WO2020038458A1

WO2020038458A1 - Class of fused ring triazole compound, preparation method, and use

Info

Publication number: WO2020038458A1
Application number: PCT/CN2019/102214
Authority: WO
Inventors: 万惠新; 潘建峰; 马金贵
Original assignee: 如东凌达生物医药科技有限公司
Priority date: 2018-08-23
Filing date: 2019-08-23
Publication date: 2020-02-27
Also published as: CN110857300A; CN110857300B

Abstract

Disclosed is a class of fused ring triazole compounds, a preparation method, and use. Specifically disclosed is a fused ring triazole compound as represented by formula (I), or its pharmaceutically acceptable salt, or its enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug, a preparation method therefor, and a pharmaceutical application thereof. (I)

Description

A class of fused ring triazole compounds, preparation method and application

This application requires a Chinese patent application CN201810965291.6 with a filing date of August 23, 2018, a Chinese patent application CN201811283207.9 with a filing date of October 31, 2018, and a Chinese patent with a filing date of December 7, 2018 Apply for the priority of CN201811498192.8. This application cites the full text of the aforementioned Chinese patent application.

Technical field

The invention belongs to the field of medicinal chemistry, and particularly relates to a class of fused ring triazole compounds, a preparation method and uses thereof.

Background technique

Receptor tyrosine kinase activation or gene mutation plays a key role in tumor occurrence, development, invasion and metastasis, and drug resistance, so as to become an important target for the development of anti-tumor drugs. Among them, fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase family, mainly including four subtypes of FGFR1, FGFR2, FGFR3 and FGFR4. Due to gene amplification, mutation, fusion, or ligand induction, FGFR members continue to activate, induce tumor cell proliferation and invasion, promote angiogenesis, and promote tumor deterioration. FGFRs are highly expressed and abnormally activated in many tumors, and are closely related to the poor prognosis of tumor patients. Therefore, FGFRs are recognized as an important target for antitumor, and the development of FGFR small molecule inhibitors has gradually received more and more attention.

Recently, researchers from Genentech found that the precise targeting of FGFR4 protein can inhibit the growth of hepatocellular carcinoma, which provides a new idea for the development of therapeutic drugs for hepatocytes. Of the more than 20 fibroblast growth factors (FGF) discovered so far, only FGF19 can specifically bind to FGFR4. FGF19 is a ligand of FGFR4, which is responsible for regulating normal bile secretion and liver cell proliferation in the liver. Its overexpression or overactivation can promote liver cell proliferation and induce liver cancer formation. This has been confirmed in transgenic mice, and knocking out the FGFR4 gene can block the development of hepatocellular carcinoma. At the same time, it has been clinically found that the occurrence of malignant tumors such as hepatocellular carcinoma, gastric cancer, pancreatic cancer and bile duct cancer is accompanied by overexpression and overactivation of FGFR gene in tumor tissues. Therefore, the specific targeting of fibroblast growth factor receptor FGFR is likely to become a new strategy for the treatment of various tumors, which has attracted wide attention of major pharmaceutical companies in recent years. However, existing FGFR inhibitor compounds such as BGJ398, AZD4547, AP24534, and BLU9931 are common or have poor target selectivity, or low target inhibitory activity, or poor pharmacological properties of the compound, or are prone to mutation resistance. , Leading to the clinical application of FGFR inhibitors. Therefore, the discovery and search of new compounds with high selectivity, high activity and high drugability of FGFR has become a hot spot at present.

Summary of the Invention

The technical problem to be solved by the present invention is to overcome the problems that the existing FGFR inhibitor compounds have a single structure, or have poor target selectivity, or low target inhibitory activity, or have poor pharmacological properties, or are prone to mutation and resistance. , And provides a class of fused ring triazole compounds, preparation method and application. The fused ring triazole compound of the present invention is a new type of specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used to treat tumors.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polycrystal Type or prodrug,

Where

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, alkane Radical, or alkoxy;

R _{5 is} selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or alkyl;

Y is N and Z is CR ₆ , or Y is CR ₆ and Z is N;

R _{6 is} selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylene- NR _6-1 R _6-2 ; preferably from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ heterocycloalkyl, or alkylene-NR _6-1 R _6-2 ; R _{6- 1} and R _{6-2 are} independently hydrogen or C ₁ -C ₆ alkyl;

M is selected from CR _a or N; R _{a is} selected from hydrogen, or halogen;

Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R _{7 is} selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; preferably from hydrogen, Halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; and one or more groups on R ₇ may interact with one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, or bridge ring ring system, the ring system has 0 to 3 heteroatoms including O, N, S; one or more of any of the above groups The hydrogen atom is optionally selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl, sulfonyl, carbonyl (-C (= O)-), 5-8 membered aryl or heteroaryl Group, 3-8 membered cycloalkyl group or 4-8 membered heterocycloalkyl group; among the substituents, one of the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group or more hydrogen atoms are optionally substituted with hydroxy, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl group, a 5-10 membered Aryl group, C ₁ -C ₆ alkyl substituted 5-10 membered heteroaryl, or substituted 3-8 membered cycloalkyl;

n is selected from 0-4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, or alkylene-NR _8-1 R _8-2 ; any of the above One or more hydrogen atoms on the group are optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide, C ₁ -C ₈ alkyl, C _1- C ₈ alkoxy, C ₁ -C ₈ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4 -8-membered cycloalkyl or heterocycloalkyl; R _8-1 and R _{8-2 are} independently hydrogen or C ₁ -C ₆ alkyl;

Wherein, the heteroaryl group includes 1-3 heteroatoms selected from the group: N, O, P, and S, and the heterocycloalkyl group includes 1-3 heteroatoms selected from the group: N , O, P, and S.

In certain preferred embodiments of the present invention, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer Conformers, solvates, polymorphs or prodrugs,

Where

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C ₁ -C ₆ alkyl Oxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy;

R _{5 is} selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or C ₁ -C ₆ alkyl;

Y is N and Z is CR ₆ , or Y is CR ₆ and Z is N;

R _{6 is} selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl, sulfonyl, C _6- C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, or C ₁ -C ₆ alkylene-NR _6-1 R _6-2 ; preferably from hydrogen, halo, C ₁ -C ₆ alkyl, 4-6 membered heterocycloalkyl, or a C ₁ -C ₆ alkylene group -NR _6-1 R _6-2; R _6- ₁ and R _{6 -2 is} independently hydrogen or C ₁ -C ₆ alkyl;

M is selected from CR _a or N; R _{a is} selected from hydrogen, or halogen;

Cy is selected from 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl; preferably from 5-6 membered cycloalkyl, 5-6 membered Heterocycloalkyl, 5-8 membered aryl, or 5-6 membered heteroaryl;

R _{7 is} selected from hydrogen, halogen, cyano, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl, sulfonyl, C ₆ -C ₁₀ aromatic Radical, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl; preferably from hydrogen, halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, Or 4- to 8-membered heterocycloalkyl; and one or more groups on R ₇ may be substituted with one or more hydrogens on the ring Cy to form the corresponding rings such as fused rings, fused rings, spiro rings, bridged rings, etc. System, the ring system has 0 to 3 heteroatoms including O, N, S; the C ₁ -C ₆ alkyl group is optionally substituted by 1-3 selected from hydroxyl, halogen, C ₁ -C ₆ alkyl Oxygen, -NR _7-2 R _7-3 , 4-8 membered heterocycloalkyl, or R _7-4 substituted 4-8 membered heterocycloalkyl; R _7-4 is C ₁ -C ₆ alkyl; R _7-2 and R _{7-3 are} independently selected from hydrogen or C ₁ -C ₆ alkyl; said C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-11 membered heterocycloalkyl or optionally independently substituted with 1-3 substituents selected from C ₁ -C ₆ alkyl, R _7-5 is a substituted C ₁ -C ₆ alkyl , -NR _7-6 R _7-7 , carbonyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl ; Wherein, R _7-5 is selected from hydroxy, cyano, C ₁ -C ₆ _alkoxy, -NR _7-5a R 7-5b, 5-10 membered heteroaryl, R _7- _5c substituted 5-10 Heteroaryl, or 3-8 membered cycloalkyl; R _7-6 , R _7-7 , R _7-5a and R _{7-5b are} independently selected from hydrogen or C ₁ -C ₆ alkyl; R _7-5c Is C ₁ -C ₆ alkyl;

n is selected from 0, 1, 2, 3, or 4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, sulfone, sulfoxide, or C ₁ -C ₆ alkylene-NR _{8- 1} R _8-2 ; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl, sulfonyl, 5- 8-membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; R _8-1 and R _{8-2 are} independently hydrogen or C ₁ -C ₆ alkyl.

Where

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;

R _{5 is} selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably, hydrogen, halogen, alkyl;

Y, Z are each independently selected from N or CR ₆ ; R _{6 is} independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ heterocycloalkyl, etc .;

M is independently selected from CR _a or N; R _{a is} independently selected from hydrogen, halogen;

Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;

R _{7 is} selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, Halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R ₇ may be linked to one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, bridge ring and other ring systems. The ring system may have 0 to 3 heteroatoms including O, N, S;

n is independently selected from 0-4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C _1- C ₈ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl ; Wherein the heteroaryl group contains 1-3 heteroatoms selected from the group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the group: N, O, P or S.

In a further embodiment, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvent thereof Compounds, polymorphs or prodrugs,

M is independently selected from CH or N;

R ₁ and R _{2 are} independently selected from hydrogen and halogen, preferably from fluorine and chlorine; R ₃ and R _{4 are} independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl, or heterocycloalkyl, and more preferably From fluorine, methoxy;

R _{5 is} selected from hydrogen, halogen, and alkyl; further preferably, hydrogen, fluorine, and methyl;

Y, Z are each independently selected from N or CR ₆ ; R _{6 is} independently selected from hydrogen, halogen, C1-C ₆ alkyl, preferably from hydrogen;

Cy is independently preferably a 4- to 6-membered cycloalkyl or heterocycloalkyl, a 5- to 6-membered aryl or heteroaryl; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, piperidine Ring, benzene ring, pyridine ring, pyrazole ring, etc .;

R _{7 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, cyano, hydroxy, amino, 4- to 8-membered heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like is more preferred. , Fluorine, cyano, amino, C ₁ -C ₆ alkyl or 4-7 membered heterocycloalkyl, etc .; more preferably hydrogen, fluorine, methyl, piperazinyl, morpholinyl, piperidinyl, Tetrahydropyrrolyl, etc .;

n is independently selected from 0-4, preferably from 0-2.

R ₈ , R _9, and R _{10 are} independently selected from hydrogen, halogen, alkyl, and cyano; further preferably, they are selected from hydrogen, fluorine, methyl, and the like.

In a further preferred embodiment, the compound has the following general formulae (IA), (IB):

Here, each group is defined as described above.

A method for preparing a compound of formula I, characterized in that the method includes steps a-d:

a) converting a compound of general formula (A) into a compound of general formula (B) by using literature methods; and

b) performing a substitution reaction or a coupling reaction between a compound of the general formula (B) and a nitro-substituted amine compound under the reaction conditions in the presence of an acid, or a base, or a transition metal catalyst to obtain a compound of the general formula (C); and

c) reacting the compound of the general formula (C) under the conditions of a metal reducing agent or a reducing agent such as hydrogen or sodium thiosulfate to obtain the general compound (D); and

d) A compound of the general formula (I) is prepared by subjecting a compound of the general formula (D) to a condensation reaction with an acrylic acid or an acryloyl chloride compound in the presence of a base catalyst or a condensation reagent.

In each formula, LG represents a leaving group, such as halogen, sulfone group, sulfoxide group, sulfonate group, etc., and the definitions of other groups are as described above;

Preferably, the steps a), b), c), and d) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate. Glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, N, N- Dimethylacetamide, dioxane, or a combination thereof.

Preferably, the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), acetic acid Palladium, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium, bis (tri-o-phenylmethylphosphine) palladium dichloride, 1,2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: Tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tri-o-phenylmethylphosphine, or combinations thereof.

Preferably, the condensation reagent is selected from the group consisting of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, TBTU, etc., or a combination thereof.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undecyl-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or a combination thereof.

Preferably, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or a combination thereof.

In certain preferred embodiments of the present invention, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug,

Where

Y is N and Z is CR ₆ ;

Or, Y is CR ₆ and Z is N;

R _{6 is} independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the like; preferably from Hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ heterocycloalkyl, etc .;

n is independently selected from 0-4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C _1- C ₈ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl .

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₁ and R _{2 are} independently When it is a halogen, the halogen is preferably fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₃ and R _{4 are} independently When it is halogen, the halogen is preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₃ and R _{4 are} independently When it is an alkoxy group, the alkoxy group is preferably a C ₁ -C ₆ alkoxy group, and more preferably a C ₁ -C ₄ alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy) , N-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), and methoxy is more preferred.

In certain preferred embodiments of the present invention, certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₆ is an alkyl group, The alkyl group is preferably a C ₁ -C ₆ alkyl group, and more preferably a C ₁ -C ₄ alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₆ is -alkylene When -NR _6-2 R _6-3 , the alkylene group is preferably a C ₁ -C ₆ alkylene group, more preferably a C ₁ -C ₄ alkylene group, and still more preferably a methylene group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R _6-2 and R _{6 When -3 is} independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is preferably C ₁ -C ₄ alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 3-8 membered hetero In the case of a cycloalkyl group, the 3-8 membered heterocycloalkyl group is preferably a 5-6 membered "heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" Heterocycloalkyl, more preferably tetrahydrofuranyl (e.g.

), Tetrahydropyrrolyl (e.g.

), Tetrahydrothienyl (e.g.

), Or tetrahydropyranyl (e.g.

), More preferably tetrahydrofuranyl or tetrahydropyranyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 yuan aromatic As the radical, the 5- to 8-membered aryl group is preferably a phenyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 membered hetero In the case of an aryl group, the 5- to 8-membered heteroaryl group is preferably a 5- to 6-membered heteroaryl group having "a heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" , More preferably pyrazolyl (e.g.

) Or pyridyl (e.g.

), More preferably pyrazolyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₇ is alkyl, The alkyl group is preferably a C ₁ -C ₆ alkyl group, and more preferably a C ₁ -C ₄ alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl, ethyl, n-propyl or isobutyl, and still more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₇ is heterocycloalkyl In this case, the heterocycloalkyl group is preferably a 4- to 11-membered heterocycloalkyl group, and more preferably 5 having a "heteroatom selected from one or more of N, O, or S, and the number of heteroatoms is 1-3." A 7-membered monocyclic heterocycloalkyl group, or an 8-9 membered bicyclic heterocycloalkyl group having "heteroatoms selected from one or more of N, O or S, and 1-3 heteroatoms"; The 5-7 membered monocyclic heterocycloalkyl group is preferably piperidinyl (e.g.

), Piperazinyl (e.g.

), Or homopiperazinyl (e.g.

); The 8-9 membered bicyclic heterocycloalkyl group is preferred

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₇ , when the When the alkyl group is optionally substituted with 1-3 C ₁ -C ₈ alkoxy groups, the C ₁ -C ₈ alkoxy group is preferably a C ₁ -C ₄ alkoxy group (for example, methoxy, ethoxy , Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy), more preferably methoxy.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₇ , when the When the alkyl group is optionally substituted with 1-3 4-8 membered heterocycloalkyl groups, said 4-8 membered heterocycloalkyl group is preferably "heteroatom selected from one or more of N, O or S A 5-6 membered heterocycloalkyl group having 1 to 3 heteroatoms, more preferably a tetrahydropyrrolyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₇ , when the When the heterocycloalkyl is optionally substituted with 1-3 C ₁ -C ₈ alkyl, the C ₁ -C ₈ alkyl is preferably C ₁ -C ₄ alkyl (eg methyl, ethyl, propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl, ethyl or isopropyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₇ , when the When a heterocycloalkyl group is optionally substituted with 1-3 4-8 membered heterocycloalkyl groups, the 4-8 membered cycloalkyl group is preferably "a heteroatom selected from one or more of N, O or S In particular, a 4- to 6-membered cycloalkyl group having 1 to 3 heteroatoms, more preferably a tetrahydropyrrolyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R ₇ , the substitutions described When one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl is preferably C ₁ -C ₄ alkyl (eg methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl Or ethyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R ₇ , the substitutions described When one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy is preferably C ₁ -C ₄ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy Or tert-butoxy), more preferably methoxy.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R ₇ , the substitutions described When one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by 5-10 membered heteroaryl group, or C ₁ -C _{When 6} alkyl substituted 5-10 membered heteroaryl is substituted, the 5-10 membered heteroaryl is preferably "a heteroatom selected from one or more of N, O or S, and the number of heteroatoms is 1- 3 "5-6 membered heteroaryl, more preferably pyrazolyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R ₇ , the substitutions described When the one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C ₁ -C ₆ alkyl group, When the heteroaryl group is substituted, the C ₁ -C ₆ alkyl group is preferably a C ₁ -C ₄ alkyl group, and more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R ₇ , the substitutions described When one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted with 3-8 membered cycloalkyl group, the The 3-8 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, and more preferably a cyclopropyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₇ , when R _{7- 2. When} R _7-3 and R _{7-4 are} independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is preferably C ₁ -C ₄ alkyl (e.g. methyl, ethyl, propyl (Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl or ethyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R _7-5 is C ₁ In the case of -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is preferably C ₁ -C ₄ alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy Group, isobutoxy, sec-butoxy or tert-butoxy), more preferably methoxy.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R _7-5 is 5- In the case of a 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted with R _7-5c , the 5- to 10-membered heteroaryl group is preferably "a heteroatom selected from one or more of N, O or S A 5-6 membered heteroaryl group having 1 to 3 heteroatoms, more preferably a pyrazolyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): When R _7-5 is 3- In the case of an 8-membered cycloalkyl group, the 3-8-membered cycloalkyl group is preferably a 3-6-membered cycloalkyl group, and more preferably a cyclopropyl group.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R _7-6 , R _{7 When -7} , R _7-5a and R _7-5b and R _{7-5c are} independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is preferably C ₁ -C ₄ alkyl (for example methyl , Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₈ is alkyl, The alkyl group is preferably a C ₁ -C ₆ alkyl group, and more preferably a C ₁ -C ₄ alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₈ , when the When the alkyl group is substituted with one or more halogens, the halogen is preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): In R ₈ , when the When the alkyl group is substituted with one or more halogens, the number of said halogens is preferably 1, 2 or 3, and more preferably 3.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R ₉ and R _{10 are} independently When it is C ₁ -C ₆ alkylene-NR _8-1 R _8-2 , the C ₁ -C ₆ alkylene is preferably C ₁ -C ₄ alkylene, and more preferably methylene.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R _8-1 and R _{8 When -2 is} independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is preferably C ₁ -C ₄ alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R ₁ and R _{2 are} independently selected From fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R ₃ and R _{4 are} independently selected Self-fluorine or methoxy, preferably methoxy.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R ₅ is hydrogen.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): Y and Z are independently selected from N , -CH-, -C (CH ₃ )-, or

N or -CH- is preferred.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): M is selected from CH or N.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): Cy is selected from

Preferred

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R _{7 is} selected from H, F, Me, CF ₃ ,

H, F, Me,

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): compounds represented by formula (I) Structure in

From

Preferred

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R _{8 is} selected from H, F, Cl, CN, Me or CF ₃ , preferably H.

In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): R ₉ and R _{10 are} independently selected From H, or

H is preferred.

Where

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from hydrogen, halogen, or alkoxy;

R ₅ is hydrogen;

Y is N and Z is CR ₆ , or Y is CR ₆ and Z is N;

R _{6 is} selected from hydrogen, alkyl, or alkylene-NR _6-1 R _6-2 ; R _6-1 and R _{6-2 are} independently hydrogen or C ₁ -C ₆ alkyl;

M is selected from CR _a or N; R _a is hydrogen;

Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

R _{7 is} selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of halogen, hydroxy, amino, Cyano, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; In the substituent, one or more hydrogen atoms on the amino group, C ₁ -C ₈ alkyl group, and 4- to 8-membered heterocycloalkyl group are optionally substituted by hydroxyl group, cyano group, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted amino, 5-10 membered heteroaryl, C ₁ -C ₆ alkyl substituted 5-10 membered heteroaryl, or 3 -8-membered cycloalkyl;

n is selected from 0-4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR _8-1 R _8-2 ; one or more hydrogen atoms on any of the above groups Optionally substituted with halogen; R _8-1 and R _{8-2 are} independently hydrogen or C ₁ -C ₆ alkyl.

Where

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from hydrogen, halogen, or C ₁ -C ₆ alkoxy;

R ₅ is hydrogen;

Y is N and Z is CR ₆ , or Y is CR ₆ and Z is N;

R _{6 is} selected from hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylene-NR _6-1 R _6-2 ; R _6-1 and R _{6-2 are} independently hydrogen or C _1- C ₆ alkyl;

M is selected from CR _a or N; R _a is hydrogen;

R _{7 is} selected from hydrogen, halogen, C ₁ -C ₆ alkyl, or 4-11 membered heterocycloalkyl; said C ₁ -C ₆ alkyl is optionally selected from 1-3, selected from hydroxyl, halogen, C ₁ -C ₆ alkoxy, -NR _7-2 R _7-3 , 4-8 membered heterocycloalkyl, or R _7-4 substituted 4-8 membered heterocycloalkyl; R _7-4 is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl; R _7-2 and R _{7-3 are} independently selected from hydrogen or C ₁ -C ₆ alkyl; said heterocyclic ring Alkyl is optionally optionally substituted with 1-3 C ₁ -C ₆ alkyl, R _7-5 substituted C ₁ -C ₆ alkyl, -NR _7-6 R _7-7 , carbonyl, 3- 8-member ring group, or a 4-8 membered heterocycloalkyl substituents; wherein, R _7- ₅ selected from hydroxy, cyano, C ₁ -C ₆ alkoxy, -NR _7-5a R _{₇ -5b} , 5-10 membered heteroaryl, R _7-5c substituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl; R _7-6 , R _7-7 , R _7-5a and R _{7-5b is} independently selected from hydrogen or C ₁ -C ₆ alkyl; R _7-5c is C ₁ -C ₆ alkyl;

n is selected from 0-4;

R ₈ , R ₉ and R _{10 are} independently selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylene-NR _8-1 R _8-2 ; any of the above One or more hydrogen atoms on the group are optionally substituted with halogen; R _8-1 and R _{8-2 are} independently hydrogen or C ₁ -C ₆ alkyl.

Where

R ₁ and R _{2 are} independently selected from halogen, or C ₁ -C ₆ alkoxy;

R ₃ and R _{4 are} independently selected from halogen, or C ₁ -C ₆ alkoxy;

R ₅ is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

R _{7 is} selected from hydrogen, halogen, C ₁ -C ₆ alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C _1- C ₆ alkyl, R _7-5 substituted C ₁ -C ₆ alkyl, -NR _7-6 R _7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R _7-5 is a 3-8 membered cycloalkyl; R _7-6 and R _{7-7 are} independently C ₁ -C ₆ alkyl;

n is selected from 0, 1 or 2;

R _{8 is} selected from hydrogen, halogen, cyano, or C ₁ -C ₆ alkyl; said C ₁ -C ₆ alkyl is optionally substituted with 1-3 halogens;

R ₉ and R _{10 are} independently selected from hydrogen, or C ₁ -C ₆ alkylene-NR _8-1 R _8-2 ; R _8-1 and R _{8-2 are} independently C ₁ -C ₆ alkyl.

Where

R ₁ and R _{2 are} independently halogen;

R ₃ and R _{4 are} independently C ₁ -C ₆ alkoxy;

R ₅ is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

n is selected from 0, 1 or 2;

R ₉ and R ₁₀ are hydrogen.

Where

R ₁ and R _{2 are} independently halogen;

R ₃ and R _{4 are} independently C ₁ -C ₆ alkoxy;

R ₅ is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is selected from a 5-8 membered aryl group, or a 5-8 membered heteroaryl group;

R _{7 is} selected from hydrogen, C ₁ -C ₆ alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 selected from C _1- C ₆ alkyl, R _7-5 substituted C ₁ -C ₆ alkyl, -NR _7-6 R _7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein R _{7 -5} is a 3-8 membered cycloalkyl group; R _7-6 and R _{7-7 are} independently C ₁ -C ₆ alkyl;

n is selected from 0, 1 or 2;

R _{8 is} selected from hydrogen, halogen, or C ₁ -C ₆ alkyl;

R ₉ and R ₁₀ are hydrogen.

Where

R ₁ and R _{2 are} independently halogen;

R ₃ and R _{4 are} independently C ₁ -C ₆ alkoxy;

R ₅ is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is a 5-8 membered aryl group;

R _{7 is} selected from hydrogen, or a 4-11 membered heterocycloalkyl group; the 4-11 membered heterocycloalkyl group is independently optionally substituted with 1-3 C ₁ -C ₆ alkyl groups;

n is selected from 0, 1 or 2;

R ₈ is hydrogen;

R ₉ and R ₁₀ are hydrogen.

In certain preferred embodiments of the present invention, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer A compound, solvate, polymorph or prodrug, wherein the compound represented by formula (I) has the following general formula (IA) or (IB):

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , Cy, M, and n are as defined above.

In certain preferred embodiments of the present invention, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, wherein the compound represented by formula (I) may be any one of the following compounds:

The invention also provides a method for preparing a compound represented by formula (I), which comprises steps a-d:

a) converting a compound of general formula (A) into a triazolium intermediate compound of general formula (B); and

c) subjecting the compound of general formula (C) to a reduction reaction in the presence of a reducing agent to obtain a compound of general formula (D); the reducing agent is a metal reducing agent hydrogen or sodium thiosulfate; and

d) in the presence of a base or a condensation reagent, subjecting the compound of general formula (D) to an acrylic acid or an acrylic acid chloride compound to perform a condensation reaction to prepare a compound represented by formula (I);

Among them, LG represents a leaving group conventionally used in such reactions in the art, such as halogen, sulfone, sulfoxide, sulfonate and the like, and the definitions of other groups are as described above.

Preferably, the conditions and operations of step a) are the same as those in the literature.

Preferably, the steps a), b), c), and d) are each performed in a solvent, and each of the solvents is independently selected from water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate. Glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, N, N- One or more of dimethylacetamide and dioxane.

Preferably, the transition metal catalyst is selected from tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), palladium acetate, chlorine Palladium, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, bis One or more of (tri-o-phenylmethylphosphine) palladium dichloride and 1,2-bis (diphenylphosphino) ethane palladium dichloride; the ligand of the transition metal catalyst is selected from tris One or more of tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, and tri-o-phenylmethylphosphine .

Preferably, the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU and TBTU.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, One or more of sodium carbonate and sodium bicarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0 ] One or more of undecyl-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, and dimethylpyridine.

Preferably, the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid.

Preferably, the reducing agent is selected from one or more of iron powder, zinc powder, stannous chloride, sodium thiosulfate, sodium sulfite, and hydrogen.

The invention also provides a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, and a pharmaceutically acceptable carrier. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or A prodrug may be a therapeutically effective amount.

The pharmaceutical composition is preferably a pharmaceutical composition for treating tumors, which is composed of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, solvates, polymorphs or prodrugs, and a pharmaceutically acceptable carrier.

The invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly The use of a crystalline form or a prodrug, or the above pharmaceutical composition in the preparation of a medicament. The medicament is preferably a medicament for preventing and / or treating tumors, or a medicament for diseases related to FGFR kinase. The tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, colon cancer, bile duct cancer, brain cancer, and leukemia. , Lymphoma, nasopharyngeal carcinoma, etc., especially liver cancer or bile duct cancer; the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.

The invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly Use of a crystalline form or a prodrug, or the above pharmaceutical composition in the preparation of an FGFR kinase inhibitor. The FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.

The present invention also provides a method for preventing and / or treating a tumor, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or pharmaceutical compositions described above.

the term

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise stated, all patents, patent applications, and published materials cited herein are incorporated by reference in their entirety.

It is to be understood that the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter of the invention. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly indicates otherwise, the singular forms used in the specification and claims include the plural forms of the matters referred to. It should also be noted that unless otherwise stated, "or", "or" is used to mean "and / or". Furthermore, the terms "including" and other forms such as "including", "containing", and "containing" are not limiting.

Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods are used. Unless specifically defined, terms used herein in analytical chemistry, organic synthetic chemistry, and related descriptions of medicinal and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or as described in the present invention. The techniques and methods described above can generally be implemented according to conventional methods well known in the art, based on descriptions in several summary and more specific references that are cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general chemical formula written from left to right, the substituent also includes a chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All documents or parts of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include carbons that may be present in the substituents of the group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below, unless specifically stated otherwise.

In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to the -OH group; "hydroxyalkyl" refers to an alkane group as defined below substituted with a hydroxyl group (-OH) "Carbonyl" refers to the -C (= O)-group; "nitro" refers to -NO ₂ ; "cyano" refers to -CN; "amino" refers to -NH ₂ ; "substituted amino" Means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arane Amino, heteroaralkylamino; "carboxy" means -COOH.

In the present application, as a group or part of another group (for example, used in a group such as a halogen-substituted alkyl group), the term "alkyl" means only composed of carbon atoms and hydrogen atoms, and no unsaturated A straight or branched hydrocarbon chain group having a bond, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule through a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl.

In the present application, as a group or part of another group, the term "alkenyl" means composed of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) (More preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butane- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

In the present application, as a group or part of another group, the term "alkynyl" means composed of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

In the present application, as a group or part of another group, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and may pass through any suitable The carbon atom is connected to the rest of the molecule by a single bond. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Acylcycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] Octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [3.2.1] octenyl, adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

In the present application, as a group or part of other groups, the term "heterocyclyl" also means "heterocycloalkyl", which means from 2 to 14 carbon atoms and 1 to 6 selected from nitrogen and phosphorus A stable 3- to 20-membered non-aromatic cyclic group consisting of heteroatoms of oxygen, oxygen and sulfur. Unless otherwise specified in this specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic ring system, which may include a fused ring system, a bridged ring system, or a spiro ring system; Nitrogen, carbon or sulfur atoms may be optionally oxidized; nitrogen atoms may be optionally quaternized; and heterocyclic groups may be partially or fully saturated. Heterocyclyl can be attached to the rest of the molecule via a carbon atom or a heteroatom and via a single bond. In a fused ring-containing heterocyclic group, one or more rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purpose of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3.5] non Alk-7-yl, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] heptane-2-yl, aza Cyclobutyl, pyranyl, tetrahydropyranyl, thioranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidine , Phthalimide and so on.

In the present application, as a group or part of another group, the term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purpose of the present invention, the aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl and the like.

In this application, the term "arylalkyl" refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.

In the present application, as a group or part of another group, the term "heteroaryl" means having 1 to 15 carbon atoms in the ring (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen A 5- to 16-membered conjugated ring system group of a heteroatom of oxygen, oxygen, sulfur, and phosphorus. Unless otherwise specified in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the The aryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring. The nitrogen, oxygen, sulfur, and phosphorus atoms in the heteroaryl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized. For the purpose of the present invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably 1 to 4 members. A stable 5- to 10-membered aromatic group from a heteroatom of nitrogen, oxygen, and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benpyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthroline, phenanthroline, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, fluorinyl, quinazolinyl, phenylthio, midindenyl, o-diazaphenanthryl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo [b] thienyl, naphthopyridyl, [1,2,4] triazolo [4 , 3-b] pyridazine, [1,2,4] triazolo [4,3-a] pyrazine, [1,2,4] triazolo [4,3-c] pyrimidine, [1, 2,4] triazolo [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine Wait.

In this application, the term "heteroarylalkyl" refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.

In this application, "optional" or "optionally" means that the event or condition described later may or may not occur, and the description includes both the occurrence or non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both a substituted aryl group and an unsubstituted aryl group.

As used herein, the terms "portion", "structural portion", "chemical portion", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.

A "stereoisomer" refers to a compound that is composed of the same atom and is bonded through the same bond, but has a different three-dimensional structure. The invention will cover various stereoisomers and mixtures thereof.

When the compound of the present invention contains an olefinic double bond, unless otherwise stated, the compound of the present invention is intended to include E- and Z-geometric isomers.

"Tautomers" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be included within the scope of the invention.

The compounds of the invention, or their pharmaceutically acceptable salts, may contain one or more chiral carbon atoms, and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry. The invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The compounds of the present invention can be prepared as racemates, diastereomers or enantiomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or salts or derivatives of ), For example, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral, Separations, Annu. Rev. Anal. Chem. 3 : 341-63, 2010; Fumiss et al. (Eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.THED., Longman Scientific and Technical Technology Ltd., Essex, 1991, 809-816; Heller, Acc.Chem .Res. 1990, 23, 128.

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , Alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base capable of maintaining the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to different solid crystalline phases produced by certain compounds of the present invention due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.

Generally, crystallization will produce a solvate of a compound of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention can form true solvates, but in some cases it is also possible to keep only the water or a mixture of water plus a portion of the solvent. The compounds of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The invention also includes prodrugs of the aforementioned compounds. In the present application, the term "prodrug" means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. When administered to an individual in need, the prodrug may not be active, but is transformed in vivo into the active compound of the invention. Prodrugs are usually rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide the advantages of solubility, histocompatibility, or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxy protecting groups. Specific prodrug preparation methods can refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable organisms. React or interact in an undesirable manner with any of the components contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authority as acceptable for human or livestock use. , Diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

The "tumor" and "abnormal cell proliferation-related diseases" described in the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "preventive," "prevention," and "prevention" include enabling a patient to reduce the likelihood of the occurrence or worsening of a disease or disorder.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) preventing the occurrence of a disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed as having the disease or condition;

(ii) inhibit a disease or disorder, that is, curb its development;

(iii) alleviates a disease or disorder, that is, regresses the state of the disease or disorder; or

(iv) alleviate symptoms caused by the disease or disorder.

As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to at least one agent or compound sufficient to a certain extent relieve one or more symptoms of the disease or condition being treated after administration. The amount. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for use in therapy is an amount of a composition comprising a compound disclosed herein that is required to provide a significant clinically alleviating effect on a condition. An effective amount suitable for any individual case can be determined using techniques such as a dose escalation test.

As used herein, the terms "taking," "administering," "administering," and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. The ones discussed in Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "pharmaceutical combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents", etc. refer to a drug treatment obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "unfixed combination" refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.

Those skilled in the art will also understand that in the methods described below, the intermediate compound functional group may need to be protected by a suitable protecting group. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M.Wuts, Protective Groups in Synthesis, (1999), 4th Ed., Wiley. The protective group may also be a polymer resin.

It should be understood that, within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them one by one here.

On the basis of conforming to common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention lies in that the fused ring triazole compound of the present invention is a novel specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used for treating tumors.

detailed description

After a long and intensive study, the present inventors prepared a class of compounds having a novel structure represented by Formula I, and found that they have good FGFR kinase inhibitory activity, and the compounds are at extremely low concentrations (can be as low as ≤ Under 10nmol / L), it has specific and irreversible inhibitory effect on FGFR kinase, and its inhibitory activity is quite excellent, so it can be used to treat related diseases such as tumors caused by FGFR kinase mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.

The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are generally specified according to conventional conditions or conditions recommended by the manufacturer. Unless stated otherwise, percentages and parts are weight percentages and parts by weight.

This application requires a Chinese patent application CN201810965291.6 with a filing date of August 23, 2018, a Chinese patent application CN201811283207.9 with a filing date of October 31, 2018, and a Chinese patent with a filing date of December 7, 2018 Apply for the priority of CN201811498192.8. This application cites the full text of the aforementioned Chinese patent application. For relevant information of the compounds involved in the present invention, if it is not specifically disclosed herein, reference may be made to the above patent application text.

Intermediate preparation

Intermediate 1: 6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2-methylthio-pyridine [2,3-d] pyrimidin-7-ylamine

Step 1: Add 1,3-dimethoxy-5-methylbenzene (30g, 0.20mol) and dichloromethane (900mL) to a dry round bottom flask (1L), and add the solution to the above solution under ice-cooling. Dichlorosulfone (52.5 g, 0.40 mol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. After completion of the reaction, a NaHCO ₃ aqueous solution was added dropwise to adjust pH = 8, and extracted with dichloromethane, washed with dilute hydrochloric acid and distilled water, dried, and concentrated under reduced pressure to obtain compound 2,4-dichloro-1,5-dimethoxy- 3-methylbenzene (31 g, white solid) was used directly in the next step.

Step 2: Dissolve 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31g, 0.14mol) in CCl ₄ (600mL) and place in a dry round bottom flask (1000mL) At room temperature, azobisisobutylcyanide (3.0 g, 0.018 mol) and NBS (27.6 g, 0.154 mol) were sequentially added at room temperature. The reaction was carried out at 80 degrees for 3 hours. The reaction was quenched by adding NaHCO ₃ aqueous solution, and then extracted with dichloromethane. The organic phase was dried, concentrated, and methyl tert-butyl ether was crystallized to obtain the compound 3-bromomethyl-2,4-dichloro-1. , 5-dimethoxybenzene (30 g, white solid).

Step 3: Add the compound 3-bromomethyl-2,4-dichloro-1,5-dimethoxybenzene (30g, 0.1mol) and acetonitrile (500mL) to a dry 1000mL round bottom flask at room temperature. Trimethylsilyl cyanide (12 g, 0.34 mmol) and tetrabutylammonium fluoride (100 mL, 1 mol / L) were added. After stirring at room temperature for 1 h, TLC showed the reaction was over. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried and concentrated. The concentrate was slurried with ethyl acetate to obtain the compound (2,6-dichloro-3,5-dimethoxy-benzene). ) -Acetonitrile (20 g, white solid).

Step 4: In a dry 250mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl) -acetonitrile (10.4g, 0.028mol) and DMF (100mL) at room temperature. Next, 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol) were sequentially added, and the reaction was stirred overnight until the reaction was completed. The reaction solution was extracted with ethyl acetate, the organic phase was washed with distilled water and saturated brine, dried and filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using an eluent system (DCM: MeOH = 30: 1) to obtain compound 6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2-methylthio-pyridine [2,3-d] pyrimidin-7-ylamine (3.7 g, yellow solid). LC-MS: ESI [M + H] ⁺ = 399.0; 1H-NMR (400MHz, CDCl ₃ ) δ8.80 (s, 1H), 7.69 (s, 1H), 6.67 (s, 1H), 3.97 (s, 6H), 2.68 (s, 3H).

Intermediate 2: 7-chloro-3- (2,6-dichloro-3,5-dimethoxy-phenyl)-[1,6] naphthyridin-2-ylamine

In a dry 250 mL round bottom flask, add 4-amino-6-chloro-pyridine-3-carboxaldehyde (2g, 0.013mol) and NMP (20mL), and then add the compound (2,6-dichloro-3,5) in this order. -Dimethoxy-phenyl) -acetonitrile (4.4 g, 0.018 mol), potassium carbonate (5.27 g, 0.039 mol), and the reaction was stirred at 80 degrees. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with distilled water and saturated brine in sequence, dried and filtered, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography with an eluent system (DCM: MeOH = 30: 1) Purification gave compound 7-chloro-3- (2,6-dichloro-3,5-dimethoxy-phenyl)-[1,6] naphthyridin-2-ylamine (0.8 g, yellow solid). LC-MS: ESI [M + H] ⁺ = 383.9; 1H-NMR (400MHz, DMSO-d6) δ 8.71 (s, 1H), 7.88 (s, 1H), 7.34 (s, 1H), 7.00 (s 1H), 3.94 (s, 6H).

Intermediate 3: 4- (4-methyl-piperazin-1-yl) -2-nitro-phenylamine

Step 1: Dissolve 4- (4-methyl-piperazin-1-yl) -aniline (5g) and triethylamine (5g) in dry ethyl acetate (20mL). Add acetic anhydride (5 mL). After the dropwise addition, the reaction was carried out at room temperature for 3 hours. A solid was precipitated in the reaction solution, filtered under reduced pressure, washed with ethyl acetate, and dried to obtain N- [4- (4-methyl-piperazin-1-yl) -phenyl] -acetamide as a solid (4 g). LC-MS: ESI [M + H] ⁺ = 234.3.

Step 2: Dissolve N- [4- (4-methyl-piperazin-1-yl) -phenyl] -acetamide (4g) in concentrated sulfuric acid (10mL), and slowly add dropwise while cooling in an ice bath. Concentrated nitric acid (3 mL), stirring was continued for 1 hour after the dropwise addition. The reaction solution was poured into ice cubes, a solid was precipitated, filtered under reduced pressure, dried, and recrystallized from ethyl acetate to obtain N- [4- (4-methyl-piperazin-1-yl) -2-nitro-phenyl ] -Acetamide solid (2.8 g). LC-MS: ESI [M + H] ⁺ = 279.1.

Step 3: Dissolve N- [4- (4-methyl-piperazin-1-yl) -2-nitro-phenyl] -acetamide (2.5g) in methanol (10mL), and add 4N hydrochloric acid The solution (10 mL) was heated at reflux for 1 hour. After the reaction, the reaction solution was diluted with water, and the pH was adjusted to 8-9 with ammonia water under ice-cooling, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4- (4-methyl- Piperazin-1-yl) -2-nitro-aniline. LC-MS: ESI [M + H] ⁺ = 237.2.

Referring to the same synthetic method and steps, the following intermediates 3A-3F were prepared:

Intermediate 3A: 4- (4-ethyl-piperazin-1-yl) -2-nitro-aniline

LC-MS: ESI [M + H] ⁺ = 251.2. 1H-NMR (400MHz, DMSO-d6) δ7.51 (d, J = 2.0Hz, 1H), 7.29 (dd, J = 2.0, 7.2Hz, 1H ), 6.95 (d, J = 7.2 Hz, 1H), 3.11 (t, J = 4.0 Hz, 4H), 2.67 (t, J = 4.0 Hz, 4H), 2.51-2.55 (m, 2H), 1.69 (t , J = 6.0Hz, 3H).

Intermediate 3B: 4- (1-methyl-piperidin-4-yl) -2-nitro-aniline

LC-MS: ESI [M + H] ⁺ = 236.3. 1H-NMR (400MHz, DMSO-d6) δ7.90 (d, J = 2.4Hz, 1H), 7.31 (dd, J = 7.6Hz, 1H), 6.92 (d, J = 7.6Hz, 1H), 3.00-3.03 (m, 2H), 2.49-2.51 (m, 1H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.84-1.87 ( m, 2H), 1.71-1.73 (m, 2H).

Intermediate 3C: [1- (4-amino-3-nitro-phenyl) -piperidin-4-yl] -dimethylamine

LC-MS: ESI [M + H] ⁺ = 265.1. 1H-NMR (400MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68 (dd, J = 2.0, 7.2Hz, 1H), 7.15 (d , J = 7.2Hz, 1H), 3.58-3.63 (m, 3H), 3.12-3.178 (m, 2H), 2.94 (s, 6H), 2.31-2.37 (m, 2H), 1.99-2.03 (m, 2H ).

Intermediate 3D: 4- (4-ethyl-piperazin-1-ylmethyl) -2-nitro-aniline

LC-MS: ESI [M + H] ⁺ = 267.1. 1H-NMR (400MHz, DMSO-d6) δ7.52 (d, J = 2.0Hz, 1H), 7.30 (dd, J = 2.4, 7.2Hz, 1H ), 6.95 (d, J = 7.2Hz, 1H), 3.59 (bs, 4H), 2.67 (t, J = 4.0Hz, 4H), 3.00 (t, J = 4.0Hz, 4H), 1.50 (s, 9H ).

Intermediate 3E: 4- (4-isopropylpiperazin-1-yl) -2-nitroaniline

LC-MS: ESI [M + H] + = 265.2. 1H-NMR (400MHz, DMSO-d6) δ7.51 (d, J = 2.4Hz, 1H), 7.28 (dd, J = 2.4, 7.2Hz, 1H ), 6.95 (d, J = 7.2Hz, 1H), 3.11 (t, J = 4.0Hz, 4H), 2.94 (s, 6H), 2.75-2.98 (m, 5H), 1.16 (d, J = 5.2Hz , 6H).

Intermediate 3F: 2-nitro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) aniline

LC-MS: ESI [M + H] + = 291.2. 1H-NMR (400MHz, DMSO-d6) δ 8.23 (s, 1H), 7.65 (d, J = 7.2Hz, 1H), 7.15 (d, J = 7.2Hz, 1H), 3.81-3.84 (m, 2H), 3.75-3.77 (m, 2H), 3.73-3.74 (m, 3H), 3.21-3.26 (m, 2H), 2.48-2.50 (m, 2H ), 2.23-2.27 (m, 4H), 2.08-2.10 (m, 2H).

Intermediate 4: 4- (2,6-chlorodichloro-3,5-dimethoxyphenyl) -8- (methylsulfonyl)-[1,2,4] triazol [1 ', 5 ': 1,6] pyridine [2,3-d] pyrimidine

Step 1: 6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2-methylthio-pyrido [2,3-d] pyrimidin-7-ylamine ( 4g, 10mmol) was dissolved in methanol (300mL), N, N-dimethylformamide dimethyl acetal (2.4g, 20mmol) was added, the temperature was raised to 80 ° C, stirred overnight, concentrated under reduced pressure, ethyl acetate Purified and purified, filtered and dried to obtain compound N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine -7-yl) -N, N-dimethylformimide (3.6 g, yellow solid) was used directly in the next reaction. LC-MS: ESI [M + H] ⁺ = 452.1.

The second step: N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine-7 -Yl) -N, N-dimethylformimide (2.3g, 5mmol) was dissolved in methanol (50mL), and pyridine (0.8g, 10mmol) and hydroxylammonium hydrochloride (417mg, 6mmol) were sequentially added at room temperature. And stirred at room temperature overnight. The reaction was monitored by LCMS and the reaction was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), trifluoroacetic anhydride (10 mL) was added, and the mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, a solid precipitated, and filtered to obtain compound 4- (2,6-dichloro-3,5- Dimethoxy-phenyl) -8- (methylthio)-[1,2,4] triazol [1 ', 5': 1,6] pyridine [2,3-d] pyrimidine (1.3g , Yellow solid). LC-MS: ESI [M + H] ⁺ = 422.0.

The third step: 4- (2,6-dichloro-3,5-dimethoxy-phenyl) -8- (methylthio)-[1,2,4] triazol [1 ', 5 ': 1,6] pyridine [2,3-d] pyrimidine (1.1g, 2.6mmol) was dissolved in chloroform (100mL), m-CPBA (1.6g, 7.8mmol) was added, and the reaction was performed at room temperature for 3h. The reaction solution was washed successively with a saturated sodium bicarbonate solution and water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain the compound 4- (2,6-dichloro-3,5-dimethoxy-phenyl). ) -8- (methylsulfonyl)-[1,2,4] triazol [1 ', 5': 1,6] pyridine [2,3-d] pyrimidine (1.1 g, yellow solid). LC-MS: ESI [M + H] ⁺ = 454.0.

The same intermediate steps and methods were used to prepare the following intermediates 4A-4D.

Intermediate 4A: 8-chloro-4- (2,6-chlorodichloro-3,5-dimethoxyphenyl)-[1,2,4] triazol [1,5-a] [1 , 6] naphthyridine

LC-MS: ESI [M + H] ⁺ = 421.3. 1H-NMR (400MHz, CDCl ₃ ) δ 9.08 (s, 1H), 8.45 (s, 2H), 7.81 (s, 1H), 6.73 (s, 1H), 3.99 (s, 6H).

Intermediate 4B: 4- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (methylsulfonyl)-[1,2,4] triazol [1 ', 5' : 1,6] pyridine [2,3-d] pyrimidine

LC-MS: ESI [M + H] ⁺ = 389.2.

Intermediate 4C: 8-chloro-4- (2,6-difluoro-3,5-dimethoxyphenyl)-[1,2,4] triazol [1,5-a] [1, 6] naphthyridine

LC-MS: ESI [M + H] ⁺ = 388.2.

Intermediate 4D: 6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylsulfonyl)-[1,2,4] triazol [4 ', 3' : 1,6] pyridine [2,3-d] pyrimidine

First step: 7-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d] pyrimidine (1.2 g, 2.88 mmol) was dissolved in ethanol (100 mL), hydrazine hydrate (4 mL) was added, and the reaction was heated to 80 degrees overnight, and concentrated under reduced pressure to obtain compound 6- (2,6-dichloro-3,5-dimethoxy). Phenyl) -7-hydrazino-2- (methylthio) pyrido [2,3-d] pyrimidine (1.2 g, yellow solid) was used directly in the next reaction. LC-MS: ESI [M + H] ⁺ = 412.0.

Second step: 6- (2,6-dichloro-3,5-dimethoxyphenyl) -7-hydrazino-2- (methylthio) pyrido [2,3-d] pyrimidine ( 1.2 g, 2.88 mmol) were dissolved in formic acid (30 mL), and heated to 100 degrees to react overnight. The reaction solution was cooled to room temperature and poured into cold water. A solid precipitated, filtered, and the filter cake was dried to obtain compound 6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio). )-[1,2,4] triazolo [4 ', 3': 1,6] pyrido [2,3-d] pyrimidine (1.1 g, yellow solid). LC-MS: ESI [M + H] ⁺ = 421.8.

The third step: 6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio)-[1,2,4] triazolo [4 ', 3 ': 1,6] pyrido [2,3-d] pyrimidine (1.1 g, 2.6 mmol) was dissolved in chloroform (100 mL), m-CPBA (1.6 g, 7.8 mmol) was added, and the reaction was performed at room temperature for 3 h. The reaction solution was washed successively with a saturated sodium bicarbonate solution and water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain the compound 4- (2,6-dichloro-3,5-dimethoxy-phenyl). ) -8- (methylsulfonyl)-[1,2,4] triazol [1 ', 5': 1,6] pyridine [2,3-d] pyrimidine (1.2 g, yellow solid). LC-MS: ESI [M + H] ⁺ = 453.8.

Intermediate 4E: 8-chloro-4- (2,6-dichloro-3,5-dimethoxyphenyl)-[1,2,4] triazol [4,3-a] [1, 6] naphthyridine

LC-MS: ESI [M + H] ⁺ = 409.7 / 411.7.

Intermediate 5: 1-methyl-4-nitro-3-amino-pyrazole

Step 1: Add triethylamine (2.5mL, 17.3mmol) to 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6g, 8.64mmol) and DMF under cooling in an ice bath. (15 mL) and tert-butanol (5 mL), DPPA (3.6 g, 12.97 mmol) was then added, and the reaction solution was heated to 80 ° C. and stirred for 4 h. After completion of the reaction, some solvents were removed under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography to obtain 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g, 90%). .

Step 2: Dissolve 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g, 7.8mmol) in DCM (10mL), and slowly add three drops to it under cooling in an ice bath. Fluoroacetic acid (6 mL). After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 1-methyl-4-nitro-3-amino-pyrazole (1 g, 80%). ESI-MS: m / z = 157 (M + H) ⁺ .

General method 1: amino substituted sulfone

The sulfone-based intermediate (1 eq.) And the raw amine (2 eq.) Were dissolved in anhydrous DMF, potassium tert-butoxide (2 eq.) Was added, and the mixture was heated to 100 ° C for 2 hours under microwave reaction. After the reaction was completed, dichloromethane was added for extraction, and the organic phase was sequentially washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain a nitro compound intermediate.

General method two: amino substituted aryl chloride

Dissolve the chloroaryl intermediate (1eq.) And raw amine (2eq.) In anhydrous DMF, bubble nitrogen for ten minutes, and add Pd ₂ (dba) ₃ (0.1eq.) And XantPhos ( 0.2 eq.) And cesium carbonate (2 eq.). It was heated to 100 ° C. in a microwave for 1 hour. After the reaction was completed, dichloromethane was added for extraction, and the organic phase was sequentially washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain an intermediate compound.

General method three: Nitro reduction

The nitro compound (1 eq.) Was dissolved in methanol, and a saturated sodium thiosulfate solution (2 eq.) And a sodium carbonate solution (2 eq.) Were added, followed by stirring at room temperature overnight. After completion of the reaction, ethyl acetate was added for extraction, and the mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain an amino intermediate.

General Method 4: Acrylation

The amino compound intermediate (1 eq.) And DIPEA (2 eq.) Were dissolved in dry DMF, and acrylic acid chloride (1.2 eq.) Was slowly added dropwise under cooling in an ice bath. After the addition was complete, the reaction was allowed to proceed at room temperature overnight. The reaction solution was quenched with dichloromethane and saturated sodium bicarbonate solution, and the organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC or Biotage Flash column. Analytical separation and purification to obtain the target compound.

Example Preparation

Using intermediates 1-5 as starting materials, and other commercial reagents such as piperazine, tetrahydropyrrole, N-methylpiperazine and other raw materials, the general methods 1 to 4 were used to sequentially prepare and synthesize the following examples. Compound:

Test Example 1 Determination of FGFR1-4 Kinase Inhibitory Activity of Compounds of the Invention

1. Test method: (1) Prepare 1 × Kinase buffer. (2) Formulation of compound concentration gradient: the test compound test concentration is 10uM starting, 3 times diluted 10 concentrations, duplicate well test, 10 different concentrations of 100 times final concentration in 96-well plate. Compounds of each concentration were then further diluted with a 1 × Kinase buffer to a 5x final concentration intermediate dilution solution. (3) 5 μL of the prepared compound solution was added to the compound wells of the 384-well plate, and each concentration was tested in a single well; 5 μL of 5% DMSO was added to the negative control well and the positive control well. (4) A 2.5-fold final concentration of the kinase solution was prepared with 1 × Kinase buffer. (5) Add 10 μL of 2.5 times the final concentration of the kinase solution to the compound well and the positive control well; add 10 μL of 1 × Kinase buffer to the negative control well. (6) Centrifuge at 1000 rpm for 30 seconds, shake and mix for 10 minutes at room temperature. (7) Prepare a mixed solution of 2.5 times the final concentration of ATP and Kinase substrate 22 with 1 × Kinase buffer. (8) Add 10 μL of a 2.5-fold final concentration of ATP and substrate mixed solution to start the reaction. (9) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, and incubate at 28 ° C for the corresponding time after shaking and mixing. (10) Add 30 μL of stop test solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix by shaking. (11) Read the conversion rate with Caliper EZ Reader II. (12) The inhibition rate of the sample is determined by the following formula: Inhibition rate (%) = (OD negative control well-OD administration well) / OD negative control well x 100%. Analysis of the results. The IC ₅₀ value was obtained by a four-parameter regression method using the software provided with the microplate reader.

2. Results: The majority of embodiments of the present invention provides inhibitory activity IC ₅₀ value is less than the FGFR4 100nM, most of the inhibitory activity of IC ₅₀ of the embodiment is less than 20nM, the inhibitory activity of some embodiments even less than 1nM, show a more Strong enzyme inhibitory activity; and FGFR1 inhibitory activity is weak, the IC ₅₀ of FGFR1 inhibitory activity of most of the compounds of the examples is greater than 20 nM, and some examples are even greater than 1000 nM, showing a higher selectivity of kinase subtypes. The specific results are shown in Table 1.

Table 1: FGFR kinase inhibitory activity of some example compounds

At the same time, it was found that, compared with the comparative compounds 1 to 3, the compounds of the embodiments of the present invention have higher activity on FGFR4 kinase or selectivity on FGFR1 isoforms, and have obvious advantages. The specific results are shown in Table 2.

Table 2: Comparison of kinase activity and selectivity of some example compounds and comparative compounds.

Test Example 2: Effect of the Example of the Invention on FGFR-Mediated Tumor Cell Proliferation Ability

1. Test method: Hep3B cells (ATCC) in logarithmic growth phase were seeded into a 96-well culture plate at an appropriate density, 100 μL per well. After overnight culture, compounds of different concentrations were added for 72 hours, and a solvent control group was set. (Negative control). Incubate at 37 ° C under 5% CO2. 10 mM compound stock solution was added to the cells, and the effect of the compounds on cell proliferation was 72 hours after the compounds were applied to the cells.

(Promega) method, add 30 μL of CTG reagent to each well, place in a 37 degree incubator for 2-4 hours, read with a full-wavelength microplate microplate reader, Envision, and measure the wavelength at 450 nm. The following formula was used to calculate the inhibition rate (%) of the compound on tumor cell growth: inhibition rate (%) = (OD negative control well-OD administration well) / OD negative control well x 100%. The IC ₅₀ value was obtained by Graphpad Prism 5 software with four-parameter regression.

2. Results: Some of the examples 1 to 50 provided by the present invention have inhibitory activity on Hep3B cells. The IC ₅₀ values are all less than 500 nM. The inhibitory activity IC ₅₀ values of some compound compounds are even less than 100 nM. Cell proliferation inhibitory activity. The specific results are shown in Table 3:

Table 3: Inhibitory activity of some example compounds on Hep3B cell proliferation.

Test Example 3: Tests of Example Compounds Not Different in Kinase Inhibition Activity

The compounds of the present invention have different kinases such as EGFR, VEGFR, PDGFR, FGFR1-3, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, FGFR1, FGFR2, FGFR3, FGFR gated mutants V550L, CSF1R, etc. Inhibitory activity was also tested, and some of the compounds of Examples, such as Example 3, Example 7, Example 11, Example 35, Example 47, etc., showed good FGFR4 kinase selectivity (IC ₅₀ <5nM). VEGFR, FGFR3, CDK and other kinases (IC ₅₀ > 500nM) are more than 100 times more selective; while for FGFR1, FGFR2, CSF1R, FGFR4 gated mutant kinases (20nM <IC ₅₀ <400nM) and other selectivity are 10-100 times; in contrast, some embodiments exhibits a higher FGFR1, FGFR2 inhibitory activity (IC ₅₀ <50nM), its FGFR4 kinase (IC _50> 1000 nM selectivity) is greater than 100 times, as described in Example 43.

Test Example 4: Test of the compound of the Example for inhibiting the proliferation of different tumor cells

SRB staining method or CCK8 method or CTG method to test a variety of tumor cells, such as BaF3-FGFR4, BaF3-FGFR V550L, HuH-7, JHH-7, MDA-MB-453, DMS114, SNU-16, KG1, UM -UC-14, HCT116, NCI-H716, MCF-7, KATOIII, Colo-205, KMS11, H1581, RT-112, RT-4, OPM-2, NCI-H460, SNU-869, SNU878, CNE, NCI -H2122, NCI-H1299, A204, A427, A549, MG63, Kappars-299, SK-OV-3, U87MG, BT474, LNCAP, A498, KYSE140, HUCC-T1, PANC-1, etc., partial implementation Exemplary compounds such as Example 3, Example 4, Example 7, Example 11, Example 32, Example 34, etc., showed a strong inhibitory activity on the inhibition of the increase in value of different cells, showing a good antitumor activity, The proliferation inhibitory activity on a variety of tumor cells is less than 1000 nM, especially for FGFR1, FGFR2, and FGFR4 positive cell lines. The inhibitory activity is less than 500 nM, and some examples such as Example 3, Example 7, Example 32 and other IC50 are even less than 50 nM.

Test Example 5: ADME Test of Example Compound

(1) Metabolic stability test: 150 microliters of liver microsomes (final concentration 0.5mg / mL) were used for metabolic stability incubation. The system contains NADPH (final concentration 1mM), 1μM test compound and positive control midazole. Or negative control atenolol, the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μL of the supernatant was injected in a 96-well plate. The compound's metabolic stability was calculated by measuring the relative decrease of the original drug.

(2) Direct inhibition test (DI test): 100 μL of human liver microsomes (final concentration 0.2 mg / mL) were used for direct inhibition incubation. The system contained NADPH (final concentration 1 mM), 10 μM compound, and positive inhibitor cocktail. (Ketoconazole 10 μM, quinidine 10 μM, sulfamethoxazole 100 μM, α-naphthylflavonoid 10 μM, tranylcypromine 1000 μM), negative control (0.1% DMSO BPS), and mixed probe substrate (midazolam 10 μM, testosterone 100 μM, dextromethorphan 10 μM, diclofenac 20 μM, phenacetin 100 μM, mephenytoin 100 μM), the reaction was terminated after 20 min incubation. The relative enzyme activity was calculated by measuring the relative amount of metabolites produced.

Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. have high metabolic stability to microsomes, T _1/2 is greater than 30 min, has no direct inhibitory effect on major metabolic enzymes, and IC ₅₀ is greater than 20uM, showing a good drugability.

Test Example 6: Test of Pharmacokinetic Parameters of Compounds of Examples in Rats and Mice in Vivo

Six male SPF-grade SD rats (Shanghai Xipuer-Bikai experimental animals) were divided into two groups, and the test compounds were configured into appropriate solutions or suspensions; one group was administered by intravenous injection (1 mg / kg dose), and the other was administered orally Administration (5 mg / kg dose). Blood was collected via jugular vein puncture, and each sample was collected at about 0.2 mL / time point. Heparin sodium was used for anticoagulation. The time points for blood collection were as follows: before administration and 5, 15, and 30 minutes after administration, 1, 2, 4, 6, 8, and 24h; After collecting blood samples, place them on ice, centrifuge the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C), and store the collected plasma at -80 ° C before analysis. Plasma samples were analyzed by LC-MS / MS.

According to the blood concentration data of the drug, the pharmacokinetic calculation software WinNonlin5.2 non-compartment model was used to calculate the pharmacokinetic parameters AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, T1 of the test product. Parameters such as / 2 and Vd and their average and standard deviation. In addition, the bioavailability (F) will be calculated by the following formula.

For samples with a concentration below the lower limit of quantification, when calculating the pharmacokinetic parameters, the sample taken before reaching Cmax should be calculated as zero, and the sample at the sampling point after Cmax should be calculated as Unquantifiable (BLQ).

Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. were administered by gavage with Cmax greater than 200 nM, AUC greater than 2000 hr * nM, and F% greater than 15%, showing good drug-making properties. .

Test Example 7: Test of Inhibition of Hep3B Xenograft Tumor Growth in Nude Mice by Compounds of Examples

The tumor tissue during the vigorous growth period was cut to about 1.5 mm ³ and inoculated subcutaneously in the right armpit of nude mice under sterile conditions. Subcutaneously transplanted tumors in nude mice were measured with vernier calipers. The diameter of the transplanted tumors was measured, and the animals were randomly divided into groups until the average tumor volume reached about 130 mm ³ . The compound of the example (configured with water for injection containing 1% Tween80 to a desired concentration for use) was orally administered daily at a given dose for three consecutive weeks, and the solvent control group was given the same amount of solvent. During the whole experiment, the diameter of the transplanted tumor was measured twice a week, and the weight of the mice was weighed. The formula for calculating tumor volume (TV) is: TV = 1/2 × a × b ² , where a and b represent length and width, respectively. The relative tumor volume (RTV) was calculated according to the measurement results, and the formula was: RTV = Vt / V0. Among them, V0 is the tumor volume obtained during divided cage administration (ie, d0), and Vt is the tumor volume at each measurement. The evaluation index of antitumor activity is 1) the relative tumor proliferation rate T / C (%), the calculation formula is as follows: T / C (%) = (TRTV / CRTV) × 100%, TRTV: RTV in the treatment group; CRTV: negative control Group RTV; 2) tumor volume growth inhibition rate GI%, the calculation formula is as follows: GI% = [1- (TVt-TV0) / (CVt-CT0)] × 100%, TVt is the tumor volume measured each time in the treatment group; TV0 is the tumor volume obtained when the therapeutic component is administered in the cage; CVt is the tumor volume measured each time in the control group; CV0 is the tumor volume obtained when the control group is divided into cages; Inhibition rate% = (Wc-WT) / Wc × 100%, Wc: tumor weight in the control group, WT: tumor weight in the treatment group.

Some of the compounds of the examples of the present invention show a good effect of inhibiting tumor growth. For example, Example 3, Example 7 and the like were administered orally for 21 days at a dose of 40 mg / kg, with T / C less than 10%, and some experimental animals. The tumors in the group subsided.

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely examples, and that various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or medicine,

Where

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, or sulfonyl;

R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, or hydroxyl;

Y is N and Z is CR 6 , or Y is CR 6 and Z is N;

R 6 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylene- NR 6-1 R 6-2 ;

M is selected from CR a or N; R a is selected from hydrogen, or halogen;

Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl;

R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and R 7 is One or more of the groups are substituted with one or more hydrogens on the ring Cy to form the corresponding fused ring, fused ring, spiro ring, or bridge ring ring system. There are 0 to 3 ring systems including O, N, A heteroatom of S; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, carbonyl, 5 -8-membered aryl or heteroaryl, 3-8-membered cycloalkyl or 4-8-membered heterocycloalkyl; among the substituents, the amino group, C 1 -C 8 alkyl group, 4-8 One or more hydrogen atoms on a heterocyclic alkyl group optionally an amino group substituted with hydroxy, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl, 5-10 membered heteroaryl, C 1 -C 6 alkyl substituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl;

n is selected from 0-4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, or alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1- C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4 -8-membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;

Wherein, the heteroaryl group includes 1-3 heteroatoms selected from the group: N, O, P, and S, and the heterocycloalkyl group includes 1-3 heteroatoms selected from the group: N , O, P, and S.
The compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly A crystalline form or a prodrug, characterized in that when R 1 and R 2 are independently halogen, the halogen is fluorine or chlorine;

And / or, when R 3 and R 4 are independently halogen, the halogen is fluorine;

And / or, when R 3 and R 4 are independently an alkoxy group, the alkoxy group is a C 1 -C 6 alkoxy group, preferably a C 1 -C 4 alkoxy group, and more preferably a methoxy group;

And / or, when R 6 is an alkyl group, the alkyl group is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, and more preferably a methyl group;

And / or, when R 6 is -alkylene-NR 6-2 R 6-3 , the alkylene is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene, more Preferably methylene;

And / or, when R 6-2 and R 6-3 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl;

And / or, when Cy is a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is "a heteroatom selected from one or more of N, O and S, and the number of heteroatoms 1-3 "5-6 membered heterocycloalkyl, preferably tetrahydrofuryl, tetrahydropyrrolyl, or tetrahydropyranyl, more preferably tetrahydrofuryl, or tetrahydropyranyl;

And / or, when Cy is a 5-8 membered aryl group, the 5-8 membered aryl group is a phenyl group;

And / or, when Cy is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is "a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1 -3 "5-6 membered heteroaryl, preferably pyrazolyl or pyridyl, more preferably pyrazolyl;

And / or, when R 7 is alkyl, the alkyl is C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably methyl, ethyl, n-propyl or isobutyl , Even more preferably methyl;

And / or, when R 7 is a heterocycloalkyl group, the heterocycloalkyl group is a 4- to 11-membered heterocycloalkyl group, and preferably "the hetero atom is selected from one or more of N, O, or S, 5-7 membered monocyclic heterocycloalkyl groups with "1-3 heteroatoms" or "heteroatoms selected from one or more of N, O or S, with 1-3 heteroatoms" 8-9 membered bicyclic heterocycloalkyl; said 5-7 membered monocyclic heterocycloalkyl is preferably piperidinyl, piperazinyl, or homopiperazinyl; said 8-9 membered bicyclic heterocyclic ring Alkyl preferred

And / or, in R 7 , when the alkyl group is optionally substituted with 1-3 C 1 -C 8 alkoxy groups, the C 1 -C 8 alkoxy group is C 1 -C 4 Alkoxy, preferably methoxy;

And / or, in R 7 , when the alkyl group is optionally substituted with 1-3 4-8 membered heterocycloalkyl, the 4-8 membered heterocycloalkyl is "heteroatom selected from One or more of N, O or S, a heterocyclic alkyl group having 5 to 6 members, preferably tetrahydropyrrolyl;

And / or, in R 7 , when the heterocycloalkyl is optionally substituted with 1-3 C 1 -C 8 alkyl, the C 1 -C 8 alkyl is C 1 -C 4 Alkyl, preferably methyl, ethyl or isopropyl;

And / or, in R 7 , when the heterocycloalkyl is optionally substituted with 1-3 4-8 membered heterocycloalkyl, the 4-8 membered cycloalkyl is "heteroatomic 4-6 membered cycloalkyl, preferably tetrahydropyrrolyl, from one or more of N, O or S, with a number of heteroatoms of 1-3 ";

And / or, in R 7 , in the substituent, when one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group is optionally C When 1- C 6 alkyl is substituted, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl or ethyl;

And / or, in R 7 , in the substituent, when one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group is optionally C When 1- C 6 alkoxy is substituted, the C 1 -C 6 alkoxy is C 1 -C 4 alkoxy, preferably methoxy;

And / or, in R 7 , in the substituent, when one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group is optionally 5 When a -10 membered heteroaryl group or a C 1 -C 6 alkyl substituted 5-10 membered heteroaryl group is substituted, the 5-10 membered heteroaryl group is "a heteroatom selected from N, O or S One or more 5-6 membered heteroaryl groups, preferably 1 to 3 heteroatoms, preferably pyrazolyl;

And / or, in R 7 , in the substituent, when one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group is optionally C When 1- C 6 alkyl substituted 5-10 membered heteroaryl is substituted, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl;

And / or, in R 7 , among the substituents, when one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group is optionally 3 When the -8-membered cycloalkyl is substituted, the 3-8-membered cycloalkyl is a 3-6-membered cycloalkyl, preferably cyclopropyl;

And / or, when R 8 is an alkyl group, the alkyl group is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, and more preferably a methyl group;

And / or, in R 8 , when the alkyl group is substituted with one or more halogens, the halogen is fluorine;

And / or, in R 8 , when the alkyl group is substituted with one or more halogens, the number of the halogens is 1, 2 or 3, preferably 3;

And / or, when R 9 and R 10 are independently C 1 -C 6 alkylene-NR 8-1 R 8-2 , the C 1 -C 6 alkylene is C 1 -C 4 alkylene Alkyl, preferably methylene;

And / or, when R 8-1 and R 8-2 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl.
The compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly A crystalline form or prodrug, characterized in that R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, or alkoxy;

And / or, R 5 is selected from hydrogen, halogen, or alkyl;

And / or, Y is N, Z is CR 6 , or Y is CR 6 , and Z is N;

And / or, R 6 is selected from hydrogen, alkyl, or alkylene-NR 6-1 R 6-2 ; R 6-1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;

And / or, M is selected from CH or N;

And / or, Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

And / or, R 7 is selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms on any of the above groups is optionally selected from being substituted by a substituent of the following group: halogen, Hydroxyl, amino, cyano, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocyclic Cycloalkyl; in the substituent, one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, and 4-8 membered heterocycloalkyl group are optionally substituted by hydroxyl group, cyano group, C 1- C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted amino, 5-10 membered heteroaryl, C 1 -C 6 alkyl substituted 5-10 membered heteroaryl Or 3-8 membered cycloalkyl;

And / or, n is selected from 0, 1, 2, 3, or 4;

And / or, R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR 8-1 R 8-2 ; one or Multiple hydrogen atoms are optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
The compound represented by formula (I) according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof , A polymorph or a prodrug, characterized in that R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or C 1 -C 6 alkoxy;

And / or, R 5 is hydrogen;

And / or, R 6 is selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ; R 6-1 and R 6-2 are independently hydrogen Or C 1 -C 6 alkyl;

And / or, Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

And / or, R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said C 1 -C 6 alkyl is optionally selected from 1-3 Substituents for hydroxy, halogen, C 1 -C 6 alkoxy, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl Substituted; wherein, R 7-4 is C 1 -C 6 alkyl or C 6 -C 10 aryl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said heterocycloalkyl is optionally independently substituted with 1-3 substituents selected from C 1 -C 6 alkyl, R 7-5 is C 1 -C 6 substituted alkyl, -NR 7-6 R 7-7, Substituted with a carbonyl, a 3-8 membered cycloalkyl, or a 4-8 membered heterocycloalkyl; wherein R 7-5 is selected from the group consisting of hydroxyl, cyano, C 1 -C 6 alkoxy, -NR 7 -5a R 7-5b, 5-10 membered heteroaryl, R 7-5c substituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl; R 7-6, R 7-7, R 7 and R 7-5b -5a independently selected from hydrogen or C 1 -C 6 alkyl group; R 7-5c is a C 1 -C 6 alkyl;

And / or, n is selected from 0, 1 or 2;

And / or, R 8, R 9 and R 10 are independently selected from hydrogen, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkylene or a group -NR 8- 1 R 8-2; One or more hydrogen atoms on any of the above groups are optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
The compound represented by formula (I) according to claim 1, 3 or 4, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, A solvate, polymorph or prodrug, characterized in that R 1 and R 2 are independently selected from halogen, or C 1 -C 6 alkoxy, preferably halogen;

And / or, R 3 and R 4 are independently selected from halogen, or C 1 -C 6 alkoxy, preferably C 1 -C 6 alkoxy;

And / or, Cy is selected from a 5-8 membered aryl group, or a 5-8 membered heteroaryl group, preferably a 5-8 membered aryl group;

And / or, R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl, preferably hydrogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl , More preferably hydrogen, or a 4-11 membered heterocycloalkyl group; said 4-11 membered heterocycloalkyl group is optionally optionally selected from 1-3 C 1 -C 6 alkyl groups, R 7-5 Substituted by C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or 4-8 membered heterocycloalkyl; wherein R 7-5 is 3-8 membered cycloalkane R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;

And / or, R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl, preferably hydrogen, halogen, or C 1 -C 6 alkyl; the C 1 -C 6 alkyl is optionally Ground is replaced by 1-3 halogens;

R 9 and R 10 are independently selected from hydrogen, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; R 8-1 and R 8-2 are independently C 1 -C 6 alkyl.
The compound represented by the formula (I) according to any one of claims 1 or 3-5, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer thereof. Isomers, solvates, polymorphs or prodrugs, characterized in that R 1 and R 2 are independently selected from fluorine or chlorine;

And / or, R 3 and R 4 are independently selected from fluorine or methoxy, preferably methoxy;

And / or, R 5 is hydrogen;

And / or, Y and Z are independently selected from N, -CH -, - C ( CH 3) -, or

And / or, M is selected from CH or N;

And / or, Cy is selected from

Preferred

And / or, R 7 is selected from H, F, Me, CF 3 ,

H, F, Me,

And / or, a structure in a compound represented by formula (I)
From

Preferred

And / or, R 8 is selected from H, F, Cl, CN, Me or CF 3 , preferably H;

And / or, R 9 and R 10 are independently selected from H, or
H is preferred.
The compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly The crystalline form or prodrug, wherein the compound represented by formula (I) is any one of the following schemes:

plan 1:

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;

R 5 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably from hydrogen, halogen, alkyl;

Y, Z are each independently selected from N or CR 6 ; R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;

M is independently selected from CR a or N; R a is independently selected from hydrogen, halogen;

Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;

R 7 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from Hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more of rings Cy Each hydrogen is substituted to form a corresponding ring system such as a condensed ring, a spiro ring, a bridge ring, and a bridge ring. The ring system may have 0 to 3 heteroatoms including O, N, and S;

n is independently selected from 0-4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl ; Wherein the heteroaryl group contains 1-3 heteroatoms selected from the group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the group: N, O, P or S;

Scenario 2:

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;

R 5 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably from hydrogen, halogen, alkyl;

Y is N and Z is CR 6 , or Y is CR 6 and Z is N;

R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the like; preferably from Hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;

M is independently selected from CR a or N; R a is independently selected from hydrogen, halogen;

Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;

R 7 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from Hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more of rings Cy Each hydrogen is substituted to form a corresponding ring system such as a condensed ring, a spiro ring, a bridge ring, and a bridge ring. The ring system may have 0 to 3 heteroatoms including O, N, and S;

n is independently selected from 0-4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl ;

Option 3:

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 1 -C 6 alkyl Oxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

R 5 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or C 1 -C 6 alkyl;

Y is N and Z is CR 6 , or Y is CR 6 and Z is N;

R 6 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6- C 10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ; preferably from hydrogen, halo, C 1 -C 6 alkyl, 4-6 membered heterocycloalkyl, or a C 1 -C 6 alkylene group -NR 6-1 R 6-2; R 6- 1 and R 6 -2 is independently hydrogen or C 1 -C 6 alkyl;

M is selected from CR a or N; R a is selected from hydrogen, or halogen;

Cy is selected from 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl; preferably from 5-6 membered cycloalkyl, 5-6 membered Heterocycloalkyl, 5-8 membered aryl, or 5-6 membered heteroaryl;

R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6 -C 10 aromatic Radical, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, Or a 4-8 membered heterocycloalkyl group; and one or more groups on R 7 are substituted with one or more hydrogens on the ring Cy to form the corresponding ring system such as a condensed ring, a parallel ring, a spiro ring, a bridge ring , The ring system has 0 to 3 heteroatoms including O, N, S; the C 1 -C 6 alkyl is optionally substituted by 1-3 selected from hydroxyl, halogen, C 1 -C 6 alkoxy Substituted with -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; wherein R 7-4 is C 1- C 6 alkyl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said C 6 -C 10 aryl, 5-10 membered heteroaryl, 3 8-membered cycloalkyl or 4-11 membered heterocycloalkyl are independently optionally substituted with 1-3 substituents selected from C 1 -C 6 alkyl, R 7-5 is a substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7, a carbonyl group, a 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl or a substituent; the , R 7-5 is selected from hydroxy, cyano, C 1 -C 6 alkoxy, -NR 7-5a R 7-5b, 5-10 membered heteroaryl, R 7-5c substituted 5-10 membered heteroaryl an aryl group, or a 3-8 membered cycloalkyl group; R 7-6, R 7-7, R 7-5a , and R 7-5b are independently selected from hydrogen or C 1 -C 6 alkyl group; R 7- 5c is C 1 -C 6 alkyl;

n is selected from 0, 1, 2, 3, or 4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, sulfone, sulfoxide, or C 1 -C 6 alkylene-NR 8- 1 R 8-2 ; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5- 8-membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;

Option 4:

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or alkoxy;

R 5 is hydrogen;

Y is N and Z is CR 6 , or Y is CR 6 and Z is N;

R 6 is selected from hydrogen, alkyl, or alkylene-NR 6-1 R 6-2 ; R 6-1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;

M is selected from CR a or N; R a is hydrogen;

Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

R 7 is selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of halogen, hydroxy, amino, Cyano, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; In the substituent, one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, and 4- to 8-membered heterocycloalkyl group are optionally substituted by hydroxyl group, cyano group, C 1 -C 6 Alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted amino, 5-10 membered heteroaryl, C 1 -C 6 alkyl substituted 5-10 membered heteroaryl, or 3 -8-membered cycloalkyl;

n is selected from 0-4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR 8-1 R 8-2 ; one or more hydrogen atoms on any of the above groups Optionally substituted by halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;

Option 5:

R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or C 1 -C 6 alkoxy;

R 5 is hydrogen;

Y is N and Z is CR 6 , or Y is CR 6 and Z is N;

R 6 is selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ; R 6-1 and R 6-2 are independently hydrogen or C 1- C 6 alkyl;

M is selected from CR a or N; R a is hydrogen;

Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said C 1 -C 6 alkyl is optionally selected from 1-3, selected from hydroxyl, halogen, C 1 -C 6 alkoxy, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; R 7-4 is C 1 -C 6 alkyl or C 6 -C 10 aryl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said heterocyclic ring Alkyl is optionally optionally substituted with 1-3 C 1 -C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, 3- 8-member ring group, or a 4-8 membered heterocycloalkyl substituents; wherein, R 7- 5 selected from hydroxy, cyano, C 1 -C 6 alkoxy, -NR 7-5a R 7 -5b , 5-10 membered heteroaryl, R 7-5c substituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl; R 7-6 , R 7-7 , R 7-5a and R 7-5b is independently selected from hydrogen or C 1 -C 6 alkyl; R 7-5c is C 1 -C 6 alkyl;

n is selected from 0-4;

R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;

Option 6:

R 1 and R 2 are independently selected from halogen, or C 1 -C 6 alkoxy;

R 3 and R 4 are independently selected from halogen, or C 1 -C 6 alkoxy;

R 5 is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;

n is selected from 0, 1 or 2;

R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;

R 9 and R 10 are independently selected from hydrogen, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; R 8-1 and R 8-2 are independently C 1 -C 6 alkyl;

Option 7:

R 1 and R 2 are independently halogen;

R 3 and R 4 are independently C 1 -C 6 alkoxy;

R 5 is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;

n is selected from 0, 1 or 2;

R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;

R 9 and R 10 are hydrogen;

Option 8:

R 1 and R 2 are independently halogen;

R 3 and R 4 are independently C 1 -C 6 alkoxy;

R 5 is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is selected from a 5-8 membered aryl group, or a 5-8 membered heteroaryl group;

R 7 is selected from hydrogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 selected from C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein R 7 -5 is a 3-8 membered cycloalkyl group; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;

n is selected from 0, 1 or 2;

R 8 is selected from hydrogen, halogen, or C 1 -C 6 alkyl;

R 9 and R 10 are hydrogen;

Option 9:

R 1 and R 2 are independently halogen;

R 3 and R 4 are independently C 1 -C 6 alkoxy;

R 5 is hydrogen;

Y is N, Z is CH, or Y is CH and Z is N;

M is selected from CH or N;

Cy is a 5-8 membered aryl group;

R 7 is selected from hydrogen, or a 4-11 membered heterocycloalkyl group; the 4-11 membered heterocycloalkyl group is independently optionally substituted with 1-3 C 1 -C 6 alkyl groups;

n is selected from 0, 1 or 2;

R 8 is hydrogen;

R 9 and R 10 are hydrogen.
The compound represented by formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly A crystalline form or prodrug, characterized in that when R 7 is -NR 7-2 R 7-3 or R 7-4 substituted 4-8 membered heterocycloalkyl, R 7-2 and R 7-3 When R 7-4 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl or ethyl;

And / or, when R 7 is R 7-5 substituted C 1 -C 6 alkyl, and R 7-5 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is C 1- C 4 alkoxy, preferably methoxy;

And / or when R 7 is R 7-5 substituted C 1 -C 6 alkyl, R 7-5 is 5-10 membered heteroaryl, or R 7-5c substituted 5-10 membered heteroaryl The 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group having "a hetero atom selected from one or more of N, O, or S, and the number of hetero atoms is 1-3", preferably pyr Oxazolyl

And / or, when R 7 is R 7-5 substituted C 1 -C 6 alkyl, and R 7-5 is 3-8 membered cycloalkyl, the 3-8 membered cycloalkyl is 3-6 Membered cycloalkyl, preferably cyclopropyl;

And / or, when R 7 is -NR 7-6 R 7-7 , R 7-6 and R 7-7 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl;

And / or, when R 7 is R 7-5 substituted C 1 -C 6 alkyl, R 7-5 is -NR 7-5a R 7-5b , or R 7-5c substituted 5-10 membered heteroaryl When R 7-5a , R 7-5b and R 7-5c are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl, preferably methyl .
The compound represented by formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly A crystalline form or a prodrug, characterized in that when the compound represented by formula (I) is Scheme 1,

M is independently selected from CH or N;

R 1 and R 2 are independently selected from hydrogen and halogen, preferably from fluorine and chlorine; R 3 and R 4 are independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl, or heterocycloalkyl, and more preferably From fluorine, methoxy;

R 5 is independently selected from hydrogen, halogen, and alkyl; further preferably selected from hydrogen, fluorine, and methyl;

Y, Z are each independently selected from N or CR 6 ; R 6 is independently selected from hydrogen, halogen, C1-C 6 alkyl, preferably from hydrogen;

Cy is independently selected from a 4-6 membered cycloalkyl or heterocycloalkyl group, a 5-6 membered aryl or heteroaryl group; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, piperidine Ring, benzene ring, pyridine ring, pyrazole ring, etc .;

R 7 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, cyano, hydroxy, amino, 4- to 8-membered heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like, more preferably From hydrogen, fluorine, cyano, amino, C 1 -C 6 alkyl or 4-7 membered heterocycloalkyl, etc .; more preferably hydrogen, fluorine, methyl, piperazinyl, morpholinyl, piperidine Radical, tetrahydropyrrolyl, etc .;

n is independently selected from 0-4, preferably from 0-2;

R 8 , R 9, and R 10 are independently selected from hydrogen, halogen, alkyl, and cyano; further preferably, they are selected from hydrogen, fluorine, methyl, and the like.
The compound represented by formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof The compound represented by the formula (I) has the following general formula (IA) or (IB):

Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Cy, M and n are defined as in any one of claims 1-9. Described.
The compound represented by the formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof The compound represented by formula (I) is any one of the following compounds: a compound, a solvate, a polymorph or a prodrug, wherein:
A pharmaceutical composition comprising the compound represented by formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer thereof Isomers, tautomers, solvates, polymorphs or prodrugs, and pharmaceutically acceptable carriers; the pharmaceutical composition is preferably a pharmaceutical composition for treating tumors.
A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Isomers, solvates, polymorphs or prodrugs, or the use of the pharmaceutical composition according to claim 12 in the preparation of a medicament; said medicament is preferably a medicament for the prevention and / or treatment of tumors, or, Drug for diseases related to FGFR kinase; the tumor is preferably non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, bile duct cancer, brain Cancer, leukemia, lymphoma, or nasopharyngeal cancer, more preferably liver cancer or bile duct cancer; the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.
A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Isomers, solvates, polymorphs or prodrugs, or the use of the pharmaceutical composition according to claim 12 in the preparation of FGFR kinase inhibitors; the FGFR kinase is preferably FGFR1 and / or FGFR4, more preferably FGFR4.
A method for preventing and / or treating tumors, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I) according to any one of claims 1-11, or a pharmacological agent thereof A salt acceptable above, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 12; The tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, colon cancer, bile duct cancer, brain cancer, and leukemia. , Lymphoma, nasopharyngeal cancer, etc., especially liver cancer or bile duct cancer.
A method for preventing and / or treating a disease related to FGFR kinase, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-11 , Or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, or as described in claim 12 A pharmaceutical composition; wherein the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.