target product (yield 90.0%). LC-MS: m/z=140.15[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ 8.12 (d, J = 1.8 Hz, 1H), 7.62 ( dd, J = 8.5, 2.4 Hz, 1H), 6.75 ( d, J = 8.5 Hz, 1H), 4.62 ( s, 2H), 3.93 ( s, 3H).

Step 10: 5-(Bromomethyl)-2-methoxypyridine

In a 25 mL single-mouth bottle, (6-methoxypyridin-3-yl)methanol (0.38 g, 2.7 mmol), dichloromethane (8 mL), phosphorus tribromide (0.31 mL, 3.3 mmol) were added in sequence and reacted at 0°C for 30 min. DCM (25 mL) was added for dilution, and the mixture was washed with saturated K ₂ CO ₃ (25 mL) aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and directly used for the next step without further purification.

Step 11: 6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 25 mL single-necked bottle, 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 0.8074 mmol), potassium carbonate (0.3382 g, 2.423 mmol), and N,N-dimethylformamide (8 mL) were added in sequence, and then 5-(bromomethyl)-2-methoxypyridine (0.50 g, 2.5 mmol) was slowly added and stirred at room temperature overnight. The reaction solution was diluted with water (25 mL), extracted with EA (50 mL × 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin drying on a silica gel chromatography column (eluent DCM/MeOH = 1: 0-20: 1) to obtain 0.2889 g of a light yellow solid, which was the target product (yield 65.82%). LC-MS: m/z = 544.10 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.39 (s, 1H), 8.22-8.17 (m, 2H), 8.11 (s, 1H), 8.02 (s, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.42 (dd, J = 14.9, 7.1Hz, 5H), 7.19 (s, 1H), 6.7 0(dd,J=13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H),3.80(s,4H),3.59(s,4H),2.22(s,1H),2.01(s,1H).

Step 12: 6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.288 g, 0.530 mmol), methanol (5 mL), palladium carbon (0.03 g, 10% mass) were added to a 50 mL single-mouth bottle in sequence. After hydrogen replacement several times, the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was dried to obtain 240 mg of a light yellow solid, which was the target product (yield 100.0%). LC-MS: m/z=454.30[M+H]. ¹ H NMR (400MHz, CDCl ₃ ) δ8.39(d,J＝1.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.21(s,1H),8.17-8.12(m,1H),7.81(dd,J＝8.1,2.2Hz,2H),7.14(s,1H),6.78(d,J＝8 .6Hz,1H),6.70(d,J＝8.3Hz,1H),5.37(s,1H),4.00-3.90(m,5H),3.73(s,4H),3.51(s,2H),2.27-2.21(m,1H),2.03(d,J＝6.6Hz,1H).

Intermediate 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane

At 0°C, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.00 g, 7.38 mmol) was dissolved in acetone (15 mL), K ₂ CO ₃ (3.06 g, 22.1 mmol) and KI (1.84 g, 11.1 mmol) were added, and after stirring for 15 min, 1-bromo-2-chloroethane (1.59 g, 11.1 mmol) was slowly added, and the temperature was naturally raised to room temperature and stirred for 4 h. The reaction was monitored by TLC (PE/EA (v/v=2/1) first and then DCM/CH ₃ OH (v/v=20/1), Rf=0.31), and the raw material was completely reacted. Water was slowly added to quench the reaction, and EA (10 mL×3) was used for extraction. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated. The product was chromatographed on a silica gel column with DCM/CH ₃ OH (v/v=40/1-20/1) as the eluent to obtain 0.49 g of a colorless viscous liquid, which was the target product, with a yield of 41%. ¹ H NMR (400MHz, CDCl ₃ ) δ4.41(s,1H),4.01(d,J＝7.9Hz,1H),3.70–3.61(m,1H),3.56(s,1H),3.53(d,J＝6.9Hz,2H),3.06–2.94(m,2H),2.94–2.88(m,1H) ),2.58(d,J＝9.9Hz,1H),1.87(d,J＝9.8Hz,1H),1.76(d,J＝9.8Hz,1H).

Step 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.08 mmol, intermediate 4) and (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (20 mg, 0.12 mmol) were dissolved in DMF (6 mL), and K ₂ CO ₃ (22 mg, 0.16 mmol) was slowly added and stirred for 10 min. Then the temperature was raised to 50°C and reacted for 12 h. The reaction was monitored by TLC (PE/EA (v/v=2/1) and then DCM/CH ₃ OH (v/v=10/1), Rf=0.07), and the raw material was completely reacted. The reaction was stopped, the reaction solution was cooled to room temperature, extracted with EA (20 mL×3), the organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. Silica gel column chromatography, eluent DCM/CH ₃ OH (v/v) = 50/1-20/1, to obtain 12 mg of yellow-brown solid, which is the target product, with a yield of 40%. LC-MS: m/z = 380.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.41(d,J＝3.4Hz,1H),8.28(s,1H),8.24(s,1H),8.08–7.98(m,1H),7.21(d,J＝1.9Hz,1H),7.18–7.11(m,1H),4.51(s,1H),4.30(brs,2H),4.22–4. 16(m,1H),3.93–3.80(m,1H),3.76(d,J＝8.2Hz,1H),3.36–3.26(m,1H),3.25(brs,2H),2.83(d,J＝8.8Hz,1H),1.91(d,J＝9.5Hz,2H).

Intermediate 3: 4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 3-Azabicyclo[3.2.1]octan-8-one hydrochloride

8-Oxo-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (1.0 g, 4.4 mmol) was added to a 25 mL single-mouth bottle, EA (5 mL) was added to dissolve it at room temperature, HCl/EA (6 mL, 24 mmol, 4 mol/L) was added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated to obtain 700 mg of a white solid as the product, with a yield of 98.00%. LC-MS: m/z = 126.25 [M+H] ⁺ .

Step 2: 3-(2-chloroethyl)-3-azabicyclo[3.2.1]octan-8-one

3-Azabicyclo[3.2.1]octan-8-one hydrochloride (300 mg, 1.86 mmol), potassium carbonate (1.1 g, 7.6 mmol), acetonitrile (5 mL), 1-bromo-2-chloroethane (0.5 mL, 6 mmol) were added to a 25 mL double-necked bottle and reacted at room temperature for 15 h. After the reaction was completed, the reaction solution was filtered to remove insoluble matter, and the filtrate was directly concentrated and chromatographed on a silica gel column with an eluent of DCM/MeOH (v/v) = 20/1 to obtain 90 mg of a colorless liquid as the product with a yield of 25.84%. LC-MS: m/z = 188.20 [M+H] ⁺ .

Step 3: 4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (110 mg, 0.4327 mmol, intermediate 4), potassium carbonate (178 mg, 1.2879 mmol), 3-(2-chloroethyl)-3-azabicyclo[3.2.1]octan-8-one (910 mg, 4.8489 mmol) were added to a 25 mL single-mouth bottle in sequence, and DMSO (2 mL) was added to dissolve it, and the reaction was carried out at 80°C for 2 h. After the reaction stopped, 10 mL of water was added to the reaction solution, and EA (40 mL×2) was used for extraction. The organic phase was washed with water (10 mL×4), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was subjected to silica gel column chromatography, and the eluent was DCM/MeOH (v/v=10/1). 70 mg of yellow solid was obtained as the product, with a yield of 39.90%. LC-MS：m/z＝406.15[M+H] ⁺ ； ¹ H NMR：(400MHz,CDCl ₃ )δ8.40(s,1H),8.27(d,J＝2.0Hz,1H),8.23(s,1H),8.02(dd,J＝11.5,4.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.13(dd,J＝8.5,2.7Hz,1H),4.24(t,J＝5.6Hz,2H),3.65(s,2H),3.09(t,J＝5.6Hz,2H),2.71(d,J＝12.6Hz,2H),2.25(d,J＝15.6Hz,2H),2.08(s,2H),1.67(d,J＝8.0Hz,2H)。

Intermediate 4: 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

At room temperature, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol), water (16.5mL, 916mmol), sodium hydroxide (16.03g, 396.8mmol), and DMAC (500mL) were added to a 1L single-mouth bottle in sequence. After stirring at room temperature for 5 minutes, the mixture was transferred to 0℃ and dodecanethiol (97mL, 397mmol) was slowly added. After the addition was completed, the reaction was transferred to 45℃ overnight. The reaction solution was poured into 3L ice water, and saturated citric acid aqueous solution was slowly added to adjust the pH to 5. After stirring for half an hour, it was allowed to stand and filtered. The filter cake was washed with water and petroleum ether several times, and dried at 60℃ to obtain 44.1g of yellow solid, which was the target product (yield 93.4%). Rf＝0.35(PE/EA(v/v＝3/1). LC-MS: m/z＝239.05[M+H] ⁺ .

Step 2: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1 g, 185 mmol), pyridine (45 mL, 559 mmol), and DCM (800 mL) were added to a 1L single-mouth bottle. The temperature was lowered to below -10°C, and trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added. After stirring for 1 hour, the mixture was naturally warmed to room temperature and reacted overnight. DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL×3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and purified by silica gel column chromatography (eluent: PE/EA (v/v＝50/1-25/1)) to obtain 61.5 g of off-yellow solid, which was the target product, with a yield of 89.7%. Rf＝0.45(PE/EA(v/v＝5/1).

Step 3: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Under nitrogen protection, 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5 g, 166 mmol), 2-fluoropyridine-5-boronate (44.5 g, 200 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.8 g, 8.3 mmol), and 1,4-dioxane (850 mL) were added into a 1L three-necked flask. The temperature was lowered to -10°C, and potassium acetate solution (115 mL, 345 mmol, 3 mol/L) was slowly added. The mixture was stirred at this temperature for 1 h and then naturally returned to room temperature and the reaction was continued overnight. The mixture was filtered and the filter cake was washed with EA (500 mL × 3). The organic phase was separated from the filtrate and washed with water (500 mL), saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by silica gel column chromatography (eluent: PE/DCM (v/v=2/1-0/1) to obtain 49 g of a white solid, which was the target product, with a yield of 93.0%. Rf=0.50 (PE/EA (v/v=1/1)). LC-MS: m/z=318.10 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.49 (d, J = 1.2 Hz, 1H), 8.73 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.27 (td, J = 8.2, 2.5 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.4, 2.5 Hz, 1H).

Step 4: 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 250mL single-necked bottle, 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8 g, 25.23 mmol), biboronic acid pinacol ester (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), and redistilled toluene (150 mL) were added in sequence under nitrogen protection. After nitrogen replacement and bubbling for 10 minutes, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2.1 g, 2.6 mmol) was added. After nitrogen replacement and bubbling for 10 minutes, the reaction was heated at 120°C overnight. Filter with diatomaceous earth, wash the filter cake with EA (50 mL×3), wash the organic phase with water (250 mL), wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin dry, and chromatograph on a silica gel column (eluent PE/DCM (v/v＝2/1-0/1) to obtain 8.5 g of an orange-yellow solid by spin drying, which is the target product (yield 93.0%). Rf＝0.15 (DCM). ¹ H NMR (400 MHz, CDCl ₃ )δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H).

Step 5: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

In a 250mL single-mouth bottle, add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol) and tetrahydrofuran (120mL) in sequence. In an ice bath, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol/L) and hydrogen peroxide (14mL, 140mmol, 30mass%) and stir at low temperature. After the reaction is complete as monitored by TLC, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol/L). After returning to room temperature, add water (250mL), extract with EA (250mL×2), and combine the organic phases and wash with 0.1M NaOH solution (500mL×2). Combine all aqueous phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 min, and filter to obtain a wet cake. Extract the mother liquor with EA (250 mL × 3), combine all organic phases, dry over anhydrous sodium sulfate, filter, spin dry, and chromatograph on a silica gel column (eluent DCM/MeOH (v/v = 100/0-100/1) to obtain a light yellow solid. Combine all solids, dry at 50 ° C to obtain 5.1 g of a light yellow solid, which is the target product (yield 86.0%). Rf = 0.25 (DCM\MeOH = 100: 1). LC-MS: m/z = 255.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H).

Example 1: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane

In a 50mL single-mouth bottle, (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (300mg, 2.2126mmol), potassium carbonate (1.26g, 9.11mmol), acetone (4.5mL) were added in sequence, stirred for 5min under ice bath conditions, 1-bromo-2-chloro-ethane (0.3mL, 4mmol) was added dropwise, and the mixture was naturally warmed to room temperature and reacted overnight. The reaction liquid was filtered, the filter cake was washed with an appropriate amount of EA, the mother liquor was spin-dried, and silica gel column chromatography (eluent PE/EA = 7/1-4/1) was collected to obtain 102mg of colorless oily liquid, which was the target product (yield: 28.52%). ¹ H-NMR (400MHz, CDCl ₃ ): δ4.40 (s, 1H), 4.00 (d, J = 7.9Hz, 1H), 3.63 (dd, J = 7.9, 1.6Hz, 1H), 3.56-3.48 (m, 3H), 3.02-2.84 (m, 3H), 2.56 (d, J = 9.9Hz, 1H), 1 .85(dd,J=9.8,1.6Hz,1H),1.77-1.72(m,1H).

Step 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 10 mL single-necked bottle, 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.04410 mmol, see Intermediate 1 for synthesis), (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (22 mg, 0.13611 mmol), potassium carbonate (0.025 g, 0.18 mmol), and DMA (1.5 mL) were added in sequence and stirred in an oil bath at 80 °C overnight. After TLC showed that the reaction was complete, the reaction solution was poured into ice water (10 mL), extracted with EA (30 mL×3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the mother liquor was spin-dried and chromatographed on a silica gel column (DCM/MeOH=50/1-10/1) to obtain 11.3 mg of an off-white solid, which was the target product (yield 44.2%). LC-MS (ES-API): m/z=579.1[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ8.39(d,J＝2.2Hz,1H),8.21(s,1H),8.15(d,J＝1.9Hz,1H),8.10(d,J＝1.7Hz,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.65(dd,J＝8.5Hz,1H),7.13(d,J＝2.0Hz,1H ),6.70(dd,J＝12.7,8.7Hz,2H),4.43(s,1H),4.17-4.11(m,2H),4.09(d,J＝8.0 Hz,1H),3.92(s,3H),3.88-3.82(m,2H),3.82-3.78(m,2H),3.68(d,J＝8.0Hz,1H),3.63-3.58(m,4H),3.16-3.05(m,3H),2.75-2.69(m,1H),2.70-2. 65(m,1H),2.05-2.00(m,1H),1.93-1.90(m,1H),1.81-1.78(m,1H),1.68-1.64(m,1H). HPLC: 89.75%.

Example 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

In a 25 mL single-mouth bottle, tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-5-carboxylate (1.0 g, 4.7 mmol) and 4-methoxybenzoic acid (1.1 g, 7.2 mmol) were added, and DCM was added to dissolve the mixture. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.4 mmol) and 4-dimethylaminopyridine (1.2 g, 9.8 mmol) were added, and the mixture was reacted at room temperature for 20 h. After the reaction was stopped, 10 mL of water was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined and washed with water (10 mL × 2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column. The eluent was DCM-DCM/MeOH (v/v=50/1), and 1.3 g of colorless liquid was obtained, which was the product, with a yield of 81.25%. LC-MS: m/z＝291.20[M-tBu+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.51 (d, J＝8.7Hz, 2H), 6.95 (d, J＝8.7Hz, 2H), 3.79 (s, 3H), 3.68 (s, 2H), 3.56–3.33 (m, 4H), 3.20 (s,1H),3.05(s,1H),2.85(s,2H),1.39(s,9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxyphenyl)methanone dihydrochloride

5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (600 mg, 1.732 mmol) was added to a 25 mL single-mouth bottle, EA (5 mL) was added to dissolve it, HCl/EA (4 mL, 16 mmol, 4 mol/L) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated by TLC detection, and 470 mg of solid was obtained by drying, which was the product with a yield of 95.95%. LC-MS: m/z=247.25[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.50 (d, J=8.7Hz, 2H), 6.96 (d, J=8.7Hz, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 3.54 (d, J=3.1Hz, 1H), 3.52 ( d,J＝2.6Hz,1H),3.32(s,2H),2.99(s,4H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.06853 mmol, intermediate 2), hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxyphenyl)methanone dihydrochloride (30 mg, 0.1061 mmol), potassium carbonate (55 mg, 0.39795 mmol) and DMSO (1.5 mL) were added to a 10 mL single-necked bottle and reacted in an oil bath at 90°C for 14 h. After the reaction solution was cooled to room temperature, 5 mL of water was added, and EA (20 mL × 2) was used for extraction. The organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 50/1-10/1) as the eluent to obtain 20 mg of a yellow solid, which was the product, with a yield of 48.18%. LC-MS: m/z = 606.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.31(d,J＝2.2Hz,1H),8.20(s,1H),8.14(d,J＝2.0Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.52(d,J＝8.7Hz,2H),7.10(d,J＝2.0Hz,1H),6.91(d,J＝8.7Hz,2 H),6.50(d,J＝8.8Hz,1H),4.44(s,1H),4.16–4.10(m,2H ),4.09(d,J＝8.0Hz,1H),4.02(s,1H),3.84(s,4H),3.77–3.72(m,1H),3.69(dd,2H),3.61(s,1H),3.51(s,3H),3.17–3.02(m,5H),2.67(d,J＝9.9Hz,1 H), 2.62 (s, 1H), 1.92 (d, J = 9.8Hz, 1H), 1.80 (d, J = 9.9Hz, 1H).

Example 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500 mg, 2.36 mmol), 2,3-dimethylbenzoic acid (530 mg, 3.5 mmol,) were added to a 25 mL single-mouth bottle, and DCM was added to dissolve it. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol) and 4-dimethylaminopyridine (580 mg, 4.75 mmol) were added, and the reaction was carried out at room temperature for 17 h. 10 mL of water was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined and washed with water (10 mL×2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column. The eluent was PE-PE/EA (v/v=1/1), and 660 mg of a colorless viscous liquid was obtained as the product, with a yield of 81.37%. LC-MS: m/z=289.25[M-tBu+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H), 3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride

5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (330 mg, 0.96 mmol) was added to a 25 mL single-mouth bottle, EA (3 mL) was added to dissolve it, HCl/EA (2 mL, 8 mmol, 4 mol/L) was added, and the reaction was carried out at room temperature for 1 h after the addition was completed. A white solid precipitated during the reaction. After TLC detection of the reaction of the raw material, the reaction solution was directly concentrated to obtain a white solid, which was dried in a vacuum drying oven at 60°C to obtain 260 mg of the product, with a yield of 85.54%. LC-MS: m/z=245.30[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ7.18 (d, J=7.3Hz, 1H), 7.13 (t, J=7.5Hz, 1H), 7.03 (d, J=7.3Hz, 1H), 3.73 (dd, J=12.6, 7.9Hz, 1H), 3.54 (dd, J ＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.07 mmol, intermediate 2), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride (30 mg, 0.11 mmol), potassium carbonate (55 mg, 0.40 mmol) and DMSO (1.5 mL) were added to a 10 mL single-necked bottle and reacted at 90 °C in an oil bath for 13 h. After the reaction solution was cooled to room temperature, 5 mL of water was added, and EA (20 mL × 2) was used for extraction. The organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 50/1-20/1) as the eluent to obtain 20 mg of a yellow solid, which was the product, with a yield of 48.34%. LC-MS: m/z = 604.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.31(d,J＝2.0Hz,1H),8.19(s,1H),8.15(d,J＝1.8Hz,1H),7.70(dd,J＝8.7,2.3Hz,1H),7.18–7.09(m,3H),7.05(d,J＝7.0Hz,1H),6.49(d,J＝8.7Hz,1H) ,4.44(s,1H),4.16–4.08(m,3H),4.00(dd,J＝12.7,7.7Hz,1H),3.87(dd,J＝10.5 ,7.8Hz,1H),3.79–3.70(m,2H),3.68(d,J＝8.0Hz,1H),3.61(s,1H),3.54–3.46(m,2H),3.40(dd,J＝10.8,4.1Hz,1H),3.18–3.02(m,6H),2.67(d,J＝10 .1Hz,1H),2.28(s,3H),2.21(s,3H),1.92(d,J＝10.0Hz,1H),1.79(d,J＝9.7Hz,1H).

Example 4: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.52 mmol), 4-methoxybenzoic acid (576 mg, 3.79 mmol), DCM, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol), 4-dimethylaminopyridine (636 mg, 5.21 mmol) were added to a 50 mL single-mouth bottle, and the mixture was reacted at room temperature for 18 h. 5 mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (20 mL), the organic phase was combined and washed with water (5 mL × 2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column with an eluent of DCM-DCM/MeOH (v/v=50/1) to obtain 270 mg of a white solid as the product with a yield of 32.21%. LC-MS: m/z=333.20[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ7.60 (d, J = 8.7Hz, 2H), 6.91 (d, J = 8.7Hz, 2H), 4.35 (d, J = 28.9Hz, 4H), 4.10 (s ,4H),3.84(s,3H),1.44(s,9H).

Step 2: (4-Methoxyphenyl)(2,6-diazaspiro[3.3]heptane-2-yl)methanone

6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.62 mmol) was added to a 25 mL single-mouth bottle, and DCM (2 mL) was added to dissolve it. Trifluoroacetic acid (0.9 mL, 10 mmol) was added at 0°C, and the mixture was reacted at room temperature for 6 h. The reaction solution was directly concentrated to obtain 130 mg of a colorless liquid as the product, with a yield of 93.01%. LC-MS: m/z=233.20[M+H] ⁺ .

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 10 mL single-necked bottle, 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (22 mg, 0.058 mmol, intermediate 2), (4-methoxyphenyl)(2,6-diazaspiro[3.3]hept-2-yl)methanone (40 mg, 0.17 mmol), potassium carbonate (55 mg, 0.40 mmol) and DMSO (1.5 mL) were added and the reaction was carried out in an oil bath at 90 °C for 14 h. After the reaction solution was cooled to room temperature, 5 mL of water was added, and EA (20 mL × 2) was used for extraction. The organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM-DCM/MeOH (v/v = 10/1) as the eluent to obtain a yellow solid, which was purified by TLC again to obtain 16 mg of an off-white solid as the product, with a yield of 12.33%. LC-MS: m/z = 592.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.29(d,J＝1.9Hz,1H),8.19(s,1H),8.15(d,J＝1.7Hz,1H),7.69(dd,J＝8.6,2.2Hz,1H),7.65(d,J＝8.7Hz,2H),7.10(d,J＝1.8Hz,1H),6.93(d,J＝8.7Hz,2 H),6.43(d,J＝8.6Hz,1H),4. 51(s,2H),4.43(s,3H),4.27(s,4H),4.14–4.06(m,3H),3.85(s,3H),3.68(d,J＝6.9Hz,1H),3.59(s,1H),3.14–3.01(m,3H),2.66(d,J＝10.1Hz,1H) ,1.91(s,1H),1.79(d,J=9.6Hz,1H).

Example 5: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500 mg, 2.36 mmol), 3-fluoro-2-methylbenzoic acid (550 mg, 3.57 mmol) were added to a 100 mL single-mouth bottle, and 10 mL of DCM was added to dissolve it. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol) and 4-dimethylaminopyridine (580 mg, 4.75 mmol) were added and reacted at room temperature for 15 h. After stopping the reaction, the reaction solution was directly concentrated and chromatographed on a silica gel column with an eluent of DCM-DCM/MeOH (v/v=50/1) to obtain 620 mg of a colorless viscous liquid as the product with a yield of 75.56%. LC-MS: m/z=293.20[M-tBu+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ7.24–7.17(m,1H),7.05(d,J＝9.0Hz,1H),7.02–6.96(m,1H),3.89(dd,J＝12.2,8.0Hz,1H),3.70–3.50(m,3H),3.41(dd,J＝11.3,7.3Hz,1H),3.32(s,1 H),3.23–3.08(m,1H),3.08–3.00(m,1H),2.97(d,J＝6.5Hz,1H),2.90–2.81(m,1H),2.23(d,J＝1.4Hz,3H),1.46(s,9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride

5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (620 mg, 1.78 mmol) was added to a 25 mL single-mouth bottle, EA (5 mL) was added to dissolve it, and HCl/EA (11 mL, 44 mmol, 4 mol/L) was added. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. After the reaction stopped, the reaction solution was directly concentrated to obtain 410 mg of a white solid as the product, with a yield of 71.73%. LC-MS: m/z＝249.20[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.30 (dd, J＝13.3, 7.8Hz, 1H), 7.20 (t, J＝8.9Hz, 1H), 7.10 (d, J＝7.4Hz, 1H), 3.73 (dd, J＝12.6, 7.8Hz, 1H) ,3.55(dd,J＝12.7,4.0Hz,1H),3.44–3.21(m,3H),3.16–3.01(m,3H),3.00–2.87(m,2H),2.15(d,J＝1.6Hz,3H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.05271 mmol, intermediate 2), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride (30 mg, 0.1053 mmol), potassium carbonate (51 mg, 0.36900 mmol) and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 15 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM-DCM/MeOH (v/v = 10/1) as the eluent, and 16 mg of a yellow solid was obtained as the product with a yield of 49.95%. LC-MS: m/z = 608.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.31(d,J＝2.0Hz,1H),8.20(s,1H),8.15(d,J＝1.7Hz,1H),7.70(dd,J＝8.7,2.3Hz,1H),7.23–7.17(m,1H),7.10(d,J＝1.7Hz,1H),7.06–6.99(m,2H),6 .50(d,J＝8.7Hz,1H),4.45(s,1H),4.21–4.09(m,3H),4.00(dd,J＝12.7,7.7Hz,1 H),3.87(dd,J＝10.5,7.8Hz,1H),3.80–3.65(m,5H),3.55–3.47(m,2H),3.41(dd,J＝10.9,4.2Hz,1H),3.19–3.11(m,4H),3.09–3.02(m,1H),2.71(d,J＝ 10.1Hz, 1H), 2.24 (d, J = 1.0Hz, 3H), 1.96 (d, J = 9.8Hz, 1H), 1.82 (d, J = 9.8Hz, 1H).

Example 6: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(6-(3-fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 6-(3-fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.52 mmol), 3-fluoro-2-methylbenzoic acid (580 mg, 3.76 mmol), DCM, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) and 4-dimethylaminopyridine (636 mg, 5.21 mmol) were added to a 50 mL single-mouth bottle, and the mixture was reacted at room temperature for 15 h. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, and DCM (40 mL × 2) was used for extraction. The organic phase was washed with water (10 mL × 2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column. The eluent was DCM-DCM/MeOH = (v/v = 50/1), and 480 mg of a colorless liquid was obtained, which was the product, with a yield of 56.92%. LC-MS: m/z=335.20[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.22–7.14 (m, 1H), 7.09–6.98 (m, 2H), 4.29 (s, 2H), 4.11 (d, J = 9.3Hz, 2H), 4.03 (d, J = 4.7Hz, 4H), 2.28 (d, J=2.1Hz, 3H), 1.43 (s, 9H).

Step 2: (3-Fluoro-2-methylphenyl)(2,6-diazaspiro[3.3]hept-2-yl)methanone

6-(3-fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (480 mg, 1.43 mmol) was added to a 25 mL single-mouth bottle, DCM (5 mL) was added to dissolve it, trifluoroacetic acid (1.2 mL, 16 mmol) was added at 0°C, and the mixture was reacted at room temperature for 2.5 h. After the reaction was completed, the reaction solution was directly concentrated by TLC to obtain 330 mg of liquid as the product, with a yield of 98.12%. LC-MS: m/z=235.15[M+H] ⁺ . Step 4: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-(6-(3-fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (23 mg, 0.06062 mmol, intermediate 2), (3-fluoro-2-methylphenyl)(2,6-diazaspiro[3.3]hept-2-yl)methanone (60 mg, 0.26 mmol), potassium carbonate (55 mg, 0.40 mmol) and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 15 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 50/1-10/1) as the eluent, and 14 mg of an off-white solid was obtained as the product with a yield of 38.90%. LC-MS: m/z = 594.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.28(d,J＝2.1Hz,1H),8.19(s,1H),8.15(d,J＝2.0Hz,1H),7.69(dd,J＝8.6,2.3Hz,1H),7.23–7.18(m,1H),7.11–7.04(m,3H),6.42(d,J＝8.6Hz,1H),4 .42(d,J＝11.7Hz,3H),4.30(d,J＝8.9Hz,2 H),4.21(d,J＝8.7Hz,2H),4.15–4.07(m,5H),3.68(d,J＝8.1Hz,1H),3.60(s,1H),3.13–3.02(m,3H),2.66(d,J＝10.2Hz,1H),2.33(d,J＝2.0Hz,3H),1.91 (d, J=10.3Hz, 1H), 1.79 (d, J=9.3Hz, 1H).

Example 7: 4-(6-(6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.52 mmol), 2,3-dimethylbenzoic acid (570 mg, 3.80 mmol), DCM, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (962 mg, 5.02 mmol) and 4-dimethylaminopyridine (620 mg, 5.07 mmol) were added to a 50 mL single-mouth bottle, and the mixture was reacted at room temperature for 23 h. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, and DCM (30 mL × 2) was used for extraction. The organic phase was washed with water (10 mL × 2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column with DCM as the eluent to obtain 360 mg of a colorless liquid as the product with a yield of 43.20%. LC-MS: m/z = 331.30 [M+H] ⁺ .

Step 2: (2,3-Dimethylphenyl)(2,6-diazaspiro[3.3]heptane-2-yl)methanone

Add 6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (360 mg, 1.090 mmol) to a 25 mL single-mouth bottle, add DCM (4 mL) to dissolve it, add trifluoroacetic acid (0.8 mL, 10 mmol) at 0°C, and react at room temperature for 2 h. After the reaction is completed, the reaction solution is directly concentrated for the next step. LC-MS: m/z=231.10[M+H] ⁺ .

Step 3: 4-(6-(6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.049 mmol, intermediate 3), 2,3-dimethylphenyl)(2,6-diazaspiro[3.3]heptane-2-yl)methanone (46 mg, 0.20 mmol), potassium carbonate (45 mg, 0.33 mmol), and DMSO (1.0 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 15 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, extracted with EA (20 mL × 2), the organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 10/1) as the eluent to obtain 5 mg of a yellow solid as the product with a yield of 16.46%. LC-MS: m/z = 616.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.29(d,J＝1.8Hz,1H),8.19(s,2H),7.69(dd,J＝8.6,2.1Hz,1H),7.19(d,J＝6.5Hz,1H),7.15–7.08(m,3H),6.42(d,J＝8.6Hz,1H),4.40(s,2H),4.29(d ,J＝8.8Hz,2H),4.25–4.19(m ,4H),4.10(s,2H),3.73(s,1H),3.61(d,J＝4.4Hz,1H),3.09(t,J＝5.3Hz,2H),2.73(d,J＝14.3Hz,2H),2.30(s,6H),2.25(d,J＝15.8Hz,2H),2.12–2.07 (m,2H),1.66(d,J=7.9Hz,2H).

Example 8: 4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500 mg, 2.36 mmol), 2,3-dimethylbenzoic acid (530 mg, 3.53 mmol,) were added to a 25 mL single-mouth bottle, and DCM was added to dissolve it. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol) and 4-dimethylaminopyridine (580 mg, 4.7475 mmol) were added, and the reaction was carried out at room temperature for 17 h. 10 mL of water was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined and washed with water (10 mL×2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column. The eluent was PE-PE/EA (v/v=1/1), and 660 mg of a colorless viscous liquid was obtained as the product, with a yield of 81.37%. LC-MS: m/z=289.25[M-tBu+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H), 3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride

5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (330 mg, 0.96 mmol) was added to a 25 mL single-mouth bottle, EA (3 mL) was added to dissolve it, HCl/EA (2 mL, 8 mmol, 4 mol/L) was added, and the reaction was carried out at room temperature for 1 h after the addition was completed. A white solid precipitated during the reaction. After TLC detection of the reaction of the raw material, the reaction solution was directly concentrated to obtain a white solid, which was dried in a vacuum drying oven at 60°C to obtain 260 mg of the product, with a yield of 85.54%. LC-MS: m/z=245.30[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.18 (d, J=7.3Hz, 1H), 7.13 (t, J=7.5Hz, 1H), 7.03 (d, J=7.3Hz, 1H), 3.73 (dd, J=12.6, 7.9Hz, 1H), 3.54 (dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H).

Step 3: 4-(6-(5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.049 mmol, intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride (27 mg, 0.085 mmol), potassium carbonate (45 mg, 0.33 mmol), and DMSO (1.0 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 16 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 20/1) as the eluent, and 10 mg of a yellow solid was obtained as the product with a yield of 32.18%. LC-MS: m/z = 630.30 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CDCl ₃ )δ8.32(s,1H),8.20(s,1H),8.19(s,1H),7.71(d,J＝8.5Hz,1H),7.18–7.09(m,3H),7.05(d,J＝6.9Hz,1H),6.50(d,J＝8.7Hz,1H),4.24(t,J＝4.6Hz,2H) ,4.01(dd,J＝12.4,7.7Hz,1H),3.85(d,J＝7.8Hz, 1H),3.80–3.71(m,3H),3.62(s,1H),3.51(d,J＝5.6Hz,2H),3.41(d,J＝6.8Hz,1H),3.20–3.00(m,6H),2.74(d,J＝15.1Hz,2H),2.28(s,3H),2.23(s,1 H), 2.21 (s, 3H), 2.10 (s, 2H), 1.67 (d, J = 7.8Hz, 2H).

Example 9: 6-(2-(2,5-diazabicyclo[2.2.1]heptane-2-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

In a 25mL single-mouth bottle, tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (400mg, 2.02mmol), CH ₃ CN (6mL), potassium carbonate (1.0g, 7.2mmol), and 1-bromo-2-chloroethane (0.5mL, 6mmol) were added, and the mixture was reacted at room temperature for 17h. After the reaction, the reaction solution was filtered, the filter cake was washed with EA for several times, and the filtrate was concentrated and chromatographed on a silica gel column with the eluent being DCM/MeOH (v/v=20/1) to obtain 130mg of a colorless liquid as the product with a yield of 24.71%. LC-MS: m/z=261.20[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ4.30 (d, J=49.6Hz, 1H), 3.51 (t, J=6.9Hz, 3H), 3.17 (t, J=8.7Hz, 1H), 3.01 (dd, J=26.6, 9.4Hz, 1H), 2.9 1(t,J＝6.6Hz,2H),2.60(dd,J＝53.6,9.4Hz,1H),1.91–1.79(m,2H),1.76–1.67(m,1H),1.46(s,9H).

Step 2: tert-Butyl 5-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.20 mmol), potassium carbonate (85 mg, 0.62 mmol), 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (130 mg, 0.50 mmol), and DMF (2.5 mL) were added to a 25 mL single-mouth bottle in sequence, and the mixture was reacted at 80°C for 5 h. After the reaction was stopped, the reaction solution was cooled to room temperature and 10 mL of water was added, and EA (40 mL×2) was used for extraction. The organic phase was washed with water (5 mL×3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v=10/1) as the eluent to obtain 70 mg of the product with a yield of 74.37%. LC-MS: m/z=479.30[M+H] ⁺ .

Step 3: tert-Butyl 5-(2-((3-cyano-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a 10 mL single-necked bottle, tert-butyl 5-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 0.1463 mmol), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride (55 mg, 0.1712 mmol, step 2 of Example 5), potassium carbonate (85 mg, 0.61501 mmol) and DMSO (1.5 mL) were added and the mixture was reacted in an oil bath at 90° C. for 24 h. After the reaction solution was cooled to room temperature, 5 mL of water was added, and EA (20 mL × 2) was used for extraction. The organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 10/1) as the eluent to obtain 70 mg of a yellow solid as the product with a yield of 67.70%. LC-MS: m/z = 707.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.31(d,J＝2.2Hz,1H),8.19(s,1H),8.13(d,J＝1.9Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.21–7.18(m,1H),7.10(d,J＝1.9Hz,1H),7.04–7.00(m,2H),6 .50(d,J＝8.7Hz,1H),4.12–4.07 (m,2H),4.03–3.97(m,1H),3.94–3.84(m,2H),3.82–3.69(m,3H),3.60(s,2H),3.53–3.48(m,3H),3.45–3.39(m,2H),3.22–3.13(m,4H),3.05(s,3 H), 2.24 (d, J = 1.6Hz, 3H), 1.46 (s, 9H).

Step 4: 6-(2-(2,5-diazabicyclo[2.2.1]heptane-2-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

5-(2-((3-cyano-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) was added to a 10 mL single-mouth bottle, EA (2 mL) was added to dissolve it, HCl/EA (0.3 mL, 1 mmol, 4 mol/L) was added under ice bath, and the temperature was naturally raised to room temperature for reaction for 30 min. TLC detection showed that the reaction of the raw material was complete, the reaction solution was directly concentrated, and then 2 mL of methanol was added to dissolve it, potassium carbonate (200 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 40 min to free the base. The reaction solution was directly concentrated and chromatographed on a silica gel column with DCM/MeOH (v/v=10/1) as the eluent to obtain a yellow solid which was purified by TLC again to obtain 24 mg of a light yellow solid as the product with a yield of 39.94%. LC-MS: m/z=607.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.31(d,J＝2.1Hz,1H),8.19(s,1H),8.12(d,J＝1.7Hz,1H),7.69(dd,J＝8.7,2.3Hz,1H),7.20(dd,J＝13.1,7.7Hz,1H),7.07(d,J＝1.8Hz,1H),7.04–6.99( m,2H),6.49(d,J＝8.7Hz,1H),4.21(s,1H),4.09(t,J＝4.9Hz,2H),4.00(dd,J＝12.8,7.7Hz,1H),3.86(dd,J＝10.5,7. 7Hz,1H),3.80–3.73(m,2H),3.72(s,2H),3.61(d,J＝9.8Hz,1H),3.51(dd,J＝10.9,6.4Hz,2H),3.41(dd,J＝11.0,4.2Hz,1H),3.23(d,J＝12.2Hz,1H),3.20 –3.16(m,2H),3.15(s,2H),3.04(dd,J＝12.3,6.5Hz,2H),2.23(s,3H),2.09(d,J＝10.6Hz,1H),2.00(d,J＝10.5Hz,1H).

Example 10: 4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.06 mmol, intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride (32 mg, 0.10 mmol, step 2 of Example 5), potassium carbonate (53 mg, 0.38 mmol) and DMSO (1.0 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 13 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 20/1) as the eluent, and 5 mg of solid was obtained as the product with a yield of 12.79%. LC-MS: m/z = 634.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.34(d,J＝1.9Hz,1H),8.22(s,1H),8.21(s,1H),7.73(dd,J＝8.7,2.2Hz,1H),7.24–7.20(m,1H),7.12(s,1H),7.06–7.01(m,2H),6.52(d,J＝8.8Hz,1 H),4.27(s,2H),4.02(dd,J＝12.7,7.7Hz,1H),3.91–3.86(m,1H),3.82–3.73(m, 3H),3.53(dd,J＝10.1,6.2Hz,2H),3.43(dd,J＝11.0,4.2Hz,1H),3.18(dd,J＝11.0,5.1Hz,2H),3.14–3.10(m,2H),3.09–3.06(m,1H),2.77(d,J＝15.7Hz,2 H), 2.64 (s, 1H), 2.29 (s, 1H), 2.26 (s, 4H), 2.11 (s, 2H), 1.69 (d, J = 8.0Hz, 2H).

Example 11: 4-(6-(5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (27 mg, 0.067 mmol, intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxyphenyl)methanone dihydrochloride (35 mg, 0.11 mmol, step 2 of Example 2), potassium carbonate (61 mg, 0.44 mmol) and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90° C. in an oil bath for 17 h. After the reaction was stopped, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 3) and brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 20/1) as the eluent, and the product was obtained and purified by TLC again to obtain 12 mg of a yellow solid, which was the product, with a yield of 28.52%. LC-MS: m/z = 632.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.32(d,J＝1.8Hz,1H),8.20(d,J＝7.0Hz,2H),7.71(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝8.6Hz,2H),7.10(d,J＝1.5Hz,1H),6.91(d,J＝8.6Hz,2H),6.50(d,J ＝8.8Hz,1H),4.24(t,J＝5.2Hz,2H),4.02(s,1H) ,3.84(s,3H),3.73(s,1H),3.66(s,4H),3.61(d,J＝3.9Hz,1H),3.51(s,3H),3.11–3.08(m,2H),2.74(d,J＝14.7Hz,2H),2.25(d,J＝15.8Hz,2H),2.09( d,J＝5.3Hz,2H),1.67(d,J＝7.9Hz,2H),1.29(s,2H).

Example 12: 4-(6-(6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (32 mg, 0.079 mmol, intermediate 3), (4-methoxyphenyl)(2,6-diazaspiro[3.3]heptane-2-yl)methanone (104 mg, 0.45 mmol, step 2 of Example 4), potassium carbonate (70 mg, 0.51 mmol) and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 16 h. After the reaction, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 4), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 10/1) as the eluent, and the product was obtained and purified by TLC again to obtain 15 mg of a yellow solid, which was the product, with a yield of 30.46%. LC-MS: m/z = 618.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.29(d,J＝1.9Hz,1H),8.21–8.17(m,2H),7.69(dd,J＝8.6,2.2Hz,1H),7.64(d,J＝8.7Hz,2H),7.09(d,J＝1.8Hz,1H),6.92(d,J＝8.7Hz,2H),6.42(d,J＝8 .6Hz,1H),4.46(d,J＝39.3H z,4H),4.26(s,3H),4.22(t,J＝5.5Hz,2H),3.85(s,3H),3.65(s,3H),3.08(t,J＝5.5Hz,2H),2.71(d,J＝13.4Hz,2H),2.24(d,J＝15.8Hz,2H),2.10–2.05 (m,2H),1.65(d,J=7.9Hz,2H).

Example 13: 4-(6-(5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octan-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.51 mmol), 4-methoxybenzoic acid (695 mg, 4.57 mmol) were added to a 25 mL single-mouth bottle, and DCM (6 mL) was added to dissolve it, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (590 mg, 3.08 mmol) and 4-dimethylaminopyridine (375 mg, 3.07 mmol) were added, and the mixture was reacted at room temperature for 21 hours. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, and the aqueous phase was extracted with DCM (20 mL × 2). The organic phases were combined and washed with water (5 mL × 2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column. The eluent was DCM/MeOH (v/v = 50/1), and 400 mg of a white solid was obtained as the product, with a yield of 79.53%.

LC-MS: m/z=333.25[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.49 (d, J=7.8Hz, 2H), 6.93 (d, J=7.9Hz, 2H) ,4.55–4.43(m,1H),3.84(s,3H),3.69(d,J＝11.2Hz,1H),3.61–3.46(m,2H),3.40(s,1H),1.90(s,1H ), 1.83 (d, J = 9.9 Hz, 2H), 1.49 (s, 6H), 1.43 (s, 3H).

Step 2: (2,5-diazabicyclo[2.2.1]hept-2-yl)(4-methoxyphenyl)methanone hydrochloride

Add 5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.60 mmol) to a 25 mL single-mouth bottle, add EA (3 mL) to dissolve it, add HCl/EA (2.1 mL, 8.4 mmol, 4 mol/L), and react at room temperature for 4 h after the addition is complete. After the reaction stops, the reaction solution is directly concentrated to obtain 130 mg of a white solid as the product, with a yield of 95.87%. LC-MS: m/z=233.20[M+H] ⁺ .

Step 3: 4-(6-(5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octan-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (27 mg, 0.067 mmol, intermediate 3), (2,5-diazabicyclo[2.2.1]hept-2-yl)(4-methoxyphenyl)methanone hydrochloride (30 mg, 0.1116 mmol), potassium carbonate (55 mg, 0.40 mmol), and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 29 h. After the reaction, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 4), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with an eluent of DCM/MeOH (v/v) = 10/1, and the product was obtained and purified by TLC again to obtain 5 mg of an off-white solid, which was the product, with a yield of 12.15%. LC-MS: m/z = 618.25 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CDCl ₃ )δ8.28(d,J＝30.5Hz,1H),8.20(s,2H),7.70(d,J＝12.5Hz,1H),7.52(s,2H),7.10(d,J＝17.3Hz,1H),6.91(dd,J＝31.2,7.5Hz,2H),6.50(dd,J＝37.0,8.9Hz ,1H),4.24(s,2H),3.84(d,J ＝15.9Hz,4H),3.71(s,2H),3.61(d,J＝4.7Hz,2H),3.09(s,2H),2.73(d,J＝15.6Hz,2H),2.25(d,J＝15.9Hz,2H),2.07(s,3H),2.03(s,2H),1.66(d,J＝8 .0Hz,2H),0.88(t,J＝6.6Hz,2H).

Example 14: 4-(6-(5-(3-fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(3-fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Add 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.51 mmol) to a 25 mL single-mouth bottle, add 3-fluoro-2-methylbenzoic acid (463 mg, 3.00 mmol), add DCM (6 mL) to dissolve it, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol), 4-dimethylaminopyridine (363 mg, 2.97 mmol), and react at room temperature for 17 hours after the addition is completed. After stopping the reaction, add 5 mL of saturated ammonium chloride solution to the reaction solution, extract the aqueous phase with DCM (20 mL × 2), wash the organic phases with water (5 mL × 2), dry them with anhydrous sodium sulfate, and chromatograph on a silica gel column. The eluent is DCM/MeOH (v/v = 50/1), and 160 mg of colorless liquid is obtained, which is the product, with a yield of 31.62%. LC-MS: m/z=335.20[M+H] ⁺ .

Step 2: 2,5-diazabicyclo[2.2.1]hept-2-yl(3-fluoro-2-methylphenyl)methanone hydrochloride

5-(3-fluoro-2-methyl-benzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (160 mg, 0.48 mmol) was added to a 25 mL single-mouth bottle, EA (3 mL) was added to dissolve it, HCl/EA (1.6 mL, 6.4 mmol, 4 mol/L) was added, and the reaction was carried out at room temperature for 1.5 h. After the reaction was stopped, the reaction solution was directly concentrated to obtain 125 mg of a white solid as the product, with a yield of 96.51%. LC-MS: m/z=235.10[M+H] ⁺ .

Step 3: 4-(6-(5-(3-fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a 5 mL single-necked bottle, 4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.062 mmol), 2,5-diazabicyclo[2.2.1]hept-2-yl(3-fluoro-2-methylphenyl)methanone hydrochloride (55 mg, 0.2032 mmol, intermediate 3), potassium carbonate (54 mg, 0.39 mmol) and DMSO (1.5 mL) were added and the reaction was carried out at 90 °C in an oil bath for 18 h. After the reaction, the reaction solution was cooled to room temperature and then 5 mL of water was added, EA (20 mL × 2) was used for extraction, the organic phase was washed with water (5 mL × 4), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 10/1) as the eluent, and the product was obtained and purified by TLC again to obtain 14 mg of a light yellow solid, which was the product, with a yield of 36.63%. LC-MS: m/z = 620.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.29(d,J＝25.2Hz,1H),8.25–8.14(m,2H),7.72(dd,J＝15.1,5.9Hz,1H),7.25–7.15(m,1H),7.14–6.92(m,3H),6.49(t,J＝9.6Hz,1H),5.05(d,J＝13.3 Hz,1H),4.24(d,J＝5.5Hz,2H),3.78(s,1H),3.70(d,J＝9.5Hz,1H),3 .62(d,J＝7.7Hz,1H),3.48(d,J＝40.1Hz,1H),3.27(dd,J＝24.6,9.7Hz,1H),3.09(dd,J＝10.5,5.2Hz,2H),2.73(d,J＝15.7Hz,2H),2.30–2.19(m,4H),2.10( s, 3H), 2.04 (s, 2H), 1.67 (d, J = 8.0Hz, 2H), 0.87 (d, J = 10.0Hz, 2H).

Example 15: 4-(6-(5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Add 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.51 mmol) to a 25 mL single-mouth bottle, add 2,3-dimethylbenzoic acid (463 mg, 3.08 mmol), add DCM (6 mL) to dissolve it, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol), 4-dimethylaminopyridine (363 mg, 2.97 mmol), and react at room temperature for 17 hours after the addition is completed. After stopping the reaction, add 5 mL of saturated ammonium chloride solution to the reaction solution, extract the aqueous phase with DCM (20 mL × 2), wash the organic phases with water (5 mL × 2), dry them with anhydrous sodium sulfate, and chromatograph on a silica gel column. The eluent is DCM/MeOH (v/v = 50/1), and 210 mg of colorless liquid is obtained, which is the product, with a yield of 42.00%. LC-MS: m/z=331.30[M+H] ⁺ .

Step 2: 2,5-diazabicyclo[2.2.1]hept-2-yl(2,3-dimethylphenyl)methanone hydrochloride

Add 5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (210 mg, 0.64 mmol) to a 25 mL single-mouth bottle, add EA (3 mL) to dissolve it, add HCl/EA (2.4 mL, 9.6 mmol, 4 mol/L), and react at room temperature for 1 h after the addition is complete. After the reaction stops, the reaction solution is directly concentrated to obtain 160 mg of a white solid as the product, with a yield of 94.35%. LC-MS: m/z=231.15[M+H] ⁺ .

Step 3: 4-(6-(5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.064 mmol, intermediate 3), 2,5-diazabicyclo[2.2.1]hept-2-yl(2,3-dimethylphenyl)methanone hydrochloride (120 mg, 0.45 mmol), potassium carbonate (52 mg, 0.38 mmol), and DMSO (1.5 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath for 16.5 h. After the reaction, the reaction solution was cooled to room temperature and then 5 mL of water was added, extracted with EA (20 mL × 2), the organic phase was washed with water (5 mL × 4), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column with DCM/MeOH (v/v = 10/1) as the eluent to obtain 13 mg of a yellow solid as the product with a yield of 32.92%. LC-MS: m/z = 616.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )δ8.29(dd,J＝24.3,1.9Hz,1H),8.20(t,J＝4.8Hz,2H),7.74–7.65(m,1H),7.22–7.05(m,4H),6.49(t,J＝9.6Hz,1H),5.03(d,J＝17.0Hz,1H),4.23(dd,J＝11 .4,5.7Hz,2H),3.78(s,1H),3.70(d,J＝10.6Hz,1H),3.53–3.40(m,1H), 3.25(dd,J＝24.9,9.7Hz,1H),3.09(dd,J＝10.8,5.4Hz,2H),2.72(d,J＝16.1Hz,2H),2.32(s,2H),2.27(s,1H),2.25(s,2H),2.23(s,3H),2.10(s,1H),2 .07(s,2H),2.02(s,2H),1.66(d,J＝8.1Hz,2H),0.88(dd,J＝9.5,5.9Hz,2H).

Using appropriate raw materials, the target compounds (223)-(227) of Examples 223-227, the target compounds (19)-(85) of Examples 19-85, the target compounds (87)-(90) of Examples 87-90, the target compound (189) of Example 189, the target compound (195) of Example 195, the target compounds (202)-(206) of Examples 202-206, the target compounds (208)-(210) of Examples 208-210, the target compounds (215)-(216) of Examples 215-216, the target compound (218) of Example 218 and the target compound (220) of Example 220 were prepared by referring to the synthetic route of Example 1 or Synthesis Scheme 1. The specific structures and characterization data are shown in Table 1 below:

Table 1

Using appropriate starting materials, the target compounds (91)-(92) of Examples 91-92, the target compounds (94)-(107) of Examples 94-107, the target compounds (111)-(122) of Examples 111-122, the target compounds (126)-(135) of Examples 126-135, the target compounds (139)-(142) of Examples 139-142, the target compounds (150)-(170) of Examples 150-170, and the target compound (173) of Examples 173-177 -(177), the target compounds (186)-(188) of Examples 186-188, the target compounds (190)-(194) of Examples 190-194, the target compounds (196)-(201) of Examples 196-201, the target compound (207) of Example 207, the target compounds (211)-(214) of Examples 211-214, and the target compound (221) of Example 221 were prepared by referring to the synthetic route of Example 1 or Synthesis Scheme 1. The specific structures and characterization data are described in Table 2 below:

Table 2

Using appropriate raw materials, the target compound (228) of Example 228, the target compounds (16)-(18) of Examples 16-18, the target compound (86) of Example 86, the target compound (93) of Example 93, the target compounds (108)-(110) of Examples 108-1110, the target compounds (123)-(125) of Examples 123-125, the target compounds (136)-(138) of Examples 136-138, the target compounds (143)-(149) of Examples 143-149, the target compounds (171)-(173) of Examples 171-173, the target compounds (178)-(185) of Examples 178-185, the target compound (217) of Example 217, the target compound (219) of Example 219 and the target compound (222) of Example 222 were prepared by referring to the synthetic route of Example 2 or Synthesis Scheme 2. The specific structures and characterization data are shown in Table 3 below:

Table 3

Biological activity test example:

Test Example 1:

1. Experimental purpose:

The inhibitory activity of the series of compounds against Ret wt and Ret V804M kinases was tested by HTRF method, and the IC ₅₀ values were calculated.

2. The experimental reagents and consumables used are as follows:

1)HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

2) Ret wt (Invitrogen, PV3082)

3)Ret V804M (Signalchem, R02-12GG-10)

4) MgCl2 (Sigma, M1028)

5) ATP (Promega, V910B)

6) DTT (Invitrogen, P2325)

7) DMSO (Sigma, D8418)

8)384-well plate, white, low volume, round-bottom (Greiner, 784075)

9) 384-Well Polypropylene microplate, Clear, Flatt Bottom, Bar Code (Labcyte, P-05525-BC)

10)96-well polypropylene plate(Nunc, 249944)

11)Plate shaker (Thermo, 4625-1CECN/THZ Q)

12)Centrifuge (Eppendorf, 5810R)

13)Envision 2104multi-label Reader (PerkinElmer, 2104-10-1)

14) Echo (Labcyte, 550)

3. Experimental steps

3.1 Prepare 1x kinase reaction buffer:

1 volume of 5X Kinase Reaction Buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

3.2 Transfer 10 nl of diluted compound to each well of an Echo 550 reaction plate (784075, Greiner);

3.3 Seal the reaction plate with a sealing film and centrifuge at 1000g for 1 minute.

3.4 Prepare 2X kinase using 1X enzyme reaction buffer.

3.5 Add 5 μl of kinase (prepared in step 3) to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 30 seconds and leave at room temperature for 10 minutes.

3.6 Prepare 4x TK-substrate-biotin and 4x ATP with 1X enzyme reaction buffer, mix well, and add 5μl K-substrate-biotin/ATP mixture to the reaction plate.

3.7 Seal the plate with sealing film and centrifuge at 1000g for 30 seconds. Incubate at room temperature for 40 minutes.

3.8 Prepare 4X Sa-XL 665 (250 nM) in HTRF detection buffer.

3.9 Add 5 μl Sa-XL 665 and 5 μl TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 1 hour.

3.10 Use Envision 2104 to read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665).

4. Data Analysis

4.1 Calculate the ratio of each well (Ratio_665/615nm)

4.2 The inhibition rate is calculated as follows:

The average of CEP-32496 readings from all positive control wells

The average of all negative control wells with DMSO

Among them, the chemical name of CEP-32496 is: N-[3-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N'-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-3-isoxazolyl]urea.

4.3 Calculate _IC50 and draw the inhibition curve of the compound:

The IC ₅₀ (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Data analysis was performed using Graphpad 6.0 software.

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×Hill Slope))

X: log value of compound concentration Y: inhibition rate (%inhibition)

5. The experimental results are shown in Table A:

Table A Kinase inhibitory activity of the compounds of the present invention

It can be seen from Table A that the compounds of the present invention have a good inhibitory effect on Ret wt. In addition, the compounds of the present invention also have a good inhibitory effect on RetV804M.

In addition to the activities of the compounds of the present invention in Table A, other compounds of the present invention also have good Ret kinase inhibitory activity.

Test Example 2:

1. Experimental purpose:

The CTG method was used to test the 50% inhibitory concentration (IC ₅₀ ) of the compounds in a series of tumor cells.

2. The experimental reagents and test samples used are as follows:

1) CellTiter-Glo (CTG) (Promega)

2) RPMI medium (Gibco)

3) FBS (fetal bovine serum) (Gibco)

4) DMSO (Sigma)

5) Double antibody (Gibco)

6) 96-well cell culture plate, white wall and opaque bottom (Corning)

7) BAF3 (purchased from Shanghai Mingjin Biotechnology)

8) BAF3-KIF5B-RET-WT (stable cell line, constructed by the Pharmacology Department of Guangdong East Sunshine Pharmaceutical Co., Ltd.)

3. Experimental steps:

1) Cell seeding

Collect BAF3 and BAF3-KIF5B-RET-WT cells in the exponential growth phase and count live cells using a Vi-Cell XR cell counter. Adjust the cell suspension to the corresponding concentration using RPMI complete medium (89% RPMI + 10% FBS + 1% double antibody). Add 90 μL of cell suspension to each well of a 96-well cell culture plate, and the final cell concentrations are 2000 cells/well and cells/well, respectively.

2) Dosing treatment

a Working solution preparation: Dissolve each test compound in DMSO to make a stock solution with a final concentration of 10 mM. Use the stock solution and RPMI complete medium (89% RPMI + 10% FBS + 1% double antibody) to prepare 3X series gradient dilutions, a total of 10 concentrations of working solution, and the final DMSO concentration of each solution is 0.1%.

Adding drugs to b cells: After the cells were incubated overnight, 10ul of working solution corresponding to 10 gradient concentrations were added in sequence and placed in a 37°C, 5% CO2 incubator for 72 hours; at the same time, a negative control without adding compounds and cells was set up.

3) Plate reading test

After 72 hours of drug treatment, according to the CTG operating instructions, 50 μl (1/2 culture volume) of CTG solution that had been melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with a multifunctional microplate reader.

4) Data analysis

The cell viability was calculated using the formula: Vsample/Vvehicle control x100%. Vsample is the reading of the drug-treated group, and Vvehicle control is the average value of the solvent control group. GraphPad Prism 5.0 software was used to draw a S-shaped dose-survival curve using a nonlinear regression model and calculate the IC ₅₀ value. The experimental results are shown in Table B.

Table B In vitro cell activities of the compounds of the present invention

As shown in Table B, the compounds of the present invention also have a good inhibitory effect on BAF3 cells transfected with KIF5B gene.

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of the different embodiments, implementation schemes or examples, without contradiction.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, substitute and vary the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims (13)

1. A compound, which is a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in, X ¹ , X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ or N; Y is O; T is C _1-6 alkylene; Ring G is a 6-12 membered bridged heterocyclic group; q is 0 or 1; ^Ra is D, oxo, methyl, ethyl, propyl, butyl, methoxy or ethoxy; E is a key; Ring A is the following substructure: wherein each Z ^1a and Z ^2a is independently NH; each Z ^3a and Z ^7a is independently CH; Z ^4a is O or NH; each Z ^5a and Z ^6a is independently CH ₂ , O or NH; Each m and t is independently 0, 1 or 2; Each n and t1 is independently 0 or 1; wherein each sub-formula of Ring A is independently optionally substituted with 1 or 2 substituents selected from F, Cl, Br, OH, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl or C _1-4 hydroxyalkyl; Q is -CH ₂ - or -(C=O)-; M is pyridyl, pyrimidinyl, pyrazinyl or phenyl; and M is optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, CN, OH, CF ₃ , CHCl ₂ , CHF ₂ , CH ₂ F, CF ₃ CH ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl or isopropyl; ^R1 is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl; ^R4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy. 2. The compound according to claim 1, wherein T is -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, or -(CH ₂ ) ₆ -. 3. The compound according to claim 1, wherein Ring G is the following substructure: in, each Z ¹ is independently N; and Each Z ² is independently CH ₂ , C═O, NH, O, S, S═(O) or S═(O) ₂ . 4. The compound according to claim 1, wherein Ring G is the following substructure: ^Ra is D, oxo, methyl, ethyl, propyl, butyl, methoxy or ethoxy. 5. The compound according to claim 1, wherein Ring A is the following substructure: wherein each sub-formula of ring A is independently optionally substituted by 1 or 2 substituents selected from F, Cl, Br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl or 2-hydroxyethyl. 6. The compound of claim 1 has a structure of formula (I-1), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the structure of formula (I-1), in, Ring A1 is the following substructure: wherein each Z ^1a and Z ^2a is independently NH; Each sub-formula of Ring A1 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl or C _1-4 hydroxyalkyl. 7. The compound according to claim 6, wherein Ring A1 is a substructure formula: wherein each sub-formula of ring A1 is independently optionally substituted by 1 or 2 substituents selected from F, Cl, Br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl or 2-hydroxyethyl. 8. The compound of claim 1 has a structure of formula (I-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the structure of formula (I-2), wherein each Z ¹ and Z ² is independently N; Z ^3a and Z ^7a are independently CH; Each m and t is independently 0, 1 or 2; Each n and t1 is independently 0 or 1; in Optionally substituted with 1 or 2 substituents selected from F, Cl, Br, OH, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl or C _1-4 hydroxyalkyl. 9. The compound according to claim 8, wherein The substructure is as follows: in Each subformula of is independently optionally substituted with 1 or 2 substituents selected from F, Cl, Br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl or 2-hydroxyethyl. 10. The compound of claim 1 has one of the following structures, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, and a pharmaceutically acceptable adjuvant. 12. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing or treating RET-related diseases. 13. The use according to claim 12, wherein the RET-related disease comprises cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.