WO2012129967A1

WO2012129967A1 - New aminopyridine compounds, the preparation method, the pharmaceutical compositions comprising these compounds and the uses thereof

Info

Publication number: WO2012129967A1
Application number: PCT/CN2012/000412
Authority: WO
Inventors: 柳红; 耿美玉; 罗成; 张登友; 艾菁; 梁中洁; 王英; 蒋华良; 陈凯先
Original assignee: 中国科学院上海药物研究所
Priority date: 2011-03-30
Filing date: 2012-03-29
Publication date: 2012-10-04
Also published as: CN102718745A

Abstract

Compounds of formula I as receptor tyrosine kinase MET inhibitor, enantiomers, diastereomers, racemes and racemic mixture, or pharmaceutical salts, preparation method, pharmaceutical composition comprising these compounds and the uses thereof are provided, which belongs to the field of pharmaceutical chemistry and pharmacotherapy.

Description

FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to receptor tyrosine kinases

Aminopyridine compounds of MET inhibitors, processes for their preparation, pharmaceutical compositions containing such compounds, and uses. BACKGROUND OF THE INVENTION Targeted therapy has undoubtedly had a major impact on cancer treatment. The occurrence, evolution, spread of tumors and the occurrence of tumor blood vessels depend on various signal transduction pathways. Significant progress has been made in targeting these signaling pathways to achieve tumor therapy, and many drugs have been successfully marketed. For example, imatinib, an anticancer drug developed based on ABL tyrosine kinase, has a good effect on chronic myeloid leukemia (CML). In recent years, members of the Met proto-oncogene family have received widespread attention. The Met family includes Met (also known as c-Met) and Ron receptors. The tyrosine protein kinase c-Met is a cellular surface receptor, the hepatocyte growth factor receptor (HGFR), encoded by the Met proto-oncogene. Unlike most other receptor tyrosine kinases, mature Met consists of an extracellular alpha chain (50 kDa) and a transmembrane beta chain (HOkDa, which anchors the intracellular domain of the kinase domain to the cell membrane). The structure of the polymer functions. HGF is a ligand for Met and acts as a multifunctional cytokine that promotes migration, anti-apoptosis and mitogenic effects.

c-Met is highly expressed in most cancers and some sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, neutrophil. Tumor, melanoma, etc. c-Met induces cell proliferation, invasion, migration, inhibition of apoptosis, and promotes angiogenesis by interacting with its ligand HGF/SF or by other pathways to activate tyrosine kinases in the intracellular segment, during tumor development. Play an important role.

In tumors, the aberrant activation mechanisms of c-Met kinase are mainly Met gene amplification, Met gene mutation, c-Met transcriptional level upregulation, ligand-dependent autocrine and paracrine loops. Met gene amplification and consequent protein overexpression and constitutive activation are present in numerous human primary cancers, including Gastric cancer and esophageal cancer, non-small cell lung cancer and medulloblastoma with acquired resistance to EGFR inhibitors. The Met gene can also carry an activating mutation. Various Met germline and somatic mutations are associated with a lower incidence of tumors. The most common Met constitutive activation in human tumors is the upregulation of non-gene amplified Met transcription, resulting in increased protein expression. In addition, HGF itself can activate the transcription of Met, and can also promote the dispersion of cancer cells by positive feedback in a paracrine manner. HGF also aberrantly activates Met in an autocrine form, more common in glioblastoma, breast cancer, rhabdomyosarcoma, and osteosarcoma.

Unlike other kinases, c-Met interacts with other tumor-associated molecules on the cell surface, such as the integrin family, death-related receptors, and other receptor tyrosine kinases, so that cross-linking activates amplifying tumor-related effects, greatly It promotes the development of tumors, in which c-Met plays a pivotal role, and inhibiting it can inhibit the effects of multiple tumor targets.

In particular, it is worth noting that the clinically acquired acquired resistance to EGFR receptor tyrosine kinase inhibitors (EGFR-TKIs) is due to the activation of the ERBB3 signaling pathway by the Met gene. Simultaneous in vitro tests have shown that Iressa can restore efficacy when c-Met is blocked. Therefore, the combination of c-Met inhibitor and EGFR inhibitor can delay the production of acquired resistance of EGFR-TKIs and prolong its clinical service life, which has important clinical significance.

As mentioned earlier, blocking HGF-c-Met signaling can be one of the strategies for anti-tumor therapy. Selective blocking of this pathway not only inhibits tumor growth, but also inhibits tumor metastasis. There are currently three strategies for targeted c-Met inhibitors targeting the HGF-c-Met signaling pathway: bio-antagonists of HGF and c-Met, small molecule inhibitors that inhibit PTK catalytic activity, and HGF and c- Specific antibodies for Met. Most of them are in the preclinical research stage, and a few enter the clinical research stage. For example, Amgen's injectable human monoclonal antibody Rilotumumab is in the second phase of clinical trials, including non-small cell lung cancer, colorectal cancer, prostate cancer, and digestive tract cancer. Pfizer's PF-02341066 small molecule inhibitor has been in clinical phase III.

Since c-Met inhibitors, especially small molecule inhibitors, are mostly in clinical research, they have not yet entered the market, and antibody drugs are often expensive, providing a broad space for the development of such drugs. Therefore, c-Met kinase is a promising target for anti-tumor drug research. Disclosure of the Invention An object of the present invention is to provide an aminopyridine compound represented by the formula, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof. Another object of the present invention is to provide a process for the preparation of a compound of the above formula. It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the above formula or a pharmaceutically acceptable salt thereof.

A further object of the present invention is to provide a compound of the above formula which is useful in the preparation of a cell proliferative disorder associated with the treatment of a tyrosine kinase c-Met signal transduction pathway, such as cancer, hyperplasia, restenosis, immune disorders and inflammation. Use in medicine.

The compounds of the invention are useful for inhibiting tyrosine kinases, particularly the receptor tyrosine kinase Met. The present invention provides a compound of the formula 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof,

among them:

X is -S -, -S(0) ₂ -, -S(0)-, -S0 ₂ N(R ⁵ )-, -CO- or -CON(R ⁵ )-;

m is 0 or 1;

R ¹ is a substituted or saturated or unsaturated C3-C12 heterocyclic group, substituted or unsubstituted

C6-C10 aryl,

The heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;

The substituted saturated or unsaturated C3-C12 heterocyclic group in R ¹ or the substituted C6-C10 aryl group includes 1 to 5 substituents, and the substituent is halogen, C1-C12 straight Chain or branched alkyl, C2-C12 linear or branched unsaturated hydrocarbon, C3-C12 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy a group, a carboxyl group, a fluorenyl group, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ ) R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ , -OR ₃ COR ⁶ , -CON (Ri)R ₃ R ⁶ ,

-R ₃ CONR ⁶ R ⁷ , -COR ₃ OH, phenyl, substituted phenyl, naphthyl, biphenyl or substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic; wherein said substitution The phenyl group includes 1 to 5 substituents, each of which is independently a halogen, a C1-C12 linear or branched alkyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, and a C3-C12 cyclic hydrocarbon group. , saturated or unsaturated C3-C12 heterocyclyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -coN(R ⁶ )R ₃ NR ⁸ R ⁹ , -SO ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R6)R ₃ COR ⁸ ,

NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ )R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ _; the substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group contains 1-4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and substituted or unsubstituted The saturated or unsaturated C3-C12 heterocyclic group contains one or more alkyl groups selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated hydrocarbon groups, C3-C12 cyclic hydrocarbon groups. , saturated or unsaturated C3-C12 heterocyclyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, -R ₃ R ⁶ , -SOR ⁶ - -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CONR ⁶ R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ )R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ Substituents in S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ ;

R ² is hydrogen, cyano, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched alkyl, C2-C6 straight a chain or branched unsaturated hydrocarbon group, a C1-C6 straight or branched alkoxy group, a C1-C6 straight or branched alkanoyl group or a C1-C6 straight or branched alkylamino group;

RR ² can be connected to each other to form a ring;

R ³ and R ⁴ are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched alkane a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched alkoxy group, a C3-C12 cyclic hydrocarbon group, a C1-C6 straight or branched alkanoyl group, a C1-C6 straight A chain or branched alkylamino group.

R ³ and R ⁴ may be joined to form a ring;

R ¹⁵ is hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight or branched unsaturated hydrocarbon, nitrile, nitro, amino, hydroxy, trifluoromethyl, trifluoromethyl Oxy, carboxyl, fluorenyl, -S(0) ₂ Ri, -R ₃ OH, -R ₃ R ₄ , -R ₃ NRiR ₂ , -R ₃ R ₅ -R ₃ CONRiR ₂ , -CONRiR ₂ , -COR ₃ OH, a substituted or unsubstituted 5- or 6-membered heterocyclic group containing at least one hetero atom selected from the group consisting of N, O and S, the substituent being a halogen, a C1 to C6 straight or branched alkyl group, Nitrile group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group, -8(0) ₂ 1 ₁ or -(^€^1 ₁ 1 _{2 ;} ^ is a substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl group containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

The substituent in the ^ is halogen, C1-C12 linear or branched alkyl, C2-C12 linear or branched unsaturated hydrocarbon, C3-C12 cycloalkyl, cyano, nitro, amino, hydroxy , hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, fluorenyl, -OR ₃ R ⁶ , -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ ,

-S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CONR ⁶ R ⁷ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ ) R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )- , -N(R ⁶ )R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ , phenyl, substituted phenyl, naphthyl, biphenyl, substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic; wherein said substitution The phenyl group includes 1 to 5 substituents, each of which is independently a halogen, a C1-C12 linear or branched alkyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, and a C3-C12 cyclic hydrocarbon group. , C3-C12 saturated or unsaturated heterocyclic group, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , R ⁶ N(R ⁷ )CON(R ⁸ )-, -N(R ⁶ )R ₃ S0 ₂ R ⁸ , R ⁷ N (R ⁶ )R ₃ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , - SR ⁶ , -OR ⁶ ,

-OR ₃ NR ⁷ R ⁸ _; the substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, and substituted saturated or unsaturated The C3-C12 heterocyclic group contains one or more alkyl groups selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated hydrocarbon groups, C3-C12 cyclic hydrocarbon groups, heterocycloalkenyl groups , C3-C12 saturated or unsaturated heterocyclic group, cyano group, nitro group, amino group, hydroxy group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group,

-SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ - -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , R ⁶ N(R ⁷ )CON(R ⁸ )-, -N(R ⁶ )R ₃ S0 a substituent in ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ and -OR ₃ NR ⁷ R ⁸ ;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ are each independently hydrogen, halogen, C1-C12 straight or branched alkyl, C2-C12 straight or branched unsaturated hydrocarbon, C3-C12 Cycloalkyl, C1-C6 alkoxy, C1-C6 acyl, C6-C12 aryl, substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclyl; substituted or unsubstituted saturated or unsaturated The C3-C12 heterocyclic group contains 1-4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted C3-C12 heterocyclic group contains one or more alkane selected from halogen, C1-C12 straight or branched chain. a C2-C12 linear or branched unsaturated hydrocarbon group, a C1-C6 alkoxy group, a C3-C12 cycloalkyl group, a saturated or unsaturated C3-C12 heterocyclic group, a cyano group, a nitro group, an amino group, a hydroxyl group, Hydroxyl a substituent in a methyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a fluorenyl group, -R ₃ OH, and -SO^; any two of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ When attached to the same nitrogen atom, a ring may be formed with the attached nitrogen atom; any two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are bonded to the same carbon atom to form a ring;

And R ₂ are each independently hydrogen or a C1 to C6 alkyl group; and R ₃ is a C1 to C6 alkylene group. Further, in a preferred embodiment of the compound of the formula I of the present invention, wherein m is 0 or 1; X is selected from -S -, -S(0) ₂ N(R ⁵ )- or -CON(R ⁵ )-; R ¹ is:

Wherein 11 is, N or O; Z is C or N; Q is N or O;

R ¹⁰ , R ^u , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 ~C6 linear or branched unsaturated hydrocarbon group, nitrile group, nitro group, amino group, hydroxyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group, -8(0) ₂ , -R ₃ OH, - R ₃ R ₄ , -R ₃ NRiR ₂ , -R3R5 , -R3CONR1R2, -CONR1R2, -COR ₃ OH, substituted or unsubstituted 5 or 6 member containing at least one hetero atom selected from N, 0, S a heterocyclic group, wherein the substituent is a halogen, a C1 to C6 linear or branched alkyl group, a nitrile group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group,巯 base, -SDR^ -CONR!R ₂ ;

Ri, R ₂ are each independently hydrogen, C1 to C6 alkyl;

R ₃ is a C1 to C6 alkylene group;

R ₄ is a substituted or unsubstituted 5- or 6-membered heterocyclic group containing at least one hetero atom selected from N, O, S, which is a halogen, a C1 to C6 straight or branched alkyl group. , nitrile group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group, -SD^R^-CONR!R _2;

R ₅ is a phenyl group substituted by 1 to 5 halogen atoms, and the halogen is fluorine, chlorine, bromine or iodine. In a further preferred embodiment of the compound I, wherein m is 0 or 1; X number

Selected from -S -, -S0 ₂ N(R ⁵ )- or -CON(R ⁵ )-;

Wherein R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are each independently hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight or branched unsaturated hydrocarbon, a nitrile group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a decyl group, -0, -OR ₃ R ₄ ; the halogen is fluorine, chlorine, bromine or iodine;

Further preferred is selected from the following structural fragments:

The definitions of R ⁵ , R ₃ and R ₄ are the same as defined above.

In a more preferred embodiment of the invention, the compound of formula I of the invention is preferably a specific compound as follows:

Chinese name structure

2-amino-N-[ l-(3-fluoro-2,6-dichlorobenzene

DC295-42 yl)ethyl]-5-(2-oxo-2,3-dihydro

-1H-吲哚-5-yl)pyridine-3-carboxamide

2-amino-N-[ l-(3-fluoro-2,6-dichlorobenzene

Ethyl] -5-{4-[2-(morpholine-4-

DC295-43

Yl) - ² - oxo-ethoxy] phenyl} pyridine

-3-carboxamide

2-amino-N-[ l-(3-fluoro-2,6-dichlorobenzene

DC295-44 yl)ethyl] -5-(pyrimidin-5-yl)pyridine-3-carboxamide

2-amino-N-[ l-(3-fluoro-2,6-dichlorobenzene

DC295-45 yl)ethyl]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridine -3-sulfonamide

N-methyl-N-(3-chloro-4-fluorophenyl)-2-

DC295-46 n ' ^N , ^^^ci

Amino-5-[1-(piperidin-4-yl)-1H-pyridyl

Zin-4-yl]pyridine-3-sulfonamide NH ₂

CI

2-amino-N-methyl-N-(3-chlorobenzene

DC295-47 base)—5—( 1 methyl 1 H-pyrazol-4-yl), ^^ pyridine-3-sulfonamide N NH ₂

CI

N-methyl- _N- (3-chlorophenyl)-2-amino group

DC295-48 -5- { [ 1 -(piperidin-4-yl)- 1 H-pyrazole-4-^^yl]phenyl}pyridine-3-sulfonamide N NH ₂

N-methyl- _N- (3-chlorophenyl)-2-amino group

DC295-49 -5- {4-[2-oxo-2-(piperazin-4-yl)B

Oxy]phenyl}pyridine-3-sulfonamide

The compounds of the invention may have asymmetric centers, chiral axes and chiral planes and may exist in the form of enantiomers, diastereomers, racemates, and mixtures thereof.

The present invention provides pharmaceutically acceptable salts of the compounds of the formula, in particular, the compounds of the formula are reacted with inorganic or organic acids to form conventional non-toxic salts. For example, conventional non-toxic salts can be prepared by reacting a compound of the formula with an inorganic or organic acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, and the like, and the organic acid. Including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, Fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid , 2-acetoxybenzoic acid and isethionate; or a compound of the formula ω with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid a sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt formed by forming an ester with aspartic acid or glutamic acid; or a methylamine salt or an ethylamine salt formed by the compound of the formula and an organic base; Ethanolamine salt; or a compound of the formula ω Lysine, arginine, ornithine ester and then with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfur a corresponding inorganic acid salt formed by an acid, nitric acid or phosphoric acid or a corresponding organic acid salt formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.

The present invention provides a process for the preparation of a compound of the formula, which process comprises the following steps, comprising:

Step a: Dissolving the 2-nitro-3-hydroxypyridine derivative in a solvent, adding a base to stir, and then adding hydrazine, hydrazine-dimethylthioformyl chloride, stirring at room temperature or stirring under heating to obtain a compound I _a The solvent is tetrahydrofuran, dimethylformamide, dioxane; preferably dimethylformamide; the base is pyridine, triethylamine, triethylenediamine (DABCO:), diisopropyl Amine, sodium hydride, potassium hydride; preferably triethylenediamine.

Step b: Disperse I _a in diphenyl ether and heat to reflux to give compound I _b .

Step c: Under ice bath, add acylating reagent, drop

Complete, stir at room temperature,

Obtaining compound I _{e ;} or obtaining compound I _c , the solvent is dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, ethylene glycol dimethyl ether or dioxane; the acylating reagent is benzenesulfonate Acyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride or naphthalenesulfonyl chloride;

Step d: The compound I _b and a suitable base are dispersed in a solvent, stirred at -10 to 40 ° C for a while, the solvent is distilled off, and 1 is added. The solution is stirred at room temperature to obtain a compound I _d , the solvent is a mixed solvent of water, methanol and tetrahydrofuran; the base is preferably potassium hydroxide;

Step e: the compound I _d is reduced with an iron powder and subjected to an acid to obtain a compound I _{e ;} the acid is hydrochloric acid or acetic acid;

Step f: bromination of compound I _e with a brominating reagent to obtain compound I _f , the brominating reagent is N-bromosuccinimide or bromine;

Step g: catalytically coupling the compound If with a boronic acid ester or boric acid under a palladium catalyst to obtain a final product;

Scenario 2

Ih

Step h: Substituting Y in compound I _e with a nitrogen-containing group W to give compound I _g which is iodine, bromine, chlorine, alkyl ester, aryl ester, alkyl sulfonyl ester or aromatic a sulfonyl ester; the w is a phthalimide group, an azide, a succinimide or a phthalimide;

Step i: reducing, hydrolyzing or hydrogenolyzing compound Ig to obtain compound I _{h ;}

Step j: The 2-amino-5-bromopyridine derivative is added to chlorosulfonic acid in portions at -10 to 0 ° C, and reacted at 140 to 180 ° C to obtain a compound I _{i ;}

Step k: The compound I _h and Ii are dissolved in a solvent to obtain a compound Ij under the action of a base, which is, but not limited to, dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, ethylene glycol Methyl ether or dioxane; the base is pyridine, triethylamine, triethylenediamine (DABCO) or diisopropylethylamine;

Step 1: Perform the same reaction as step g;

Option 3

Step m: 2-aminonicotinic acid derivative is brominated to obtain compound I _{k ;} the brominating reagent is N-bromosuccinimide or bromine;

Step n: neutralizing compound I _k and I _h to obtain compound Ii;

Step 0: Perform the same reaction as step g;

Option 4

Step p:

Compound I was obtained. Step q: performing the same reaction as step k;

Step r: The same reaction as in step g is carried out. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the above formula (I:) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may further contain an odorant, a fragrance, and the like.

The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1 to 99%, preferably in a ratio of 65 wt% to 99 wt% of the total weight of the compound of the formula (I) as an active ingredient, and the balance being pharmaceutically acceptable. An acceptable carrier, diluent or solution or salt solution.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be presented in suitable solid or liquid carriers or diluents. Neutralizes a suitable sterilizing device for injection or drip.

Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts. The formulation of the formulation comprises 0.05 to 200 mg of the compound of the formula (I). Preferably, the formulation of the formulation comprises 0.1 mg to 100 mg of the compound of the formula (I).

The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered by the oral, nasal, cutaneous, pulmonary, or gastrointestinal tract routes. Most preferably oral. The most preferred daily dose is 0.01 to 200 mg/kg body weight, taken once, or 0.01 to 100 mg/kg body weight. Regardless of the method of administration, the optimal dosage for the individual should be based on the particular treatment. It is usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.

Further, the inventors have found through experiments that the compound of the general formula (I) can be used to modulate receptor tyrosine kinase activity, particularly a member of the receptor tyrosine kinase Met subfamily. The regulation described in the present invention is to increase or decrease the activity of Met kinase. In one embodiment, the compounds of the invention inhibit the activity of Met kinase.

The compounds and compositions of the invention are useful in the treatment and prevention of cancer, hyperplasia, restenosis, immune disorders and inflammation, including, but not limited to, histiocytic lymphoma, ovarian cancer, head and neck squamous cell carcinoma, Gastric cancer, breast cancer, childhood hepatocellular carcinoma, colorectal cancer, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, pancreatic cancer, glioblastoma, prostate cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma , thyroid cancer, testicular cancer, cervical cancer, lung adenocarcinoma, colon cancer, papillary renal cell carcinoma, glioblastoma, endometrial cancer, esophageal cancer, leukemia, renal cell carcinoma, bladder cancer, liver cancer and star Cell tumors and the like; more preferably used for the treatment of cancers such as head and neck squamous cell carcinoma, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, Gastric cancer, colon cancer, multiple myeloma, and glioblastoma. The compounds and compositions of the present invention are useful for treating, preventing or regulating metastatic tumors of cancer cells and cancer, in particular for preventing or regulating ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinoma, gastric cancer, breast Metastatic tumors of cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastoma, and sarcoma.

detailed description

The invention will be further illustrated in the following examples. These examples are only intended to illustrate the invention, but are not intended to limit the invention in any way.

The starting materials used in the present invention are commercially available unless otherwise specified.

Some of the abbreviations used in the flowcharts and examples are defined as follows:

DMF dimethylformamide

Et ₃ N triethylamine

DABCO triethylene diamine

DMAP to dimethylaminopyridine

MsCl methanesulfonyl chloride

THF tetrachlorofuran

NBS bromosuccinimide

DME ethylene glycol dimethyl ether

EA ethyl acetate

Pd(dppf)Cl ₂ Ι, Γ-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane complex

ΤΒΑΙ tetra-n-butylammonium iodide

EDCI Ν-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HATU 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate

DIPEA Ν, Ν-diisopropylethylamine

HPLC high performance liquid chromatography

DCC dicyclohexylcarbimide

Flow chart 1

Example 1

Step 1: Preparation of hydrazine, hydrazine-dimethyl-l-[(2-nitropyridine-3)-oxy]thiocarboxamide

2-Nitro-3-hydroxypyridine (10.00 g, 71.38 mmol), hydrazine, hydrazine-dimethylaminothiocarbamoyl chloride (10.59 g, 85.66 mmol) was dissolved in 50 mL of DMF, and DABCO (triethylene) was added. Diamine) ( 9.61 g, 85.66 mmol), stirred at room temperature for 24 h, then 150 mL of water was added to the reaction mixture, and extracted with ethyl acetate 600 mL. The organic phase was washed successively with 3×100 mL water and saturated brine. dried over Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure to give a yellow solid. Used directly in the next step without purification. ^ NMR (400 MHz, CDC1 ₃ ) δ 8.47 (dd, J = 2.4, 4.4 Hz, 1H), 7.77 (dd, J = 2.4, 8.0 Hz, 1H), 7.70 (dd, J= 4.4, 8.0 Hz, 1H ), 3.45 (s, 3 ), 3.40 (s, 3H).

Step 2: Preparation of hydrazine, hydrazine-dimethyl-l-[(2-nitropyridine-3)-thio]carboxamide (1)

The crude hydrazine obtained from the upper hydrazine, Ν-dimethyl-1-[(2-nitropyridine-3)-oxy]thiocarboxamide was dispersed in 150 mL of Ph ₂ O under argon protection at 160 The mixture was reacted for 3 h, cooled, purified by column chromatography (EtOAc/EtOAc/EtOAc/EtOAc/EtOAc. : 60%). ^ NMR (300 MHz, CDC1 ₃ ) δ 8.53 (dd, J = 1.8, 4.8 Hz, 1H), 8.18 (dd, J = 1.8, 8.1 Hz, 1H), 7.60 (dd, J = 4.8, 8.1 Hz, 1H ), 3.12 (s, 3H), 3.04 (s, 3H).

Flow chart 2

Example 2

Step 1: Preparation of l-(3-fluoro-2,6-dichlorophenyl)ethanol

1-(3-Fluoro-2,6-dichlorophenyl)ethanone (20.00 g, 96.60 mmol) was dissolved in 100 mL of MeOH and NaB3⁄4 ( 7.31 g, 193.21 mmol) , water was added to the reaction mixture 20 mL, and the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate 150 mL, organic phase was washed with saturated brine, dried over anhydrous Na ₂ S0 _4, filtered, and evaporated under reduced pressure Solvent, a colorless transparent oily liquid. Used directly in the next step without purification. Step ^2: Preparation of l- (3- fluoro - ^2, 6-dichlorophenyl) methanesulfonyl ester ⁽²⁾

Ho the resulting 1- (3-fluoro-2,6-dichlorophenyl) ethanol The crude product was dissolved in 150 mL C¾Cl ₂ was added a catalytic amount of Et _{3 N (13.43 mL, 96.60 mmol} ) DMAP, cooled to 0 ° C, dropwise addition of MsCl ( 7.48 mL, 96.60 mmol), maintaining 0 ° C lh, 30 mL of water was added, the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, evaporated The product was separated and purified by flash column chromatography (EtOAc/EtOAcEtOAcEtOAc. ^l H NMR (300 MHz, CDC1 ₃ ) δ 7.34 (dd, J = 4.5, 9.0 Hz, 1H), 7.70 (dd, J = 7.8, 9.0 Hz, 1H), 6.46 (q, J = 6.6 Hz, 1H) , 2.91 (s, 3H), 1.84 (d, J = 6.6 Hz, 3H).

Flow chart 3

Example 3

Step 1: Preparation of 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 2-nitropyridine

Ν,Ν-dimethyl-1-[(2-nitropyridine-3)-thio]carboxamide (10.00 g, 44.01 mmol), KOH (5.43 g, 96.81 mmol) was placed in a 250 mL eggplant flask Under argon protection, place the flask in an ice water bath, add MeOH/THF/3⁄40 (2/2/1, v/v/v) 100 mL with a syringe, add, remove the ice water bath, stir at room temperature, wait When TLC is used to detect the absence of hydrazine, Ν-dimethyl-1-[(2-nitropyridine-3)-thio]formamide, the organic solvent is distilled off under reduced pressure, and under the protection of argon, a syringe is added. -(3-Fluoro-2,6-dichlorophenyl)methanesulfonylethyl ester (12.64g, 44.01mmol) in THF (120mL), stirred at room temperature for 24h, then the organic solvent was evaporated under reduced pressure. ester 300 mL. The organic phase washed with water 3x40 mL, washed with saturated aqueous sodium chloride solution and dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure. Used directly in the next step without purification. iH NMR pOO MHz, CDCl ₃ ) 5 8.36 (d, J = 3.9 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.46 (m, 1H), 7.33-7.26 (m, 1H), 7.08 -7.03 (m, 1H) 5.33-5.24 (m, 1H), 1.88-1.85 (m, 3H).

Step 2: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine-2-amine

The crude 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 2-nitropyridine obtained from the upper hydrazine was dissolved in 150 mL of EtOH, and reduced iron powder ( 12.06 g, 216.02 mmol ), 1 M HC1 10 mL, gradually warmed to 80 ° C, refluxed for 8 h, filtered, evaporated under reduced pressure, and the residue was extracted with CH ₂ C1 ₂ The organic phase was washed with saturated brine, dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure, the obtained crude product was recrystallized from petroleum ether / ethyl acetate (4/1, v / v), the remaining part separated by flash Column chromatography (petroleum ether/ethyl acetate 6/1, v/v) was isolated and purified to afford 6.6 g of white solid. (Total yield of two mites: 47.28%). ^l R NMR (400 MHz, CDC1 ₃ ) δ 8.01 (d, J = 4.8 Hz, 1H), 7.42 (m, 1H), 7.46 (m, 1H), 7.29-7.26 (m, 0.5H), 7.17 (dd , J = 5.2, 8.8 Hz, 0.5H), 7.01-6.97 (m, 1H), 6.53-6.49 (m, 1H), 5.17 (br, 2H), 5.04-4.97 (m, 1H), 1.84-1.81 ( m, 3H).

Step 3: Preparation of 5-bromo-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine (3) 3-{[1-( 3-Fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine (4.00 g, 12.61 mmol) dissolved in 100 mL CH ₂ C1 ₂ , cooled to -10 ° C, dropwise NBS ( 2.24g, 12.61 mmol) of CH ₂ C1 ₂ solution 100 mL or CH ₃ CN 20 mL solution, after completion, the organic solvent was evaporated under reduced pressure in CH ₂ C1 ₂ , petroleum ether / ethyl acetate (4/1 , v/v ), recrystallization, the residue was purified by flash column chromatography ( petroleum ether / ethyl acetate 8/1, v/v) to give white solid 4.89 g, yield 97.9%. ^ NMR pOO MHz, CDC1 ₃ ) δ 8.05-8.04 (m, 1H), 7.52 (dd, J = 2.4, 5.4 Hz, 1H), 7.32-7.26 (m, 0.5H), 7.21 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.05-6.99 (m, 1H), 5.18 (br, 2H), 5.07-4.98 (m, 1H), 1.84 (dd, J= 2.7, 7.2 Hz, 3H).

Flow

Example 4

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(l-methyl-1Η-pyrazol-4-yl)pyridin-2-amine (DC295-4)

5-Bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine (80 mg, 0.20 mmol), 1 in a microwave reactor -methyl-4-pyrazoleboronic acid pinacol ester (50.43 mg, 0.24 mmol), potassium fluoride dihydrate (57.03 mg, 0.61 mmol), tetrakistriphenylphosphine palladium (10.42 mg, 0.01 mmol) dispersed in 3 In the DME/H ₂ 0/EtOH (7/3/2, v/v/v), the microwave was heated at 110 ° C for 50 min, extracted with ethyl acetate, and the organic phase was washed with saturated brine. _dried S0 _4, filtered, and the solvent was distilled off under reduced pressure, purification by preparative TLC _{(C¾Cl 2 / MeOH 50/1, v} / v), to give a pale yellow solid 50 mg, yield 62 · 3%. NMR (300 MHz, CDC1 ₃ ) δ 8.14 (d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 7.51 (dd, J= 2.4, 3.6 Hz, 1H), 7.45 (s, 1H), 7.32-7.27 (m, 0.5H), 7.17 (dd, J= 4.8 8.7 Hz, 0.5H), 7.01-6.96 (m , 1H), 5.23 (s, 2H), 5.09-5.00 (m, 1H), 3.93 (s, 3H) 1.86-1.83 (m, 3H).

5

Example 5

Step 1: Preparation of 4-(methanesulfonyloxy)piperazine-1-carboxylic acid tert-butyl ester

4- (methane) was prepared in the same manner as in Example 1 except that tert-butyl 4-hydroxypiperazine-1-carboxylate was replaced with 1-(3-fluoro-2,6-dichlorophenyl:)ethanol. Tert-butyl sulfonyloxy)piperazine-1-carboxylate.

Step 2: Preparation of 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester

4-Bromo-1H-pyrazole (2.63 g, 17.90 mmol) was dissolved in 40 mL of DMF and placed in an ice bath. The mass fraction of 60% sodium hydride (787.49 mg, 19.69 mmol) was added in portions. After stirring for lh, 4-(methanesulfonyloxy)piperazine-1-carboxylic acid tert-butyl ester (5.00 g, 17.90 mmol) was added, the mixture was warmed to 100 ° C, stirred overnight, cooled to room temperature, and added to the reaction mixture. 100 mL of 3⁄4O, EA extraction (3 <200 mL), the organic layer was combined, washed with 3⁄40 (3×50 mL), 100 mL of saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. Column chromatography (petroleum ether/ethyl acetate 10/1-5/1, v/v) was isolated and purified to yield white solid 4.3 g, yield 72.77% ^. R NMR (300 MHz, CDC1 ₃ ) δ 7.46 (s, 1 Η ), 7.43 (s, 1H), 4.28-4.18 (m, 3H), 2.92-2.83 (m, 2H), 2.12-2.08 (m, 2H), 1.94-1.80 (m, 2H), 1.47 (s, 9H ).

Step 3: Preparation of N-tert-Butoxycarbonyl-4-pyrazoleboronic acid pinacol ester 4-(4-Bromo-1Η-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 6.06 mmol), bis-pinacol-diborane (1.85 g, 7.27 mmol) Potassium acetate (1.78 g, 17.17 mmol), Pd(dppf)Cl ₂ (247 mg, 0.303 mmol), dispersed in 15 mL of DMF, placed under an argon atmosphere, placed in an oil bath at 80 ° C, and allowed to react overnight. After cooling to room temperature, 45 mL of H ₂ 0 was added to the reaction solution, and EA was extracted (3×100 mL). The organic layer was combined and washed with 3⁄40 (3×50 mL), 100 mL of saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ The mixture was filtered, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjj ^l R NMR (300 MHz, CDC1 ₃ ) δ 7.79 (s, 1H), 7.73 (s, 1H), 4.32-4.23 (m, 3H), 2.92-2.84 (m, 2H), 2.15-2.10 (m, 2H) ), 1.96-1.82 (m, 2H), 1.47 (s, 9H), 1.32 (s, 12H).

Step 4: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[l-(N-tert-butoxycarbonylpiperidin-4-yl)- 1 H-pyrazol-4-yl]pyridin-2-amine

The reaction was carried out in the same manner as in Example 4 except that N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester. Preparative HPLC separation. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.14-8.12 (m, 1H), 7.56 (s, 1H), 7.51-7.49 (m, 2H), 7.32-7.26 (m, 0.5H), 7.17 (dd, J = 4.8, 9.0 Hz, 0.5H), 7.02-6.96 (m, 1H), 5.19 (s,

2H), 5.09-5.01 (m, 1H), 4.31-4.23 (m, 3H), 2.93-2.86 (m, 2H), 2.12-2.18 (m, 2H), 1.90-1.99 (m, 2H), 1.86- 1.83 (m, 3H), 1.48 (s, 9H).

Step 5: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-1Η-pyrazole- 4-yl]pyridin-2-amine (DC295-5)

3-{[1-(3-Fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[1-(indolyl-tert-butoxycarbonylpiperidin-4-yl)-1H -pyrazol-4-yl]pyridin-2-amine (20.00 mg, 0.035 mmol) was dissolved in 2 mL of CH ₂ C1 ₂ , then added dropwise toluene (0.5 mL) and stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness. ₂ / MeOH (10 / l, v / v) dissolved, washed with saturated sodium bicarbonate solution, the aqueous phase was extracted with C3⁄4C1 ₂ , the organic layer was combined, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated , a white solid was obtained with a yield of 80%. ^ NMR (400 MHz, CDCI3) δ 8.15-8.14 (m, 1H), 7.57 (s, 1H), 7.52 (s, 1H), 7.50-7.49 (m, 1H),

7.30 (dd, J = 4.8, 8.8 Hz, 0.5H), 7.18 (dd, J = 4.8, 8.8 Hz, 0.5H), 7.03-6.98 (m, 1H), 5.13 (s, 2H), 5.08-5.02 ( m, 1H), 4.31-4.24 (m, 1H), 3.36-3.32 (m, 2H), 2.90-2.83 (m, 2H), 2.25-2.22 (m, 2H), 2.06-1.97 (m, 2H), 1.86-1.83 (m, 3H).

Example ό

Preparation (R)-3-{[l-(3-Fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-l-pyrazole

4-yl]pyridin-2-amine (DC295-5-A) Flow chart 6

Step 1: Preparation of (S)-l-(3-fluoro-2,6-dichlorophenyl)ethanol

1-(3-Fluoro-2,6-dichlorophenyl)ethanol (24 g, 114.81 mmol), Boc-L-valine (16.06 g, 74.63 mmol) was dispersed in 300 mL of 1,2-dichloro In ethane, cooled to 0 ° C, EDCI (17.61 g, 91.85 mmol), DMAP (1.68 g, 13.78 mmol) were added successively, maintained at 0 ° C, and allowed to react overnight. 100 m water was added to the reaction mixture to collect organic layers. , the organic layer is washed with saturated NaCl solution, anhydrous

Dried over Na ₂ S0 _4, filtered, and the solvent was distilled off under reduced pressure, a white solid was isolated to give 7 g was purified by column chromatography (petroleum ether / ethyl acetate 100 / 1-50 / 1, v / v), yield 58%. Ee% >99%.

Step 2: Preparation of (S)- l-(3-fluoro-2,6-dichlorophenyl)methanesulfonylethyl ester

The same as in Example 2 except that 1-(3-fluoro-2,6-dichlorophenyl)ethanol was replaced with (S)-l-(3-fluoro-2,6-dichlorophenyl)ethanol. The way to react.

Step 3: Preparation of (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 2-nitropyridine except (S)-1-(3-fluoro -2,6-dichlorophenyl:) methanesulfonylethyl ester was replaced by 1-(3-fluoro-2,6-dichlorophenyl:)methanesulfonylethyl ester in the same manner as in Example 3. Carry out the reaction.

Step 4: Preparation of (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine Replaced with (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-2-nitropyridine

The reaction was carried out in the same manner as in Example 3 except for 3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio 2-nitropyridine.

Step 5: Preparation of (R)-5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine in addition to (R)-3 -{[l-(3-Fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine replaces 3-{[1-(3-fluoro-2,6-dichlorophenyl) The reaction was carried out in the same manner as in Example 3 except for ethyl]thio}pyridin-2-amine.

Step 6: Preparation of (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[1-(indolyl-tert-butoxycarbonylpiperidine-4 -yl)-1H-pyrazol-4-yl]pyridin-2-amine

In addition to replacing 5-bromo with (R)-5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine-2-amine

The reaction was carried out in the same manner as in Example 5 except for -3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio}pyridine-2-amine.

Step 7: Preparation of (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[1-(piperidin-4-yl)-1H-pyridyl Zin-4-yl]pyridin-2-amine

In addition to (R)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[1-(indolyl-tert-butoxycarbonylpiperidin-4-yl) -1H-pyrazol-4-yl]pyridin-2-amine replaces 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio _5- [l-( _N- The reaction was carried out in the same manner as in Example 5 except that tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. Ifi NMR (400 MHz, CDC1 ₃ ) δ 8.15-8.14 (m, 1Η), 7.57 (s, 1H), 7.52 (s, 1H), 7.51-7.50 (m, 1H), 7.30 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.18 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.02-6.98 (m, 1H), 5.16 (s, 2H), 5.09-5.02 (m,

1H), 4.26-4.19 (m, 1H), 3.29-3.26 (m, 2H), 2.83-2.76 (m, 2H), 2.19-2.14 (m, 2H), 1.98-1.88 (m, 2H), 1.86- 1.83 (m, 3H).

Example 7

Preparation of (S)-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[l-(piperidin-4-yl)-l-pyrazole-4 -yl]pyridin-2-amine (DC295-5-

The compound DC295-5 obtained in Example 5 was isolated by preparative HPLC. Separation conditions: Chiralpak l A chiral column (10 x 250 mm); flow rate: 6 mL/min; eluent: ethanol/n-hexane = 87/13 ^ NMR (400 MHz, CDC1 ₃ ) δ 8.15-8.14 (m, 1 Η ), 7.57 (s, 1H), 7.52 (s, 1H), 7.51-7.50 (m, 1H), 7.30 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.18 (dd, J= 4.8, 8.8 Hz , 0.5H), 7.02-6.98 (m, 1H), 5.15 (s, 2H), 5.09-5.02 (m, 1H), 4.26-4.20 (m, 1H),

3.29-3.26 (m, 2H), 2.83-2.76 (m, 2H), 2.20-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.86-1.83 (m, 3H).

Example 8

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-1H-pyrazol-3-yl Pyridine-2-amine (DC295-6)

Compound DC295- was prepared in the same manner as in Example 5 except that N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester was replaced with N-tert-butoxycarbonyl-3-pyrazoleboronic acid pinacol ester. 6. MS (ESI, m/z): 466.1 [M+H] ⁺ .

Example 9

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-1H-imidazol-3-yl] Pyridin-2-amine (DC295-7)

Compound DC295-7 was prepared in the same manner as in Example 5 except that N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester was replaced with N-tert-butoxycarbonyl-4-imidazolium boronic acid pinacol ester. . MS (ESI, m/z): 466.0 [M+H] ⁺ .

Example 10

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-1H-pyrazol-4-yl Pyridine-2-amine (DC295-8)

In addition to replacing 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine with 5-bromo-3-{[1-( Compound DC295-8 was prepared in the same manner as in Example 5 except for 2,3-difluoro-6-chlorophenyl:)ethyl]thio}pyridin-2-amine. MS (ESI, m/z): 450.1 [M+H] ⁺ .

Example 11

Preparation of 3-{[l-(3,5-difluoro-2-chlorophenyl)ethyl]thio}-5-[l-(piperidin-4-yl)-1H-pyrazol-4-yl Pyridine-2-amine (DC295-9)

In addition to replacing 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine with 5-bromo-3-{[1-( Compound DC295-9 was prepared in the same manner as in Example 5 except for 3,5-difluoro-2-chlorophenyl)ethyl]thio}pyridin-2-amine. MS (ESI, m/z): 450.1 [M+H] ⁺ . Example 12

Preparation of 3-{[1-(3,5-difluoro-2,6-dichlorophenyl)ethyl]thio 5-[1-(piperidin-4-yl)-1Η-pyrazole-4- Pyridine-2-amine (DC295-10)

In addition to replacing 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine with 5-bromo-3-{[1-( Compound DC295-10 was prepared in the same manner as in Example 5 except for 3,5-difluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine. MS (ESI, m/z): 484.0 [M+H] ⁺ .

Example 13

Preparation of 3-{[l-(2,3-difluorophenyl)ethyl]thio 5-[l-(piperidin-4-yl)-l-pyrazol-4-yl]pyridin-2-amine (DC295-11)

In addition to 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine-2-amine was replaced by 5-bromo

Compound DC295-11 was prepared in the same manner as in Example 5 except for -3-{[1-(2,3-difluorophenyl:)ethyl]thio}pyridin-2-amine. MS (ESI, m/z): 416.1 [M+H] ⁺ .

Example 14

Preparation of 3-(l-{2,3-difluoro-4-[(2-morpholin-4-yl)ethoxy]phenyl}ethylthio)-5-[1-(piperidin-4- -1H-pyrazol-4-yl]pyridin-2-amine (DC295-12)

In addition to replacing 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine with 5-bromo-3-(1-{2 Compound DC295-12 was prepared in the same manner as in Example 5 except that 3-difluoro-4-[(2-morpholin-4-yl)ethoxy]phenyl}ethylthiopyridin-2-amine. MS (ESI, m/z): 545.2 [M+H] ⁺ .

Flow chart 6

Example 15

Step 1: Preparation of 2-(4-bromo-1Η-pyrazol-1-yl)ethanol 4-Bromo-1H-pyrazole (1.00 g, 6.80 mmol), bromoethanol (0.53 mL, 7.48 mmol), cesium carbonate (2.66 g, 8.16 mmol), TBAI (tetra-n-butylammonium iodide) (502.63 mg , 1.36 mmol) , dispersed in 20 mL DMF, placed in a 90 ° C oil bath, reacted for 2 h, cooled to room temperature, added 60 mL H ₂ 0 to the reaction solution, extracted with EA (3 x 100 mL), combined The organic layer was washed successively with 3⁄40 (3×50 mL), 60 mL of saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. 3, v / v:) isolated and purified to light yellow oily liquid 850 mg, the yield of 65.38%. ^ NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 1Η), 7.48 (s, 1H), 4.23 (t, J = 4.8 Hz, 2H), 3.99 (t, J = 4.8 Hz, 2H), 2.73 ( Br, 1H).

Step 2: Preparation of N-2-hydroxyethyl-4-pyrazoleboronic acid pinacol ester

In addition to replacing 2-(4-bromo-1H-pyrazol-1-yl)ethanol with 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester, The reaction was carried out in the same manner as in Example 5, and the product was isolated and purified by column chromatography (PE/EA l/l→CH ₂ Cl ₂ /MeOH 50/l). NMR (300 MHz, CDC1 ₃ ) δ 7.81 (s, 1H), 7.74 (s, 1H), 4.27 (t, J = 4.8 Hz, 2H), 3.99 (t, J = 4.8 Hz, 2H), 1.32 (s , 12H).

Step 3: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[l-(hydroxyethyl)-1H-pyrazol-4-yl]pyridine -2-amine (DC295-13)

The reaction was carried out in the same manner as in Example 4 except that the pinacol ester of N-2-hydroxyethyl-4-pyrazoleboronic acid was replaced with the 1-methyl-4-pyrazoleboronic acid pinacol ester. Separated by preparative HPLC, Yield l S o / H NMR (300 MHz, CDC1 ₃ ) δ: 8.09 (s, 1 Η, 7.59 (s, 1H), 7.53 (s, 1H), 7.51-7.49 (m, 1H) , 7.30 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.17 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.03-6.97 (m, 1H), 5.19 (s, 2H), 5.07-5.02 (m, 1H), 4.26 (t, J = 4.8 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 1.86-1.83 (m, 3H).

Flow chart 7

Example 16

Step 1: Preparation of 2-(4-bromo-1H-pyrazol-1-yl)acetate

4-Bromo-1H-pyrazole (1.00 g, 6.80 mmol) was dissolved in 10 mL of DMF and placed in an ice bath. The mass fraction of 60% sodium hydride (326.56 mg, 19.69 mmol) was added in portions. After stirring for 1 h, ethyl bromoacetate (0.83 mL, 7.48 mmol), KI (225.90 mg, 1.36 mmol) was added, and the mixture was warmed to 80 ° C for 8 h, cooled to room temperature, and 20 mL H ₂ 0 was added to the reaction mixture. , EA extraction (2x75 mL), the organic layer was combined, then washed with 3⁄40 (3×15 mL), 40 mL of saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, evaporated and evaporated. The crude liquid (1.327 g) was isolated and purified ( petroleum ether / ethyl acetate 10/1, v/v), yield 83.46%. ^ NMR (300 MHz, CDC1 ₃ ) δ 7.51 (s, 2 Η), 4.87 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H).

Step 2: Preparation of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-IH-pyrazol-1-yl]acetate In addition to replacing 2-(4-bromo-1Η-pyrazol-1-yl)acetate with 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester The reaction was carried out in the same manner as in Example 5, and the product was purified by column chromatography (CH ₂ Cl ₂ /MeOH, 50/1).

Step 3: Preparation of 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-{ 1-[(2-ethoxy-2-oxo)B -1 H-pyrazol-4-yl}pyridin-2-amine

In addition to replacing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate with ethyl acetate The reaction was carried out in the same manner as in Example 4 except for the 1-methyl-4-pyrazoleboronic acid pinacol ester. The product was purified by column chromatography (petrole ether/ethyl acetate 1/1, v/v). , the yield was 33.5%.

Step 4: Preparation of 2-[4-(2-amino-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-5-yl)-1H- Pyrazol-1-yl]acetic acid

3-{[1-(3-Fluoro-2,6-dichlorophenyl)ethyl]thio}-5-{1-[(2-ethoxy-2-oxo)ethyl]- 1H-pyrazol-4-yl}pyridin-2-amine 46 mg is dissolved in 2 mL of THF, added with 1 mL of 2N NaOH solution, refluxed, reacted for 5 h, and the organic solvent is evaporated to adjust the pH of the aqueous layer to 2-3 , extracted with EA, dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure to give 43 mg crude product.

Step 5: Preparation of 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[1-(indolyl-dimethylcarbonylethyl)-1H-pyridyl Zin-4-yl]pyridin-2-amine (DC295-14)

2-[4-(6-Amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-3-yl)-1H-pyrazole- 1-Base]acetic acid (43 mg, 0.097 mmol) was dissolved in 2 mL of DMF and placed in ice-bath, then HATU (39 mg, 0.102 mmol), DIPEA (0.036 mL, 0.205 mmol), dimethylamine hydrochloride Solid (9.53 mg, 0.117 mmol), add, remove the ice bath, stir at room temperature, after 1 h of reaction, add 1 mL of saturated NaHC0 ₃ solution to the reaction solution, extract with 50 mL of EA, and then use 3⁄40 (2x 10 mL), saturated washed with 10 mL NaCl solution, dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was distilled off under reduced pressure, separated by flash column chromatography (EA / MeOH 100/3, v / v) separation and purification, to give 22 mg of white solid, yield The rate is 48.21%.

Flow chart 8

Example 17

Step 1: Preparation of methyl 4-(2-amino-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine-5-yl)benzoate

5-Bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine (1.2 g, 3.03 mmol), 4-methoxycarbonyl Phenylboronic acid (0.65 g, 3.64 mmol), sodium carbonate (0.96 g, 9.09 mrnol), bistriphenylphosphine palladium dichloride (0.21 g, 0.30 mmol) dispersed in 10 mL DME/H ₂ 0 (4/1, In v/v), under the protection of argon, heated to 80 ° C, after 17 h of reaction, the reaction solution was evaporated to dryness, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ The mixture was filtered, and the solvent was evaporated evaporated evaporated.

Step 2: Preparation of 4-(2-Amino-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine-5-yl)benzoic acid

The crude product obtained from the upper hydrazine was dissolved in 15 mL of THF, 10 mL of 2N NaOH solution was added, refluxed, and reacted for 5 h, cooled to room temperature, extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 3, suction filtration, and the filter cake was washed with water and acetic acid. The ethyl ester was washed and the filter cake was dried to give 0.71 g (total yield of two oximes: 53.59%). iH NMR (400 MHz, DMSO-i ₆ ) δ 12.94 (br, 1 Η), 58.35 (t, J = 2.4 Hz 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 5.2, 8.8 Hz, 0.5H), 7.52-7.46 (m, 3H), 7.40-7.35 (m, 1.5H), 6.54 (d, J= 6.8 Hz, 2H), 5.07 (q, J= 7.2 Hz, 1H), 1.82-1.80 (m, 3H).

Step 3: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-{4-[(morphin-4-yl)carbonyl]phenyl}pyridine- 2-amine (DC295-15) In addition to replacing the morpholine ring with a dimethylamine hydrochloride solid, 4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridine -3yl)benzoic acid was replaced by 2-[4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio}pyridine-3- The reaction was carried out in the same manner as in Example 16 except for the base of -m-pyrazol-1-yl]acetic acid. The product was isolated and purified by flash column chromatography (EA/MeOH 100/1, v/v). White solid, yield 72.3%. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.26 (d, J = 2.1 Hz, 1H), 7.66

(d, J = 2.1 Hz, IH), 7.47-7.41 (m, 4H), 7.30 (dd, J= 5.1, 8.4 Hz, 0.5H), 7.17 (dd, J = 5.1, 8.4 Hz, 0.5H), 7.03-6.97 (m, IH), 5.31 (br, 2H), 5.12-5.04 (m, IH), 3.80-3.46 (m, 8H), 1.87-1.84 (m, 3H).

Example 18

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(4-{[4-(pyrrolidin-1-yl)piperidin-1- Carbonyl]phenyl)pyridin-2-amine (DC295-16)

Compound DC295-16 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with 4-(pyrrolin-1-yl)piperidine, yield 76.3%. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.26 (d, J = 2.4 Hz, IH), 7.65 (d, J = 2.4 Hz, IH), 7.43-7.38 (m, 4H ), 7.29 (dd, J = 5.1 , 8.7 Hz, 0.5H), 7.17 (dd, J = 5.1, 8.7 Hz, 0.5H), 7.02-6.97 (m, IH), 5.24 (s, 2H),

5.10-5.03 (m, IH), 4.67-4.60 (m, IH), 3.83-3.77 (m, IH), 3.07-2.86 (m, 2H), 2.68-2.55 (m, 4H), 2.30-2.66 (m , IH), 2.15-1.55 (m, 11H).

Example 19

Preparation of 4-(6-amino-5-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-3-yl)-N-[2- (diethyl Amino)ethyl]benzamide (DC295-17)

Compound DC295-17 was obtained in the same manner as in Example 17, except that the morpholine was replaced with Ν', Ν'-diethylethylenediamine, yield 73.5%. NMR (300 MHz, CDC1 ₃ ) δ 8.26 (d, J = 1.8 Hz, IH), 7.80 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 2.4 Hz, IH), 7.42 (d, J = 8.4 Hz _: 2H), 7.30-7.26 (m, 0.5H), 7.17-7.11 (m, 1.5H), 7.02-6.96 (m, IH), 5.36 (s, 2H), 5.09-5.02 (m, IH ), 3.52-3.45 (m, 2H), 2.65 (t, J= 5.7 Hz, 2H), 2.57 (q, J= 7.2 Hz _:

4H), 1.83 (dd, J= 2.4, 7.2 Hz, 3H), 1.04 (t, J= 7.2 Hz, 6H).

Example 20

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio}-5-{4-[(4-methylpiperazin-1-yl)carbonyl]benzene Pyridyl-2-amine (DC295-18)

Compound DC295-18 was prepared in the same manner as in Example 17, except that the morpholine ring was replaced with 4-methylpiperazine, yield 73.7% ^ NMR (300 MHz, CDC1 ₃ ) δ 8.26 (d, J = 2.8 Hz, Tl painting o

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Compound DC295-22 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with (S)-3-hydroxypyrrole, yield 54.0%. ^l R NMR (300 MHz, CDC1 ₃ ) δ 8.25 (s, 1Η), 7.66 (s, 1H), 7.60-7.54 (m, 2H), 7.40 (d, J = 4.5 Hz, 2H), 7.32-7.26 ( m, 0.5H),

7.17 (dd, J = 5.1, 9.0 Hz, 0.5H), 7.02-6.97 (m, 1H), 5.32 (s, 2H), 5.11-5.03 (m, 1H), 4.60 (s, 0.5H), 4.48 ( s, 0.5H), 3.84-3.46 (m, 4H), 2.14-1.99 (m, 3H), 1.87-1.84 (m, 3H).

Example 25

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-{4-[(4-methanesulfonylpiperazin-1-yl)carbonyl]benzene Pyridyl-2-amine (DC295-23)

Compound DC295-23 was prepared in the same manner as in Example 17, except that the morpholine ring was replaced with 4-methanesulfonylpiperazine, yield 5.53 %. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.27 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.45 (s, 4H), 7.30 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.17 (dd, J= 4.8, 8.7 Hz, 0.5H), 7.03-6.97 (m, 1H), 5.33 (s, 2H), 5.12-5.05

(m, 1H), 3.89-3.67 (m, 4H), 3.28 (br, 4H), 2.82 (s, 3H), 1.87-1.84 (m, 3H).

Example 26

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(4-{[(3-hydroxy)piperidin-1-yl]carbonyl} benzene Pyridine-2-amine (DC295-24)

Compound DC295-24 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with 3-hydroxypiperidine, yield 42.0%. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.25 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.32-7.26 (m, 0.5H), 7.17 (dd, J = 5.1, 8.7 Hz, 0.5H), 7.02-6.97 (m, 1H), 5.33 (s, 2H), 5.11 -5.03 (m, 1H), 3.95-3.28 (m, 5H), 2.07-1.48 (m, 7H).

Example 27

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(4-{[4-(2-hydroxyethyl)piperazin-1-yl ]carbonyl}phenyl)pyridin-2-amine (DC295-25)

Compound DC295-25 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with 2-(piperazin-1-yl)ethanol. The yield was 68.6 %. NMR (400 MHz, CDC1 ₃ ) δ 8.24 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.44-7.39 (m, 4H), 7.29 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.16 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.01-6.96 (m, IH), 5.39 (s, 2H), 5.07-5.04 (m, IH), 3.81-3.46 (m, 6H), 2.70-2.51 (m, 6H), 1.85-1.83 (m, 3H).

Example 28

Preparation of 4-(2-amino-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-5-yl)-N-[(4-fluorobenzene) Methyl]benzamide (DC295-26)

Compound DC295-26 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with 4-fluorophenylmethylamine, yield 6.63 %. ^l R NMR (400 MHz, CDC1 ₃ ) δ 8.23 (d, J = 2.4 Hz, IH), 7.83 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, IH), 7.40 (d , J = 8.0 Hz, 2H), 7.34-7.26 (m, 2.5H), 7.14 (dd, J = 4.8, 8.8 Hz, 0.5H), 7.04-6.95 (m, 3H), 6.85 (t, J= 5.6 Hz, IH), 5.41 (s, 2H), 5.09-5.04 (m, IH), 4.60 (d, J= 5.6 Hz, 2H),

1.86-1.83 (m, 3H).

Example 29

Preparation of 4-(2-amino-3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-5-yl)-N-[(3,5- Difluorophenyl)methyl]benzamide (DC295-27)

Compound DC295-27 was obtained in the same manner as in Example 17, except that the morpholine ring was replaced with 3,5-difluorophenylmethylamine, yield 68.4%. NMR (400 MHz, CDC1 ₃ ) δ 8.25 (d, J = 2.0 Hz, IH), 7.85 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 2.0 Hz, IH), 7.42 (d, J = 8.4 Hz _: 2H), 7.31-7.26 (m, 0.5H), 7.15 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.03 (t, J= 6.0 Hz, 1H) _: 7.00-6.96 (m, IH), 6.88-6.84 (m, 2H), 6.73-6.67 (m, IH), 5.41 (s, 2H), 5.08-5.04 (m, IH), 4.62 (d, J = 6.0 Hz, 2H), 1.86 -1.84 (m, 3H).

Example 30

Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-[2-(4-methylpiperazin-1-yl)pyridine-5-yl]pyridine -2-amine (DC295-28)

In addition to replacing the N-tert-butoxycarbonyl-3-pyrazole boronic acid pinacol ester with 2-(4-methylpiperazin-1-yl)-5-pyridineboronic acid pinacol ester, Compound DC295-28 was prepared in the same manner, yield 32% NMR (400 MHz, CDC1 ₃ ) δ 8.22 (br, IH), 8.17 (d, J = 2.0 Hz, IH), 7.56 (t, J = 3.2 Hz, IH), 7.52-7.48 (m, IH), 7.30-7.26 (m, 0.5H), 7.17 (dd, J= 4.8, 8.8 Hz, 0.5H), 7.01-6.97 (m, IH), 6.69 (d, J= 8.8 Hz, IH), 5.21 (s, 2H), 5.10-5.03 (m, IH), 3.62-3.59 (m, 4H), 2.57-2.55 (m, 4H), 2.87 (s, 3H), 1.86 -1.83 (m, 3H).

Example 31 Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(pyrimidin-5-yl)pyridin-2-amine (DC295-29)

Compound DC295-29 was obtained in the same manner as in Example 5 except that the N-tert-butoxycarbonyl-3-pyrazoleboronic acid pinacol ester was replaced with 5-pyrimidineboronic acid pinacol ester, and the yield was 28.73%. Ifi NMR (300 MHz, CDC1 ₃ ) δ 9.16 (s, 1H), 8.74 (s, 2H), 8.24-8.22 (m, 2H), 7.61-7.60 (m, 1H), 7.31 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.18 (dd, J = 4.8, 8.7 Hz, 0.5H), 7.05-6.98 (m, 1H), 5.62 (br, 2H), 5.12-5.03 (m, 1H), 1.88-1.84 (m, 3H).

Example 32

Step 1: Preparation of 2-(4-bromophenoxy)-1-morpholinone

² - ^{(4-bromophenoxy)} acetic acid ^{(2 .00 g, 8.66 mmol)} , morpholine (0.83 mL, 9.52 mmol) was dissolved in 40 mL CH _₂ Cl _2, was added DCC (1.88 g, 9.09 mmol) , at room temperature After stirring for 3 h, the mixture was suction filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography ( petroleum ether / ethyl acetate / 1/1, v/v) to yield 2.30 g, yield 88.5% ^ NMR (300 MHz, CDC1 ₃ ) δ 7.39 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.67 (s, 2H), 3.66-3.58 (m, 8H).

Step 2: Preparation of 1-(morpholin-4-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy Ethyl ketone

In addition to replacing 2-(4-bromophenoxy)-1-morpholinone with tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylate, The reaction was carried out in the same manner as in Example 5, and the product was subjected to column chromatography (PE/EA, 3/2) Separation and purification, yield 71.3% Ή NMR (300 MHz, CDC1 ₃ ) δ 7.76 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.72 (s, 2H), 3.66-3.61 (m, 8H), 1.33 (s, 12H).

Step 3: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-{4-[(morphin-4-yl)carbonylmethoxy]phenyl }pyridin-2-amine (DC295-30)

In addition to 1-(morpholin-4-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] The reaction was carried out in the same manner as in Example 4 except that the ethyl ketone was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester, and the product was purified by preparative HPLC to yield 25.84%. ^l R NMR (400 MHz, CDC1 ₃ ) δ 8.19 (d, J = 1.6 Hz 1H), 7.60 (t, J = 2.0 Hz, 1H), 7.32-7.27 (m, 2.5 H), 7.17 (dd, J = 4.8, 8.8 Hz, 0.5H), 7.02-6.97 (m, 3H), 5.23 (s, 2H), 5.07-5.04 (m, 1H), 4.73 (s, 2H), 3.70-3.61 (m, 8H), 1.86-1.83 (m, 3H).

Example 33

Step 1: Preparation of 4-(5-bromopyridin-2-yl)morpholine

2 g of 2,5-dibromopyridine was dispersed in 10 mL of morpholine, microwaved at 120 ° C for 100 min, and 150 mL of EA was added to the reaction solution, followed by 0.1 N HC1 30 mL, H ₂ 0 30 mL, The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated to dryness.

Step 2: Preparation of 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine in addition to 4-( The same procedure as in Example 5 was carried out except that 5-bromopyridin-2-yl)morpholine was replaced with 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester. The product was isolated and purified by rapid separation column chromatography (PE/EA 4/1, v/v) with a yield of 62.83%. NMR (300 MHz, CDC1 ₃ ) δ 8.55-8.54 (m, 1H), 7.84 (dd, J = 1.8, 8.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 3.80 (t, J= 4.8 Hz, 4H), 3.57 (t, J = 4.8 Hz, 4H), 1.32 (s, 12H).

Step 3: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[6-(morpholin-4-yl)pyridin-3-yl] Pyridin-2-amine (DC295-31) In addition to replacing 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine with 1-methyl- The reaction was carried out in the same manner as in Example 4 except for the 4-pyridazole boronic acid pinacol ester, and the product was purified by preparative HPLC (yield: 22.03%). ^ NMR (300 MHz, CDC1 ₃ ) 5 8.21 (d, J = 2.4 Hz IH), 8.14 (d, J = 2.4 Hz, IH), 7.55 (t, J = 2.7 Hz, IH), 7.52-7.48 (m , IH), 7.29-7.24 (m, 0.5H), 7.15 (dd, J= 4.8, 8.7 Hz, 0.5H), 7.02-6.97 (t, J= 8.7 Hz _: IH), 6.65 (d, J= 8.7 Hz, IH), 5.38 (s, 2H), 5.09-4.99 (m, IH), 3.84-3.80 (m, 4H), 3.52-3.49 (m, 4H), 1.86-1.83 (m, 3H).

Flowchart 11

Example 34

Step 1: Preparation of tetrahydropyran-4-ol

The reaction was carried out in the same manner as in Example 2 except that the tetrahydropyran-4-one was replaced with 1-(3-fluoro-2,6-dichlorophenyl:)ethanone.

Step 2: Preparation of tetrahydropyran-4-ylmethanesulfonate

The reaction was carried out in the same manner as in Example 2 except that tetrahydropyran-4-ol was replaced with 1-(3-fluoro-2,6-dichlorophenyl:)ethanol.

Step 3: Preparation of 1-(tetrahydropyran-4-yl)-4-bromo-1 7-pyrazole

The reaction was carried out in the same manner as in Example 5 except that tetrahydropyran-4-ylmethanesulfonate was replaced with 4-(methanesulfonyloxy)piperazine-1-carboxylic acid tert-butyl ester. 'H NMR (300 MHz, DMSO-i ₆ ) δ 8.06 (s, IH), 7.55 (s, IH), 4.41-4.35 (m, IH), 3.95-3.92 (m, 2H), 3.47-3.40 (m , 2H), 1.95-1.87 (m, 4H).

Step 4: Preparation of 1-(tetrahydropyran-4-yl)-4-pyrazoleboronic acid pinacol ester In addition to replacing 1-(tetrahydropyran-4-yl)-4-bromo-1 7-pyrazole with 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl In the same manner as in Example 5, the reaction H NMR (300 MHz _: CDC1 ₃ ) δ 7.80 (s, 1H), 7.75 (s, 1H), 4.42-4.31 (m, 1H), 4.12-4.07. (m, 2H), 3.57-3.49 (m, 2H), 2.13-1.99 (m, 4H), 1.32 (s, 12H).

Step 5: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[l-(pyran-4-yl)-1Η-pyrazole- 4-yl]pyridin-2-amine (DC295-32)

The same procedure as in Example 4 except that the 1-(tetrahydropyran-4-yl)-4-pyrazoleboronic acid pinacol ester was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester. The reaction was carried out in the same manner, and the product was purified by reverse-phase chromatography column or recrystallized from methanol, yield: 29.66% NMR (300 MHz, CDC1 ₃ ) δ 8.12-8.11 (m, 1H), 7.56 (s, 1H), 7.51- 7.489 (m, 2H), 7.30-7.26 (m, 0.5H), 7.16 (dd, J = 5.1, 9.0 Hz, 0.5H), 7.01-6.95 (m, 1H), 5.25 (s, 2H), 5.08- 5.00 (m, 1H), 4.37-4.28 (m, 1H), 4.13-4.08 (m, 2H), 3.58-3.46 (m, 2H), 2.12-2.00 (m, 4H), 1.87-1.83 (m, 3H ).

Stream 12

Example 35

Step 1: Preparation of 5-bromoindole-2-one

2-nonanone (1 g, 7.51 mmol) was dissolved in 30 mL CH ₂ C1 ₂ /CH ₃ CN (1:1, v/v), cooled to -10 ° C, and NBS (N-bromo) was added dropwise. 10 mL of C3⁄4CN solution of succinimide) (1.34 g, 7.51 mmol), after completion of the reaction, the reaction was carried out for 5 h, transferred to room temperature for 2 h, and filtered to obtain 1.255 g of a brown solid.

78.8%.

Step 2: Preparation of indole-2-one-5-boronic acid pinacol ester

In the same manner as in Example 5 except that 5-bromoindol-2-one was replaced with 4-(4-bromo-1H-pyrazol-1-yl)piperazine-1-carboxylic acid tert-butyl ester. Carry out the reaction. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.57 (br, 1H), 7.71-7.67 (m, 2H), 6.89 (d, J = 7.5 Hz, 1H), 3.52 (s, 2H), 1.34 (s, 12H ).

Step 3: Preparation of 5-(6-amino-5-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-3-yl)-2,3-di Hydrogen-1H-indol-2-one (DC295-33) The reaction was carried out in the same manner as in Example 4 except that the indol-2-one-5-boronic acid pinacol ester was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester. The product was isolated and purified (CH ₂ Cl ₂ /MeOH 50/1, v/v) (yield: 32.69 %). ^ NMR (300 MHz, CDC1 ₃ ) δ 8.20 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.62-7.61 (m, 1H), 7.32-7.15 (m, 3H), 7.02-6.96 (m, 1H), 6.90 (d, J = 8.1Hz, 1H), 5.22 (s, 2H), 5.10-5.03 (m, 1H), 3.59 (s, 2H), 1.86 (d, J= 7.2 Hz, 3H).

Example 36

Step 1: Preparation of Ν,Ν-dimethyl-1H-4-pyrazoleboronic acid pinacol ester

1H-4-pyrazoleboronic acid pinacol ester (150 mg, 0.77 mmol), triethylamine (0.27 mL, 1.93 mmol), DMAP catalytic amount dissolved in 5 mL anhydrous dichloromethane, added in ice bath Ν, Ν-dimethylformyl chloride (0.18 mL, 1.93 mmol), added, transferred to room temperature for 34 h, added 5 mL of water to the reaction solution, extracted with 40 mL of dichloromethane, and brine washed, dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was distilled off under reduced pressure, product was purified by flash column chromatography (petroleum ether / ethyl acetate 4/1, v / v) separation and purification, to give 145 mg as a white solid, The yield was 70.75%. Ifi NMR (300 MHz, CDC1 ₃ ) δ 8.40 (s, 1H), 7.87 (s, 1H), 3.21 (s, 6H), 1.33 (s, 12H).

Step 2: Preparation of 3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(lN,N-dimethylcarbonyl-1H-pyrazole-4- Pyridyl-2-amine (DC295-34)

The reaction was carried out in the same manner as in Example 4 except that the fluorene, dimethyl-l-methyl-1H-4-pyrazoleboronic acid pinacol ester was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester. The product was isolated and purified by preparative TLC, yield 41.26%. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.20—8.19 (m, 1H), 8.17-8.16 (m, 1H), 7.72 (d, J = 1.5Hz, 1H), 7.53 (d, J = 1.5Hz, 1H ), 7.31 (dd, J = 5.1, 8.7Hz, 0.5H), 7.18 (dd, J = 5.1, 8.7Hz, 0.5H), 7.03-6.98 (m, 1H), 5.22 (s, 2H), 5.10- 5.01 (m, 1H), 3.26 (s, 6H), 1.86-1.83 (m, 3H).

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Zll7000/Z10ZN3/X3d In addition to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester The reaction was carried out in the same manner as in Example 4 except that it was replaced with 1-methyl-4-pyrazoleboronic acid pinacol ester, and the product was subjected to rapid separation column chromatography (C3⁄4Cl ₂ /MeOH 50/1). , v/v) isolated and purified, the yield was 71.52%;

Step 2: Preparation of 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(1,2,3,6-tetrahydropyridin-4-yl) Pyridin-2-amine

In addition to 4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-3-yl)-indole, fluorenyl-dimethyl -1, 2, 3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester to replace 3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio 5-[1 The compound was prepared in the same manner as in Example 5 except that -(Ν-tert-butoxycarbonylpiperidin-4-yl)-1?-pyrazol-4-yl]pyridin-2-amine;

Step 3: Preparation of 4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-3-yl)-indole, fluorene-di Methyl-1, 2, 3, 6-tetrahydropyridine-1-carboxamide (DC295-38)

In addition to 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio 5-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-2- Amine replacement of 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}-5-[1-(piperidin-4-yl)-1Η-pyrazole-4- Compound DC295-38 was prepared in the same manner as Example 39 except for the pyridine-2-amine. Yield: 36.37%. NMR (400 MHz, CDC1 ₃ ) δ 8.05 (s, 1 Η), 7.44 (dd, J = 2.1, 4.5 Hz, 1H), 7.31-7.26 (m, 0.5H), 7.18 (dd, J = 5.1, 8.7 Hz, 0.5H), 7.03-6.97 (m, 1H), 5.83-5.80 (m, 1H ), 5.15 (s, 2H), 5.0-4.97 (m, 1H), 3.89-3.87 (m, 2H), 3.42 (t, J = 5.7 Hz, 2H), 2.86 (s, 6H), 2.42-2.40 ( m, 2H), 1.84-1.81 (m, 3H).

Flow chart 16

Example 41

Step 1: Preparation 2-(1-azidoethyl)-4-fluoro-1,3-dichlorobenzene

1-(3-Fluoro-2,6-dichlorophenyl)methanesulfonylethyl ester (1 g, 3.48 mmol), sodium azide (0.45 g 6.97 dish 01) was dissolved in 10 11^ 0^^ The mixture was heated to 50 ° C under nitrogen, and the reaction was allowed to stand overnight. The reaction mixture was cooled to room temperature, then added with 20 mL of water and extracted with ethyl acetate (2×10 mL). The Na ₂ S0 _{4 was} dried, filtered and evaporated <RTI ID=0.0>

Step 2: Preparation of 1-(3-fluoro-2,6-dichlorophenyl)ethylamine

2-(1-Azidoethyl)-4-fluoro-1,3-dichlorobenzene (815 mg, 3.48 mmol), zinc powder (296.1 mg 4.53 mmol), ammonium chloride (428.4 mg, 8.61 mmol) Disperse in 8 mL of EtOH/H ₂ 0 (3 / l, v / v), stir at room temperature for 3 h, if the reaction is not complete, can be heated to reflux, add 10 mL of CH ₂ Cl ₂ to the reaction solution, suction filtration, filtration The cake was washed with CH ₂ C1 ₂ and the filtrate was evaporated evaporated. Dried organic layer was washed with saturated brine and dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure to give the product, sufficiently pure, a yield of 70.67%, was used directly in the next ho.

Step 3: Preparation of 5-bromo-2-aminonicotinic acid

Disperse diaminonicotinic acid (10 g, 72.40 mmol) in 40 mL HAc, add 20 mL of bromine (4.82 mL, 94.12 mmol) in HAc solution, stir vigorously for 30 min, suction filtration, filter cake washed with HAc After drying the crude product, it was recrystallized from methanol to give a white solid (14.5 g, yield: 92.29%). MS (ESI, m/z): 216.8 [M+H] ⁺ .

Step 4: Preparation of 5-bromo-2-amino-N-(l-(3-fluoro-2,6-dichlorophenyl)ethyl)nicotinamide in addition to 5-bromo-2-aminonicotinic acid , 1-(4-Fluoro-2,6-dichlorophenyl)ethylamine replaces 2-[4-(2-amino-3-{[1-(3-fluoro-2,6-dichlorophenyl) The compound was prepared in the same manner as in Example 19 except that ethyl]thio]pyridin-5-yl)-1H-pyrazol-1-yl]acetic acid, dimethylamine hydrochloride, %. NMR (300 MHz, DMSO-i ₆ ) δ 9.12 (d, J = 5.1 Hz, IH), 58.27 (d, J = 2.1 Hz, IH), 8.15 (d, J = 2.1 Hz, IH), 7.50-7.45 (m, IH), 7.39-7.34 (m, IH), 7.12 (s, 2H), 5.62-5.53 (m, IH), 1.56 (t, J = 8.7 Hz, 3H).

Step 5: Preparation of 4-[4-(6-Amino-5-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]carbamoyl}pyridine

-3-yl)- 1 H-pyrazole-1 -yl]piperidine 1 tert-butyl formate

In addition to replacing 5-bromo-2-amino-N-(l-(3-fluoro-2,6-dichlorophenyl)ethyl)nicotinic acid amide with 5-bromo-3-{[1-(2 The reaction was carried out in the same manner as in Example 4 except that 6-dichloro-3-fluorophenyl:)ethyl]thio}pyridin-2-amine, and the product was subjected to reversed phase column chromatography (MeOH/H20 3 /1, v/v) was isolated in a yield of 37.59%.

Step 6: 2-Amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-[1-(piperidin-4-yl)-1H-pyrazole

4-yl]pyridine-3-carboxamide (DC295-39)

In addition to 4-[4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]aminoformyl}pyridin-3-yl)-IH-pyridyl Replacement of 3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio- _5- [l-( _N- ) with tert-butyl ester of oxazol-1-yl]piperidine-1-carboxylate Compound DC295-39 was prepared in the same manner as in Example 5 except for t-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. NMR (300 MHz, CDC1 ₃ ) δ 8.29 (d, J

= 2.1 Hz, IH), 7.72 (d, J = 2.1 Hz, IH), 7.69 (s, IH), 7.61 (s, IH), 7.33-7.27 (m, IH), 7.17 (d, J= 8.4 Hz , IH), 7.08-7.03 (m, IH), 6.24 (s, 2H), 6.19-6.08 (m, IH), 4.31-4.23 (m, IH), 3.31-3.27 (m, 2H), 2.86-2.77 (m, 2H), 2.23-2.19 (m, 2H), 2.03-1.94 (m, 2H), 1.68 (d, J = 6.9 Hz, 3H).

Example 42 Preparation of 2-amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-[l-(morpholin-4-yl)-pyridin-3-yl]pyridine -3-carboxamide (DC295-40)

In addition to replacing N-tert-butoxycarbonyl with 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine Compound DC295-40 was obtained in the same manner as in Example 41 except for the 4-pyridazole boronic acid pinacol ester, yield 40.32%. NMR (400 MHz, CDC1 ₃ ) δ 8.34 (dd, J= 0·8, 2.4

Hz, IH), 8.26 (d, J = 2.4 Hz, IH), 7.83 (d, J = 2.4 Hz, IH), 7.65 (dd, J = 2.8, 8.8 Hz, IH) 7.32-7.28 (m, IH) , 7.23 (d, J = 9.6 Hz, IH), 7.07-7.03 (m, IH), 6.74 (dd, J = 0.4, 8.8 Hz, IH), 6.60 (s, 2H), 6.19-6.09 (m, IH ), 3.86 (t, J = 8.8 Hz, 4H), 3.57 (t, J = 8.8 Hz, 4H), 1.69 (d, J = 7.2 Hz, 3H).

Example 43

Preparation of 2-amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-[l-(pyran-4-yl)-IH-pyrazole-4- Pyridine-3-carboxamide (DC295-41)

The same as in Example 41 except that the 1-pinahydrocarbonyl-4-pyrazoleboronic acid pinacol ester was replaced with 1-(tetrahydropyran-4-yl)-4-pyrazoleboronic acid pinacol ester. Compound DC295-41, yield 59.06% ^l H NMR (300 MHz, CDC1 ₃ ) δ 8.28 (d, J = 1.8 Hz, IH), 7.75 (d, J =

1.8 Hz, IH), 7.69 (s, IH), 7.60 (s, IH), 7.32-7.25 (m, IH), 7.17 (d, J = 8.4 Hz, IH), 7.08-7.02 (m, IH), 6.32 (s, 2H), 6.16-6.07 (m, IH), 4.42-4.32 (m, IH), 4.14-4.09 (m, 2H), 3.59-3.51 (m, 2H), 2.14-2.07 (m, 4H ), 1.68 (d, J = 6.9 Hz, 3H).

Example 44

Preparation of 2-amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-(2-oxo-2,3-dihydro-IH-indole-5 -yl)pyridine-3-carboxamide (DC295-42)

Compound DC295-42 was prepared in the same manner as in Example 41 except that N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester was replaced with indole-2-one-5-boronic acid pinacol ester. The yield was 19.50%. NMR (300 MHz, DMSO-i ₆ ) δ 12.94 (br, IH), δ 10.45 (s, IH), 9.15 (d, J = 5.1 Hz,

IH), 8.35 (d, J = 2.1 Hz, IH), 8.27 (d, J = 2.1 Hz, IH), 7.55 (s, IH), 7.50-7.45 (m, IH), 7.36 (t, J = 8.7 Hz, IH), 6.96 (s, 2H), 6.90 (d, J = 8.1 Hz, IH), 5.68-5.59 (m, IH), 3.56 (s, 2H), 1.60 (d, J= 7.2Hz, 3H ).

Example 45

Preparation of 2-amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-{4-[2-(morpholin-4-yl)-2-oxo Ethoxy]phenyl}pyridine-3-carboxamide (DC295-43) In addition to 1-(morpholin-4-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] Compound DC295-43 was obtained in the same manner as in Example 41, except for the N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester. The yield was 46.06%. ^ NMR (400 MHz, CDC1 ₃ ) δ 8.34 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 2A Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.31-7.28 ( m, 1H), 7.19 (d, J= 8.8 Hz, 1H), 7.06-7.01 (m, 3H), 6.32 (s, 2H), 6.15-6.08 (m, 1H),

4.73 (s, 2H), 3.70-3.66 (m, 4H), 3.63-3.61 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H).

Example 46

Preparation 2-Amino-N-[ l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-(pyrimidin-5-yl)pyridine-3-carboxamide (DC295-44)

Compound DC295-44 was obtained in the same manner as in Example 41 except that the pyridin-5-boronic acid pinacol was replaced with N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester in a yield of 37.22%. NMR (400 MHz, CDC1 ₃ ) δ 9.21 (s, 1H), 8.90 (s, 2H), 8.40 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.08-7.04 (m, 1H), 6.57 (s, 2H), 6.18-6.10 (m, 1H), 1.69 (d, J= 6.8 Hz, 3H).

Flow Figure 17

Example 47

Step 1: Preparation of 5-bromo-2-aminopyridine-3-sulfonyl chloride Add 5-bromo-2-aminopyridine 700 mg to 5 mL of chlorosulfonic acid in portions at -15 °C. The reaction solution was homogeneous, gradually warmed to 160 ° C, reacted for 3 h, cooled to room temperature. Under stirring, slowly pour into ice cubes, pour out a white solid, suction filtration, and collect the filter cake to obtain 400 mg of 5-bromo-2-aminopyridine-3-sulfonyl chloride.

Step 2: Preparation of 5-bromo-2-amino-N-(l-(3-fluoro-2,6-dichlorophenyl)ethyl)pyridine-3-sulfonamide 1-(3-Fluoro-2 ,6-dichlorophenyl)ethylamine (306.51 mg, 1.47 mmol), triethylamine (205 L, 1.47 mmol) dissolved in 10 mL of dry dichloromethane. The crude product of 2-aminopyridine-3-sulfonyl chloride was added, and the reaction mixture was stirred at room temperature overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered and evaporated. The product was separated and purified by rapid separation column chromatography (PE/EA 3/2, v/v). The total yield of the two oximes was 20.86%. NMR (300

MHz, DMSO-i ₆ ) δ 8.78 (br, 1H), 58.11 (d, J = 2.4 Hz, 1H), 7.48-7.24 (m, 3H), 6.77 (s, 2H), 5.19-5.12 (m, 1H ), 1.50 (d, J = 7.2 Hz, 3H).

Step 3: Preparation of 4-[4-(6-amino-5-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]aminesulfonyl}pyridine-3-yl)-1 H-pyrazole-1 -yl]piperidine 1 tert-butyl formate

In addition to replacing 5-bromo-2-amino-N-(l-(3-fluoro-2,6-dichlorophenyl)ethyl)pyridine-3-sulfonamide

The reaction was carried out in the same manner as in Example 4 except for 5-bromo-3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine. Separation by column chromatography (MeOH/CH.sub.2. NMR (300 MHz, CDC1 ₃ ) δ: 8.11 (d, J = 1.5 Hz, 1H), 7.79-7.76 (m, 1H), 7.63 (s, 1H), 7.57-7.54 (m, 1H), 7.02-6.91 (m, 1H), 6.77-6.72 (m, 1H), 6.28-6.17 (m, 1H), 5.51 (s, 2H), 5.47-5.37 (m, 1H),

4.35-4.25 (m, 3H), 2.96-2.85 (m, 2H), 2.19-2.16 (m, 2H), 2.01-1.89 (m, 2H), 1.60 (d, J=7.2 Hz, 3H), 1.49 ( s, 9H).

Step 4: Preparation of 2-amino-N-[l-(3-fluoro-2,6-dichlorophenyl)ethyl]-5-[l-(piperidin-4-yl)-1Η-pyrazole 4-yl]pyridine-3-sulfonamide (DC295-45)

In addition to 4-[4-(6-amino-5-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]aminesulfonyl}pyridin-3-yl)-1H-pyridyl Replacement of 3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio- _5- [l-( _N- ) with tert-butyl ester of oxazol-1-yl]piperidine-1-carboxylate Compound DC295-45 was prepared in the same manner as in Example 5 except for t-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. ¹ H NMR (300 MHz, CDC1 ₃ ) δ 8.13 (d, J = 2.4 Hz, 1H), 7.79-7.76 (m, 1H), 7.63 (s, 1H), 7.58-7.56 (m, 1H), 7.03- 6.95 (m, 1H), 6.78-6.73 (m, 1H), 6.32 (br, 1H), 5.52 (s, 2H), 5.44-5.37 (m, 1H), 4.31-4.22 (m, 1H), 3.30-3.26 (m, 2H), 2.83-2.76 (m, 2H), 2.23-2.18 (m, 2H), 1.99-1.86 (m: 2H), 1.60 (d, J=7.5 Hz , 3H).

Example 48

Step 1: Preparation of 4-fluoro-3-chloro-N-methylaniline

Sodium methoxide (1.86 g, 34.35 mmol) was dissolved in 50 mL of methanol, followed by 3-fluoro-4-chloroaniline (1 g, 6.87 mmol), paraformaldehyde (1.03 g, 34.35 mmol), refluxed for 3 h and then cooled To 0 ° C, NaB3⁄4 (1.30 g, 34.35 mmol) was added to the reaction mixture. After the addition, the mixture was refluxed for 2 h, cooled to room temperature, then 10 mL of water was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered, and evaporated to give the product 960 mg of pale yellow liquid, which was sufficiently pure, yield 87.56 %. NMR (300 MHz, CDC1 ₃ ) δ 6.96 (t, J = 9.0 Hz, 1H), 56.60-6.57 (dd, J = 2.4, 6.0 Hz, 1H), 6.45-6.40 (m, 1H), 3.64 (br, 1H), 2.80 (s, 3H).

Step 2: Preparation of 5-bromo-2-amino-N-methyl-N-(4-fluoro-3-chlorophenyl)-pyridine-3-sulfonamide 4-Fluoro-3-chloro-N-A The aniline (294 mg, 1.84 mmol) was dissolved in 8 mL of triethylamine. Under a nitrogen atmosphere, 5-bromo-2-aminopyridine-3-sulfonyl chloride (500 mg, 1.84 mmol) was added and heated to 60 ° The reaction mixture was evaporated to dryness. /v) Separate and purified to give a final product of 200 mg, yield 27.5 ^l R NMR (300 MHz, CDC1 ₃ ) δ 8.27 (d, J = 2.4 Hz, 1H), 57.78 (d, J = 2.4 Hz, 1H), 7.31-7.28 (m, 1H), 7.12-7.08 (m, 1H), 5.53 (s, 2H), 3.22 (s, 3H). Step 3: Preparation of N-methyl-N-(3-chloro-4-fluorophenyl)-2-amino-5-[1-(1-tert-butoxycarbonylpiperidine-4-yl)-1H -pyrazol-4-yl]pyridine-3-sulfonamide

In addition to replacing 5-bromo-2-amino-N-methyl-N-(3-chloro-4-phenyl)-pyridine-3-sulfonamide with 5-bromo-3-{[1-(2, The reaction was carried out in the same manner as in Example 4 except for 6-dichloro-3-fluorophenyl:)ethyl]thio}pyridin-2-amine. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.38 (d, J = 2.4 Hz, 1H), 7.68 (d, J =

2.4 Hz, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.32-7.29 (m, 1H), 7.13-7.10 (m, 2H), 5.52 (s, 2H), 4.33-4.23 (m , 3H), 3.23 (s, 3H), 2.95-2.86 (m, 2H), 2.18-2.13 (m, 2H), 2.00-1.91 (m, 2H), 1.49 (s, 9H).

Step 4: Preparation of N-methyl-N-(3-chloro-4-fluorophenyl)-2-amino-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl Pyridine-3-sulfonamide (DC295-46)

In addition to N-methyl-N-(3-chloro-4-fluorophenyl)-2-amino-5-[1-(1-tert-butoxycarbonylpiperidin-4-yl)-m-pyrazole -4-yl]pyridine-3-sulfonamide substituted 3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]thio _5- [l-( _N -tert-butoxycarbonyl) Compound DC295-46 was prepared in the same manner as in Example 5 except that piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. NMR (300 MHz, CDC1 ₃ ) δ 8.39 (d, J = 2.1 Hz 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 0.6 Hz, 1H), 7.56 (d, J = 0.6

Hz, 1H), 7.32-7.29 (m, 1H), 7.13-7.10 (m, 2H), 5.52 (s, 2H), 4.31-4.21 (m, 1H), 3.32-3.26 (m, 2H), 3.23 ( s, 3H), 2.85-2.77 (m, 2H), 2.22-2.17 (m, 2H), 2.06-1.91 (m, 3H) o

Example 49

Preparation 2-Amino-N-methyl-N-(3-chlorophenyl)-5-(1-methyl-IH-pyrazol-4-yl)pyridine-3-sulfonylamine (DC295-47)

Replacing 5-bromo-3-{[1-(3-fluoro-2) with 5-bromo-2-amino-N-methyl-N-(3-chlorophenyl)-pyridine-3-sulfonamide Compound DC295-47 was prepared in the same manner as in Example 4 except for 6-dichlorophenyl:ethyl]thio]pyridin-2-amine. NMR (300 MHz, CDC1 ₃ ) δ 8.36 (d, J = 2.4 Hz 1H), 7.65 (d, J = 2A Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.28-7.24 ( m, 3 H), 7.15-7.12

(m, 1H), 5.55 (s, 2H), 3.94 (s, 3H), 3.25 (s, 3H).

Example 50

Preparation of N-methyl-N-(3-chlorophenyl)-2-amino-5-{[l-(piperidin-4-yl)-IH-pyrazol-4-yl]phenyl}pyridine- 3-sulfonamide (DC295-48)

In addition to 5-bromo-2-amino-N-methyl-N-(3-chlorophenyl)-pyridine-3-sulfonamide instead of 5-bromo

In the same manner as in Example 5 except for -3-{[1-(3-fluoro-2,6-dichlorophenyl:)ethyl]thio}pyridin-2-amine Compound DC295-48 was prepared in the formula. NMR (300 MHz, DMSO-i ₆ ) δ 8.53 (d, J = 2.1 Hz 1H), 8.18 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.41- 7.38 (m, 2H), 7.34 (s, 1H), 7.28-7.23 (m, 1H), 6.36 (s, 2H), 4.22-4.11 (m, 1H), 3.22 (s, 3H), 3.06-3.02 ( m, 2H), 2.63-2.55 (m, 2H), 1.98-1.94 (m, 2H), 1.84-1.71 (m, 2H).

Example 51

Preparation of N-methyl-N-(3-chlorophenyl)-2-amino-5-{4-[2-oxo-2-(piperazin-4-yl)ethoxy]phenyl}pyridine -3-sulfonamide (DC295-49)

In addition to 5-bromo-2-amino-N-methyl-N-(3-chlorophenyl)-pyridine-3-sulfonamide, 4-(2-(4-(4,4,5,5-) Tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetyl)piperazine-1-carboxylate replaces 5-bromo-3-{[1-(3- Fluorin-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine, N-tert-butoxycarbonyl-4-pyrazoleboronic acid pinacol ester in the same manner as in Example 5. Preparation of compound DCSQS^^ ¹ !! NMR (300 MHz, CDC1 ₃ ) δ 8.41 (d, J = 2.4 Hz 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.32-7.24 (m, 5H), 7.15 -7.11 (m, 1H), 7.00 (d, J= 8.7 Hz, 2H), 5.61 (s, 2H), 4.73 (s, 2H), 3.63-3.55 (m, 4H), 3.26 (s, 3H), 2.89-2.83 (m, 4H).

Example 52

Preparation of N-methyl-N-(3-chlorophenyl)-2-amino-5-(pyridin-4-yl)pyridine-3-sulfonamide (DC295-50)

In addition to 5-bromo-2-amino-N-methyl-N-(3-chlorophenyl)-pyridine-3-sulfonamide, pyridine-4-boronic acid was substituted for 5-bromo-3-{[1-( 3-fluoro-2,6-dichlorophenyl)ethyl]thio}pyridin-2-amine, 1-methyl-4-pyrazoleboronic acid pinacol ester, in the same manner as in Example 4. Preparation of compound DCSQS-SO^H NMR (300

_{MHz, CDC1 3) δ 8.66-8.64 (} m, 2H), 8.57 (d, J = 2.1 Hz 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.34-7.29 (m, 4H), 7.17-7.13 (m, 1H), 5.82 (s, 2H), 3.27 (s, 3H).

Example 53

Preparation of N-methyl-N-[3-(trifluoromethyl)phenyl]-2-amino-5-[ l -(piperidin-4-yl)-1H-pyrazol-4-yl]pyridine -3-sulfonamide (DC295-51)

Replacing 5-bromo-3-{[1-(3-fluoro) with 5-bromo-2-amino-N-methyl-N-(3-trifluoromethylphenyl)-pyridine-3-sulfonamide Compound DC295-51 was prepared in the same manner as in Example 5 except for the 2,6-dichlorophenyl:)ethyl]thio}pyridin-2-amine. ^l H NMR (300 MHz, DMSO-i ₆ ) δ 8.54 (d, J = 2.7 Hz 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.45-7.37 (m, 1H), 7.21-7.12 (m, 3H), 6.38 (s, 2H), 5.52 (s, 2H), 4.48-4.39 (m, 1H), 3.39-3.32 (m,

2H), 3.22 (s, 3H), 3.08-2.99 (m, 2H), 2.27-2.16 (m, 2H), 2.11-1.97 (m, 2H). Preparation of N-methyl-N-(pyridin-3-yl)-2-amino-5-[1-(piperidin-4-yl)-1Η-pyrazol-4-yl]pyridine-3-sulfonamide (DC295-52)

Replacing 5-bromo-3-{[1-(3-fluoro-2) with 5-bromo-2-amino-N-methyl-N-(pyridin-3-yl)-pyridine-3-sulfonamide Compound DC295-52 was prepared in the same manner as in Example 5 except for 6-dichlorophenyl)ethyl]thio}pyridin-2-amine. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.56-8.52 (m, 2H), 8.38 (d, J = 2.4 Hz 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.61-7.58 (m, 2H) , 7.55 (s, 1H), 7.32-7.26 (m, 2H), 5.50 (s, 2H), 4.26-4.18 (m, 1H), 3.31-3.24 (m, 5H), 2.82-2.74 (m, 2H) , 2.20-2.14 (m, 2H), 1.96-1.83 (m, 2H), 1.74-1.67 (m, 2H).

Example 55

Preparation of N-methyl-N-(3-chlorophenyl)-2-amino-5-{4-[(piperazin-4-yl)carbonyl]phenyl}pyridine-3-sulfonamide (DC295-53 )

Replacing 5-bromo-3-{[1-(3-fluoro-2) with 5-bromo-2-amino-N-methyl-N-(3-chlorophenyl)-pyridine-3-sulfonamide Compound DC295-53 was prepared in the same manner as in Example 5 except for 6-dichlorophenyl:ethyl]thio}pyridin-2-amine. ^ NMR (300 MHz, CDC1 ₃ ) δ 8.48 (d, J = 2.4 Hz 1H),

7.81 (d, J = 2.4 Hz, 1H), 7.51-7.41 (m, 4H), 7.32-7.25 (m, 3H), 7.17-7.13 (m, 1H) _: 5.72 (s, 2H), 3.79-3.74 ( m, 2H), 3.49-3.43 (m, 2H), 3.27 (s, 3H), 2.97-2.82 (m, 4H).

Test example

Example 56

Kinase level inhibition assay

The enzyme reaction substrate Poly (Glu, Tyi 4 _{:1) was} diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 2 (^g/ml, 125 μΐ/well). The plate was coated and placed at 37 ° C for 12-16 hours. Discard the liquid in the well and wash the plate. Wash the plate three times with 200 μM/well of T-PBS (PBS containing 0.1% Tween-20). 5 minutes. The plate was dried in an oven at 37 °C for 1-2 hours.

An ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ V0 ₄ , 1 mM DTT) was added to each well for 50 μ at a final concentration of 5 μM. The drug was diluted to a suitable concentration in 1% DMSO, 10 μΐ/well, and each tyrosine kinase protein diluted in 40 μl of reaction buffer was added. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The plate was washed three times with T-PBS. (Each experiment requires three wells without enzyme control wells and control wells with corresponding DMSO concentration:) Add primary antibody

PY99 100 μΐ/well (p-Tyr (PY99), Cell Sinaling Technology, antibody containing BSA 5 mg/ml

54 T-PBS 1: 1000 dilution), shaken at 37 ° C for 0.5 hours. The plate was washed three times with T-PBS. A second anti-horseradish peroxidase-labeled goat anti-mouse IgG 100 μΐ/well (antibody diluted with BSA 5 mg/ml T-PBS1:2000) was added and shaken at 37 ° C for 0.5 hour. The plate was washed three times with T-PBS. Add 2 mg/ml OPD chromogenic solution 100 μΐ/well (diluted with 0.1 Μ citric acid-sodium citrate buffer (ρΗ=5.4) containing 0.03% 3⁄40 ₂ ), 1-2 minutes at 25 ° C in the dark . (Ultrasound is required for the dissolution of OPD, and the coloring solution needs to be used now). The reaction was stopped by the addition of 2 MH ₂ SO ₄ 50 l/well and read with a tunable wavelength microplate microplate SPECTRA MAX 190 at a wavelength of 492 nm.

The inhibition rate of the sample is obtained by the following formula:

Compound OD value - no enzyme control well OD value

Inhibition rate % χ 100%

Negative control OD value - no enzyme control well OD value c ₅₀ value was calculated by a four-parameter fit through the inhibition curve.

Example 57

Western Blot

NIH3T3-TPR-Met cells were seeded in a 12-well plate, and after 60% confluency, different concentrations of the drug and SU11274 were added for 6 hours. The cells were collected, washed once with cold PBS (containing 1 mM sodium vanadate), and added to l xSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, I mM sodium vanadate, 0.1% bromophenol blue) lysed cells. The cell lysate was heated in a boiling water bath for 10 minutes and then centrifuged at 4 V 12000 rpm for 10 minutes.

The supernatant was taken for SDS-PAGE electrophoresis. After electrophoresis, the protein was transferred to a nitrocellulose membrane (Amersham Life Sciences, Arlington Heights, IL, USA) using a semi-dry electrotransfer system, and the nitrocellulose membrane was placed in a blocking solution. (5% skimmed milk powder diluted in TBS/T containing 1 mM sodium vanadate) was blocked at room temperature for 1 hour, and then the membrane was placed in an antibody against phosphorylated c-Met (Y1234/1235, Cell Sinaling Technology) (1:1000) Or anti-actin (Cell Sinaling Technology) antibody (1:6000) was blocked at room temperature for 2 hours. Wash three times with TBS/T containing 1 mM sodium vanadate for 15 min each time. The membrane was placed in a secondary antibody (1:2000) solution for 1-2 hours at room temperature. After washing the membrane three times as above, the color was developed with ECL reagent, tableted, and developed.

The above nitrocellulose membrane was peeled off with a ReblotTM solution of Chemicon (Temecula, CA, USA) to remove the bound antibody, and then re-blocked (5% skimmed milk powder diluted in TBS/T) with anti-c-Met (C12, Santa Cruz Biotechnology) antibody (1:500) and secondary antibody (1:2000) showed the bioassay results of the selected compounds of the invention according to Table 1 above, in terms of ICso OtM); Table 1

Table 2 shows the results of biological tests for kinase selectivity of selected compounds of the invention.

Table 2

Example 58

Cell proliferation inhibition assay

A certain number of cells in the logarithmic growth phase were inoculated into 96-well culture plates at 90 μl per well. After incubation overnight, different concentrations of the compound were added, and three concentrations were set, and each concentration was 3 wells. After the compound was allowed to act for 72 hours, the culture solution was discarded, fixed with pre-cooled 10% TCA at 4 ° C for 1 hour, washed with distilled water 5 times, and naturally dried in the air. Then, 4 μg/ml of sulforodamine B (SRB) solution prepared from 1% glacial acetic acid was added to each well to 100 μl, and stained at room temperature. Minutes, discard the staining solution, wash it with 1% glacial acetic acid 5 times, and dry naturally in the air. Finally, 150 μl of Tris-HCL solution (10 mM Tris, pH 10.0) was added to each well, and the absorbance 0D value was measured at a wavelength of 515 nm by a microplate reader.

Table 3 shows the effect of the selected compounds of the invention on Met-mediated cell proliferation ability, and the difference in the inhibition rate (%) of the NIH3T3-TPR-Met cells and the NIH3T3 background control cells was shown.

Claims

Rights request

A compound represented by the formula (I:), an enantiomer, a diastereomer, a racemate, a mixture thereof or a pharmaceutically acceptable salt thereof,

among them,

X is -S -, -S(0) ₂ -, -S(0)-, -S0 ₂ N(R ⁵ )-, -CO- or -CON(R ⁵ )-;

m is 0 or 1;

R ¹ is a substituted or unsaturated C3-C12 heterocyclic group, a substituted or unsubstituted C6-C10 aryl group,

The substituted saturated or unsaturated C3-C12 heterocyclic group or substituted C6-C10 aryl group in R ¹ includes 1 to 5 substituents, which are halogen, C1-C12 straight chain or Branched alkyl, C2-C12 straight or branched unsaturated hydrocarbon, C3-C12 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, Carboxyl, fluorenyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )- , -N(R ⁶ )R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ , -OR ₃ COR ⁶ , -CON(Ri ) R ₃ R ⁶ ,

-R ₃ CONR ⁶ R ⁷ , -COR ₃ OH, phenyl, substituted phenyl, naphthyl, biphenyl, or substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic; The substituted phenyl group includes 1 to 5 substituents each independently a halogen, a C1-C12 linear or branched alkyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, and a C3-C12 ring. Hydrocarbyl, saturated or unsaturated C3-C12 heterocyclyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ )R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ or -OR ₃ NR ⁷ R ⁸ _; the substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group contains 1- 4 a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted saturated or unsaturated C3-C12 heterocyclic group contains one or more alkyl groups selected from 3⁄4, C1-C12 straight or branched, C2- C12 straight or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, saturated or unsaturated C3-C12 heterocyclic group, cyano group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoro Methoxy, carboxyl, fluorenyl, -R ₃ R ⁶ , -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CONR ⁶ R ₃ NR ⁸ R ⁹ ,

-S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ ) a substituent in R ₃ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ and -OR ₃ NR ⁷ R ⁸ ;

R ² is hydrogen, cyano, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched alkyl, C2-C6 straight Chain or branched unsaturated hydrocarbon group,

a C1-C6 linear or branched alkoxy group, a C1-C6 straight or branched alkanoyl group, or a C1-C6 straight or branched alkylamino group;

R ¹ , R ² may be connected to each other to form a ring;

R ³ and R ⁴ are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched alkane a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched alkoxy group, a C3-C12 cycloalkyl group, a C1-C6 straight or branched alkanoyl group, or a C1-C6 group; a linear or branched alkylamino group;

R ³ and R ⁴ may be joined to form a ring;

R ¹⁵ is hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight or branched unsaturated hydrocarbon, nitrile, nitro, amino, hydroxy, trifluoromethyl, trifluoromethyl Oxyl, carboxyl, sulfhydryl,

-S(0) ₂ Ri, -R ₃ OH, -R ₃ R ₄ , -R ₃ NRiR ₂ , -R ₃ R ₅ -R ₃ CONRiR ₂ , -CONRiR ₂ , -COR ₃ OH, substituted or unsubstituted a 5- or 6-membered heterocyclic group containing at least one hetero atom selected from the group consisting of N, O and S, the substituent being a steroid, a C1 to C6 linear or branched alkyl group, a nitrile group, a nitro group, an amino group , hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, -8(0) ₂ 1 ₁ or -(^€^1 ₁ 1 _2;

a substituted or unsubstituted C6-C10 aryl group, or a substituted or unsubstituted C5-C12 heteroaryl group, the heteroaryl group having 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen;

The substituent in the ^Y is a halogen, a C1-C12 linear or branched alkyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, a C3-C12 cycloalkyl group, a cyano group, a nitro group, an amino group, Hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, fluorenyl, -OR ₃ R ⁶ , -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -SO3R ⁶ , -CONR ⁶ R ⁷ , -CONR ⁶ R ⁷ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -ORgCONR'R ⁸ , -N(R°)R ₃ COR ⁸ , NR ⁰ R'CON(R ^s )- , -N(R ⁰ )R ₃ S0 ₂ R , NR ⁶ R ⁷ S0 ₂ N(R ⁸ -, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ , -OR ₃ NR ⁷ R ⁸ , phenyl, substituted phenyl, naphthyl, biphenyl, or substituted or unsubstituted saturated or unsaturated The C3-C12 heterocyclic group; wherein the substituted phenyl group comprises 1 to 5 substituents, each of which is independently a halogen, a C1-C12 straight or branched alkyl group, a C2-C12 straight chain or Branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, C3-C12 saturated or unsaturated heterocyclic group, cyano group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group , carboxy, fluorenyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , S0 ₂ NR ⁶ R ⁷ , -OCON(R ⁶ )R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , R ⁷ N(R ⁶ )CON(R ⁸ )-, - N(R ⁶ )R ₃ S0 ₂ R ⁸ , R ⁷ N(R ⁶ )R ₃ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ or -OR ₃ NR ⁷ R ^8; a substituted or unsubstituted, saturated or unsaturated C3-C12 The cyclic group contains 1-4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted saturated or unsaturated C3-C12 heterocyclic group contains one or more selected from halogen, C1-C12 straight or branched chain. Alkyl, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, heterocycloalkenyl group, C3-C12 saturated or unsaturated heterocyclic group, cyano group, nitro group, amino group, hydroxyl group, Hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, fluorenyl, -SOR ⁶ , -S0 ₂ R ⁶ , R ⁶ CO-, -COOR ⁶ , -S0 ₃ R ⁶ , -CONR ⁶ R ⁷ , -CON(R ⁶ )R ₃ NR ⁸ R ⁹ , -S0 ₂ NR ⁶ R ⁷ , -OCONR ⁶ R ⁷ , -OR ₃ CONR ⁷ R ⁸ , -N(R ⁶ )R ₃ COR ⁸ , NR ⁶ R ⁷ CON(R ⁸ )-, -N(R ⁶ )R ⁷ S0 ₂ R ⁸ , NR ⁶ R ⁷ S0 ₂ N(R ⁸ )-, -NR ⁶ R ⁷ , -SR ⁶ , -OR ⁶ and

a substituent in -OR ₃ NR ⁷ R ⁸ ;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ are each independently hydrogen, halogen, C1-C12 straight or branched alkyl, C2-C12 straight or branched unsaturated hydrocarbon, C3-C12 a cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 acyl group, a C6-C12 aryl group, or a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group; said substituted or unsubstituted saturated or unsaturated The C3-C12 heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted C3-C12 heterocyclic group contains one or more selected from the group consisting of halogen, C1-C12 straight or branched. Alkyl, C2-C12 straight or branched unsaturated hydrocarbon group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, saturated or unsaturated C3-C12 heterocyclic group, cyano group, nitro group, amino group, hydroxyl group a substituent in a methylol group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a fluorenyl group, -R ₃ OH, and -SO^; any of R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ When two are connected to the same nitrogen atom, they can form with the connected nitrogen atom. a ring; any two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are bonded to the same carbon atom to form a ring;

And R ₂ are each independently hydrogen or a C1 to C6 alkyl group; and are C1 to C6 alkylene groups.

2. A compound of the formula (I), an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein m is 0 Or 1 ; X is selected from -S -,

5) - and -CON(R ⁵ )-; R ¹ is a group selected from the group consisting of:

Where 11 is , N or 0; Z is C or N; Q is N or 0;

10 12 , 13

ΙΤ\R", R", RR ¹⁴ , R ¹⁵ , R ^lb , R ^l R ^1S and 1 ¹⁹ are each independently hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight chain Or branched unsaturated hydrocarbon group, nitrile group, nitro group, amino group, hydroxyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group, -8(0) ₂ , -R ₃ OH, -R ₃ R ₄ And -R ₃ NRiR ₂ , -R3R5, -R3CONR1R2, -CONR1R2, -COR3OH, a substituted or unsubstituted 5- or 6-membered heterocyclic group containing at least one hetero atom selected from N, 0 and S, The substituent is halogen, C1 to C6 straight or branched alkyl, nitrile, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, decyl, -8 (0 ) ₂ 1 ₁ or - (^ € ^ 1 _{1 ;}

And R ₂ are each independently hydrogen or a C1 to C6 alkyl group;

R ₃ is a C1 to C6 alkylene group;

R ₄ is a substituted or unsubstituted 5- or 6-membered heterocyclic group containing at least one hetero atom selected from N, 0 and S, the substituent being a halogen, a C1 to C6 straight or branched alkyl group , nitrile group, nitro group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, fluorenyl group, -8(0) ₂ , -CONRiR^

R ₅ is a phenyl group substituted by 1 to 5 halogen atoms, and the halogen is fluorine, chlorine, bromine or iodine.

3. A compound of the formula (I) according to claim 1 or 2, which is an enantiomer, a diastereomer, a racemate and a mixture thereof or a pharmaceutically acceptable salt thereof, wherein "for

Wherein R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are each independently hydrogen, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight or branched unsaturated hydrocarbon, a nitrile group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a fluorenyl group, -0 or -0 _; the halogen is fluorine, chlorine, bromine or iodine;

The definitions of said, and R ₄ are the same as defined in claim 2.

The compound of the formula (I), the isomer, the diastereomer, the racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 3, wherein the structure is selected from the following structures Fragment:

5. A compound of the formula (I), an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound Selected from the following compounds:

Number Chinese name structure

(2'S)-3-{[l-(3-fluoro-2,6-dichlorophenyl)

3-{[1-(3-Fluoro-2,6-dichlorophenyl)ethyl]thio}-5-(4-{[4-(propan-2-yl)piperazine

-1-yl:)]carbonyl]phenyl:)pyridine-2-amine

(3'S)-3-{[l-(3-fluoro-2,6-dichlorophenyl)

DC295-22 Ethyl]thio 5-({4-[(3'-hydroxy)pyrrole

Phenyl-1-yl]carbonyl}phenyl)pyridine-2-amine

3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]

DC295-23 thiol }-5-{4-[(4-methanesulfonylpiperazine)

-1-yl)carbonyl]phenyl}pyridine-2-amine

3-{[1-(3-fluoro-2,6-dichlorophenyl)ethyl]

DC295-24 thio}- ₅ -(4-{[(3-hydroxy)piperidin-1-yl]

Carbonyl }phenyl)pyridine-2-amine

3- {[1-(3-Fluoro-2,6-dichlorophenyl)ethyl]

DC295-25 thiol }-5-(4-{[4-(2-hydroxyethyl)piperidin

Pyrazin-1-yl]carbonyl}phenyl:)pyridin-2-amine

4-(2-Amino-3-{[l-(3-fluoro-2,6-dichloro)

3-{[l-(3-fluoro-2,6-dichlorophenyl)ethyl]

DC295-35 jobs - i-P-hydroxy 诵

Pyridin-4-yl)-1 H-pyrazole-4-yl]pyridine-2-amine

3-{[1-(3-Fluoro-2,6-dichlorophenyl)ethyl] DC295-36 thiol-[μ^-methanesulfonylpiperidin-4-yl)-1H-pyrazole- 4-yl]pyridin-2-amine

6. A compound of the formula (I), an enantiomer, a diastereomer, a racemate, and mixtures thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein said The pharmaceutically acceptable salt is a non-toxic salt formed by reacting a compound of the formula (I) with an inorganic or organic acid;

Or an ester of the formula with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid followed by an inorganic base a sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt formed;

Or a methylamine salt, an ethylamine salt or an ethanolamine salt formed by the compound of the formula and an organic base; or the compound of the formula (I) is esterified with lysine, arginine or ornithine, and then with hydrochloric acid, hydrobromic acid, a corresponding inorganic acid salt formed by hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid or a corresponding organic acid salt formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.

The compound of the formula (I), the enantiomer, the diastereomer, the racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and Sulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, Hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and isethionic acid.

Step a: The 2-nitro-3-hydroxypyridine derivative is dissolved in a solvent, stirred with a base, and then hydrazine, dimethyl-dimethylthiocarbonyl chloride, stirred at room temperature or stirred under heating to obtain a compound I _a . The dissolution The agent is tetrahydrofuran, dimethylformamide or dioxane; the base is pyridine, triethylamine, triethylenediamine, diisopropylethylamine, sodium hydride or potassium hydride;

Step b: heating the diphenyl ether to reflux to obtain the compound I _b;歩c: adding an acylating reagent dropwise in an ice bath, dropping, stirring at room temperature

Step d: The compound I _b and the base are dispersed in a solvent, stirred at -10 to 40 ° C, and the solvent is distilled off, and 1 is added. The solution is stirred at room temperature to obtain a compound I _d , the solvent is a mixed solvent of water, methanol and tetrahydrofuran; the base is potassium hydroxide;

Step e: reducing the compound I _d with iron powder, and reacting with an acid to obtain a compound I _e; the acid or acetic acid;

Step f: bromination of compound I _e with a brominating agent to obtain compound I _f , the brominating reagent is N-bromosuccinimide or bromine;

Step h: Substituting Y in compound I _e with a nitrogen-containing group W to give compound I _g which is iodine, bromine, chlorine, alkyl ester, aryl ester, alkyl sulfonyl ester or aromatic a sulfonyl ester; the w is a phthalimide group, an azide, a succinimide group or a phthalimide;

Step k: dissolving the compounds I _h and Ii in a solvent to obtain a compound Ij under the action of a base, the solvent being dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, ethylene glycol dimethyl ether or Dioxane; the base is pyridine, triethylamine, triethylenediamine or diisopropylethylamine;

Step 1: Perform the same reaction as step g;

Option 3

RR ² , R ³ , R ⁴ , and R ⁵ are the same as defined in claim 1.

A pharmaceutical composition for treating and preventing cancer associated with tyrosine protein kinase c-Met, which comprises the compound of the formula (I:) according to any one of claims 1 to 7, which is Isomers, diastereomers, racemates, and mixtures thereof, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carriers, diluents or excipients.

The pharmaceutical composition according to claim 9, wherein the compound of the formula (I), its enantiomer, diastereomer, racemate, and mixture thereof or a drug thereof The salt used is from 1 to 99% by weight based on the total weight of the composition.

A pharmaceutical composition according to claim 9 or 10 which further comprises an odorant or a flavoring agent.

The compound of the formula (I) according to any one of claims 1 to 5, which is an enantiomer, a diastereomer, a racemate and a mixture thereof or a pharmaceutically acceptable salt thereof Use in the preparation of a medicament for the treatment and prevention of a disease associated with the tyrosine kinase c-Met signaling pathway.

13. The use according to claim 12, wherein the disease comprises hyperplasia, restenosis, immune disorder, inflammation, histiocytic lymphoma, ovarian cancer, head and neck squamous cell carcinoma, gastric cancer, breast cancer, Childhood hepatocellular carcinoma, colorectal cancer, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, pancreatic cancer, glioblastoma, prostate cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, thyroid cancer, testis Cancer, cervical cancer, lung adenocarcinoma, colon cancer, papillary renal cell carcinoma, glioblastoma, endometrial cancer, esophageal cancer, leukemia, renal cell carcinoma, bladder cancer, liver cancer, and astrocytoma.

14. The use according to claim 12, wherein the disease is a condition of: head and neck squamous cell carcinoma, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, Papillary renal cell carcinoma, liver cancer, gastric cancer, colon cancer, multiple myeloma and glioblastoma, hyperplasia, restenosis, immune disorders, and inflammation.

The compound of the formula (I) according to any one of claims 1 to 5, which is an enantiomer, a diastereomer, a racemate, a mixture thereof or a pharmaceutically acceptable salt thereof Use in the treatment and prevention of diseases associated with the tyrosine kinase c-Met signaling pathway.