CN110857300B

CN110857300B - Condensed ring triazole compounds, preparation method and application

Info

Publication number: CN110857300B
Application number: CN201910782471.5A
Authority: CN
Inventors: 万惠新; 潘建峰; 马金贵
Original assignee: Shanghai Lingda Biomedical Co Ltd
Current assignee: Shanghai Lingda Biomedical Co Ltd
Priority date: 2018-08-23
Filing date: 2019-08-23
Publication date: 2021-11-05
Anticipated expiration: 2039-08-23
Also published as: CN110857300A; WO2020038458A1

Abstract

The invention discloses a condensed ring triazole compound, a preparation method and application thereof. The invention particularly discloses a condensed ring triazole compound shown as a formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, a preparation method and pharmaceutical application thereof.

Description

Condensed ring triazole compounds, preparation method and application

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a condensed ring triazole compound, a preparation method and application thereof.

Background

Abnormal expression activation or gene mutation of receptor tyrosine kinase plays a key role in various links of generation, development, invasion and transfer, drug resistance generation and the like of tumors, so that the receptor tyrosine kinase plays an important target for research and development of anti-tumor drugs. Wherein, a Fibroblast Growth Factor Receptor (FGFR) is an important member of a tyrosine kinase family, and mainly comprises four subtypes of FGFR1, FGFR2, FGFR3 and FGFR 4. Due to gene amplification, mutation, fusion or ligand induction and the like, each member of FGFR is continuously activated, thereby inducing the proliferation and invasion of tumor cells, promoting angiogenesis and promoting the tumor deterioration. FGFRs are highly expressed and abnormally activated in a variety of tumors and are closely associated with poor prognosis in tumor patients. Therefore, FGFRs are recognized as important targets for anti-tumor, and development of small FGFR molecule inhibitors is receiving increasing attention.

Recently, researchers from the gene tack company in the United states find that the FGFR4 protein can be accurately targeted to inhibit the growth of hepatocellular carcinoma, and a brand-new idea is provided for the development of liver cell therapeutic drugs. Only FGF19 of the more than 20 Fibroblast Growth Factors (FGFs) discovered to date specifically binds FGFR 4. FGF19 is a ligand of FGFR4 and is responsible for regulating normal bile secretion of liver and liver cell proliferation, and the over-expression or over-activation of the FGF19 can promote the liver cell proliferation and induce liver cancer formation. This has been demonstrated in transgenic mice that knocking out the FGFR4 gene can block the generation of hepatocellular carcinoma. Meanwhile, the clinical findings show that the malignant tumors such as hepatocellular carcinoma, gastric cancer, pancreatic cancer, cholangiocarcinoma and the like are all accompanied with the overexpression and over-activation of FGFR genes of tumor tissues. Therefore, FGFR, which specifically targets fibroblast growth factor receptor, is likely to become a new strategy for the treatment of various tumors, and has attracted extensive attention of various pharmaceutical companies in recent years. However, the existing FGFR inhibitor compounds such as BGJ398, AZD4547, AP 245634, BLU9931 and the like have problems of generally poor target selectivity, low target inhibition activity, poor drug-induced property of the compounds, easy generation of mutation resistance and the like, and thus the clinical application of the FGFR inhibitor compounds is hindered. Therefore, finding and searching novel FGFR compounds with high selectivity, high activity and high drugability is a current hot spot.

Disclosure of Invention

The invention aims to solve the technical problems that the existing FGFR inhibitor compounds have single structure, poor target selectivity, low target inhibition activity, poor chemical property of the compounds, easy mutation resistance and the like, and provides a condensed ring triazole compound, a preparation method and application thereof. The fused ring triazole compound is a novel specific FGFR kinase irreversible inhibitor, has good target selectivity and can be used for treating tumors.

The invention solves the technical problems through the following technical scheme.

The invention provides a compound shown as a formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorph or a prodrug thereof,

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, or sulfonyl; preferably selected from hydrogen, halogen, alkyl, or alkoxy;

R₅selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, or hydroxy; preferably selected from hydrogen, halogen, or alkyl;

y is N, Z is CR₆Or, Y is CR₆Z is N;

R₆selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acylSulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylene-NR_6-1R_6-2(ii) a Preferably selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Heterocycloalkyl, or alkylene-NR_6-1R_6-2；R_6-1And R_6-2Independently is hydrogen or C₁-C₆An alkyl group;

m is selected from CR_aOr N; r_aSelected from hydrogen, or halogen;

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

R₇selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; preferably selected from hydrogen, halogen, C₁-C₆Alkyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; and R is₇One or more of the groups on (a) may be substituted with one or more hydrogens on ring Cy to form a corresponding fused, spiro, or bridged ring system having from 0 to 3 heteroatoms including O, N, S; one or more hydrogen atoms on any of the above groups are optionally substituted with a substituent selected from the group consisting of: deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl, sulfonyl, carbonyl (-C (═ O) -), 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; in the substituent, the amino group and C₁-C₈Alkyl, one or more hydrogen atoms of a 4-to 8-membered heterocycloalkyl group optionally substituted by hydroxy, cyano, C₁-C₆Alkoxy radical, C₁-C₆Alkyl radical, C₁-C₆Alkyl-substituted amino, 5-to 10-membered heteroaryl, C₁-C₆Alkyl-substituted 5-to 10-membered heteroaryl, or 3-to 8-membered cycloalkyl;

n is selected from 0 to 4;

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, or alkylene-NR_8- ₁R_8-2(ii) a One or more hydrogen atoms on any of the above groups are optionally substituted with a substituent selected from the group consisting of: deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; r_8-1And R_8-2Independently is hydrogen or C₁-C₆An alkyl group;

wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S, said heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P and S.

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

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Independently selected from hydrogen, halogen, C₁-C₆Alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C₁-C₆Alkoxy, amino, acyl, or sulfonyl; preferably selected from hydrogen, halogen, C₁-C₆Alkyl, or C₁-C₆An alkoxy group;

R₅selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, amino, or hydroxy; preferably selected from hydrogen, halogen, or C₁-C₆An alkyl group;

y is N, Z is CR₆Or, Y is CR₆Z is N;

R₆selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl, sulfonyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocycloalkyl, or C₁-C₆alkylene-NR_6-1R_6-2(ii) a Preferably selected from hydrogen, halogen, C₁-C₆Alkyl, 4-6 membered heterocycloalkyl, or C₁-C₆alkylene-NR_6-1R_6-2；R_6-1And R_6-2Independently is hydrogen or C₁-C₆An alkyl group;

m is selected from CR_aOr N; r_aSelected 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;

R₇selected from hydrogen, halogen, cyano, hydroxy, amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl, sulfonyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl; preferably selected from hydrogen, halogen, C₁-C₆Alkyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; and R is₇One or more of the groups in (a) may be substituted with one or more hydrogens on ring Cy to form a corresponding fused, spiro, bridged or like ring system having from 0 to 3 heteroatoms including O, N, S; said C₁-C₆Alkyl is optionally substituted by 1-3 substituents selected from hydroxy, halogen, C₁-C₆Alkoxy, -NR_7-2R_7-34-8 membered heterocycloalkyl, or R_7-4Substituted with a substituent of a substituted 4-8 membered heterocycloalkyl group; wherein R is_7-4Is C₁-C₆An alkyl group; r_7-2And R_7-3Independently selected from hydrogen or C₁-C₆An alkyl group; said C₆-C₁₀Aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl are independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5SubstitutionC of (A)₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; wherein R is_7-5Selected from hydroxy, cyano, C₁-C₆Alkoxy, -NR_7-5aR_7-5b5-10 membered heteroaryl, R_7-5cSubstituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl; r_7-6、R_7-7、R_7-5aAnd R_7-5bIndependently selected from hydrogen or C₁-C₆An alkyl group; r_7-5cIs C₁-C₆An alkyl group;

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

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl, sulfone, sulfoxide, or C₁-C₆alkylene-NR_8-1R_8-2(ii) a One or more hydrogen atoms on any of the above groups are optionally substituted with a substituent selected from the group consisting of: deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; r_8-1And R_8-2Independently is hydrogen or C₁-C₆An alkyl group.

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably selected from hydrogen, halogen, alkyl, alkoxy;

R₅selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxy, and the like; preference is given toFrom hydrogen, halogen, alkyl;

y and Z are each independently selected from N or CR₆；R₆Independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and the like; preferably selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Heterocycloalkyl, and the like;

m is independently selected from CR_aOr N; r_aIndependently selected from hydrogen, halogen;

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

R₇selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and the like; preferably selected from hydrogen, halogen, C₁-C₆Alkyl, 3-to 8-membered cycloalkyl, 4-to 8-membered heterocycloalkyl, and the like; and R is₇One or more of the groups in (a) may be substituted with one or more hydrogens on ring Cy to form a corresponding fused, spiro, bridged or like ring system, which may have from 0 to 3 heteroatoms including O, N, S;

n is independently selected from 0-4;

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, and the like; one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, acyl or sulfonyl, 5-to 8-membered aryl or heteroaryl, 4-to 8-membered cycloalkyl or heterocycloalkyl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S.

In a further embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, is characterized in that,

m is independently selected from CH or N;

R₁、R₂independently selected from hydrogen, halogen, preferably from fluorine, chlorine; r₃、R₄Independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl or heterocycloalkyl, further preferably from fluoro, methoxy;

R₅selected from hydrogen, halogen, alkyl; further preferably selected from hydrogen, fluorine, methyl;

y and Z are each independently selected from N or CR₆；R₆Independently selected from hydrogen, halogen, C1-C₆Alkyl, preferably from hydrogen;

cy is independently preferably selected from 4-6 membered cycloalkyl or heterocycloalkyl, 5-6 membered aryl or heteroaryl; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, a piperidine ring, a benzene ring, a pyridine ring, a pyrazole ring, or the like;

R₇selected from hydrogen, halogen, C₁-C₆Alkyl, cyano, hydroxy, amino, 4-to 8-membered heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like, and is further preferably selected from hydrogen, fluorine, cyano, amino, C₁-C₆Alkyl or 4-7 membered heterocycloalkyl, etc.; more preferably hydrogen, fluoro, methyl, piperazinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl and the like;

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

R₈、R₉And R₁₀Independently selected from hydrogen, halogen, alkyl, cyano; further preferably selected from hydrogen, fluorine, methyl and the like.

In a further preferred form, the compounds have the following general formula (IA), (IB):

wherein each group is as defined above.

A process for preparing a compound of formula I, said process comprising steps a-d:

a) converting the compound of the general formula (A) into a triazole intermediate compound of the general formula (B) by a literature method; and

b) carrying out substitution reaction or coupling reaction on the compound with the general formula (B) and a nitro-substituted amine compound under the reaction condition of the presence of acid, alkali or a transition metal catalyst to obtain a compound with a general formula (C); and

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

d) the compound (D) with the general formula and acrylic acid or acryloyl chloride compound are subjected to condensation reaction under the condition of alkali catalysis or the presence of a condensation reagent to prepare the compound with the general formula (I).

In each formula, LG represents a leaving group such as halogen, sulfone group, sulfoxide group, sulfonate group and the like, and the definition of each other group is as described above;

preferably, said steps a), b), c), d) are each carried out in a solvent and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, 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) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenyl)Phosphino) 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-benzylphosphine, tricyclohexylphosphine, tri-o-phenylphosphine, or a combination thereof.

Preferably, the condensing agent is selected from the group consisting of: DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, TBTU, and the like, or combinations thereof.

Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, 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 combinations thereof.

in the formula (I), the compound is shown in the specification,

R₅selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxy, and the like; preferably selected from hydrogen, halogen, alkyl;

y is N, Z is CR₆；

Or Y is CR₆Z is N;

R₆independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acylSulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and the like; preferably selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₆Heterocycloalkyl, and the like;

n is independently selected from 0-4;

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, and the like; one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C₁-C₈Alkyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, 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 compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₁And R₂When independently halogen, the halogen is preferably fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are as followsDefinitions (undefined groups are as described in any of the preceding schemes): when R is₃And R₄When independently halogen, said halogen is preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₃And R₄When independently alkoxy, said alkoxy is preferably C₁-C₆Alkoxy, more preferably C₁-C₄Alkoxy (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 compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆When it is an alkyl group, the alkyl group is preferably C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and a methyl group is more preferable.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₆is-alkylene-NR_6-2R_6-3When the alkylene group is C₁-C₆Alkylene, more preferably C₁-C₄Alkylene, still more preferably methylene.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_6-2And R_6-3Independently is C₁-C₆When alkyl, said C₁-C₆Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain of the compounds of formula (I) are describedThe groups are defined as follows (undefined groups are as described in any of the preceding schemes): when Cy is a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is preferably a 5-6 membered heterocycloalkyl group having "one or more hetero atoms selected from N, O and S and 1-3 hetero atoms", more preferably a tetrahydrofuranyl group (e.g., a 3-8 membered heterocycloalkyl group)

) Tetrahydropyrrolyl (e.g. phenyl)

) Tetrahydrothienyl (e.g. as

) Or tetrahydropyranyl (e.g. methyl)

) Further preferred is a tetrahydrofuranyl group or a tetrahydropyranyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when Cy is a 5-8 membered aryl group, the 5-8 membered aryl group is preferably phenyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when Cy is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is preferably a 5-6 membered heteroaryl group having "one or more hetero atoms selected from N, O and S and 1-3 hetero atoms", more preferably a pyrazolyl group (e.g., a 5-8 membered heteroaryl group)

) Or pyridyl (e.g. of

) Further, pyrazolyl is more preferable.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes):when R is₇When it is an alkyl group, the alkyl group is preferably C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group (e.g., 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 compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₇In the case of heterocycloalkyl, the heterocycloalkyl group is preferably a 4-to 11-membered heterocycloalkyl group, more preferably a "5-to 7-membered monocyclic heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, or a" 8-to 9-membered bicyclic heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; said 5-to 7-membered monocyclic heterocycloalkyl is preferably piperidinyl (e.g.

) Piperazinyl (e.g. piperazine)

) Or homopiperazinyl (e.g. of the formula I)

) (ii) a Said 8-to 9-membered bicyclic heterocycloalkyl is preferably

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇When said alkyl group is optionally substituted by 1-3C₁-C₈When alkoxy is substituted, said C₁-C₈Alkoxy is preferably C₁-C₄An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.

In the invention, some advantagesIn alternative embodiments, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇When the alkyl group is optionally substituted with 1 to 3 4-to 8-membered heterocycloalkyl groups, the 4-to 8-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group having "one or more hetero atoms selected from N, O or S and 1 to 3 hetero atoms, more preferably a tetrahydropyrrole group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇When said heterocycloalkyl is optionally substituted by 1-3C₁-C₈When substituted by alkyl, said C₁-C₈Alkyl is preferably C₁-C₄An alkyl group (e.g., 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 compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇When the heterocycloalkyl group is optionally substituted with 1 to 3 4-to 8-membered heterocycloalkyl groups, the 4-to 8-membered cycloalkyl group is preferably a 4-to 6-membered cycloalkyl group having "one or more heteroatoms selected from N, O or S and 1 to 3" heteroatoms, more preferably a tetrahydropyrrole group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇In the substituents, when the amino group and the C are mentioned₁-C₈One or more hydrogen atoms of alkyl, 4-8 membered heterocycloalkyl optionally substituted by C₁-C₆When substituted by alkyl, said C₁-C₆Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group or an ethyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined below (undefined)As described in any of the preceding schemes): r₇In the substituents, when the amino group and the C are mentioned₁-C₈One or more hydrogen atoms of alkyl, 4-8 membered heterocycloalkyl optionally substituted by C₁-C₆When alkoxy is substituted, said C₁-C₆Alkoxy is preferably C₁-C₄An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇In the substituents, when the amino group and the C are mentioned₁-C₈One or more hydrogen atoms on alkyl, 4-8 membered heterocycloalkyl optionally substituted with 5-10 membered heteroaryl, or C₁-C₆When the alkyl-substituted 5-to 10-membered heteroaryl group is substituted, the 5-to 10-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having 1 to 3 hetero atoms, and "hetero atoms" selected from N, O or S is one or more, and is more preferably pyrazolyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇In the substituents, when the amino group and the C are mentioned₁-C₈One or more hydrogen atoms of alkyl, 4-8 membered heterocycloalkyl optionally substituted by C₁-C₆When alkyl-substituted 5-to 10-membered heteroaryl is substituted, said C₁-C₆Alkyl is preferably C₁-C₄Alkyl, more preferably methyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇In the substituents, when the amino group and the C are mentioned₁-C₈When one or more hydrogen atoms of the alkyl group, the 4-to 8-membered heterocycloalkyl group, is optionally substituted with a 3-to 8-membered cycloalkyl group, said 3-to 8-membered cycloalkyl group is preferably a 3-to 6-membered cycloalkyl group, more preferably a cyclopropyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇In when R is_7-2、R_7-3And R_7-4Independently is C₁-C₆When alkyl, said C₁-C₆Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group or an ethyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_7-5Is C₁-C₆At alkoxy, said C₁-C₆Alkoxy is preferably C₁-C₄An alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), more preferably a methoxy group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_7-5Is 5-10 membered heteroaryl, or R_7-5cIn the case of a substituted 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is preferably a 5-to 6-membered heteroaryl group having 1 to 3 hetero atoms, and "hetero atoms" selected from N, O or S, and more preferably pyrazolyl.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_7-5In the case of a 3-to 8-membered cycloalkyl group, the 3-to 8-membered cycloalkyl group is preferably a 3-to 6-membered cycloalkyl group, and more preferably a cyclopropyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_7-6、R_7-7、R_7-5aAnd R_7-5bAnd R_7-5cIndependently is C₁-C₆When alkyl, said C₁-C₆Alkyl is preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₈When it is an alkyl group, the alkyl group is preferably C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), more preferably a methyl group.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₈When the alkyl group is substituted with 1 or more halogens, the halogen is preferably fluorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₈When the alkyl group is substituted with 1 or more halogens, the number of the halogens is preferably 1,2 or 3, more preferably 3.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is₉And R₁₀Independently is C₁-C₆alkylene-NR_8-1R_8-2When, C is said₁-C₆Alkylene is preferably C₁-C₄Alkylene, more preferably methylene.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): when R is_8-1And R_8-2Independently is C₁-C₆When alkyl, said C₁-C₆Alkyl is preferably C₁-C₄Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methylAnd (4) a base.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₁And R₂Independently selected from fluorine or chlorine.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₃And R₄Independently selected from fluoro or methoxy, preferably methoxy.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₅Is hydrogen.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding 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 compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): m is selected from CH or N.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): cy is selected from

Preference is given to

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₇Selected from H, F, Me, CF₃、

Preferably H, F, Me,

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): the structure in the compound shown as the formula (I)

Is selected from

Preference is given to

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₈Selected from H, F, Cl, CN, Me or CF₃Preferably H.

In certain preferred embodiments of the present invention, certain groups of the compounds of formula (I) are defined as follows (undefined groups are as described in any of the preceding schemes): r₉And R₁₀Independently selected from H, or

H is preferred.

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Independently selected from hydrogen, halogen, or alkoxy;

R₅is hydrogen;

y is N, Z is CR₆Or, Y is CR₆Z is N;

R₆selected from hydrogen, alkyl, or alkylene-NR_6-1R_6-2；R_6-1And R_6-2Independently is hydrogen or C₁-C₆An alkyl group;

m is selected from CR_aOr N; r_aIs hydrogen;

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

R₇selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms of any of the above groups being optionally substituted by a substituentGeneration: halogen, hydroxy, amino, cyano, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; in the substituent, the amino group and C₁-C₈Alkyl, one or more hydrogen atoms of a 4-to 8-membered heterocycloalkyl group optionally substituted by hydroxy, cyano, C₁-C₆Alkoxy radical, C₁-C₆Alkyl radical, C₁-C₆Alkyl-substituted amino, 5-to 10-membered heteroaryl, C₁-C₆Alkyl-substituted 5-to 10-membered heteroaryl, or 3-to 8-membered cycloalkyl;

n is selected from 0 to 4;

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR_8-1R_8-2(ii) a One or more hydrogen atoms on any of the above groups are optionally substituted with halogen; r_8-1And R_8-2Independently is hydrogen or C₁-C₆An alkyl group.

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Independently selected from hydrogen, halogen, or C₁-C₆An alkoxy group;

R₅is hydrogen;

y is N, Z is CR₆Or, Y is CR₆Z is N;

R₆selected from hydrogen, C₁-C₆Alkyl, or C₁-C₆alkylene-NR_6-1R_6-2；R_6-1And R_6-2Independently is hydrogen or C₁-C₆An alkyl group;

m is selected from CR_aOr N; r_aIs hydrogen;

R₇selected from hydrogen, halogen, C₁-C₆Alkyl, or 4-11 membered heterocycloalkyl; said C₁-C₆Alkyl is optionally substituted by 1-3 substituents selected from hydroxy, halogen, C₁-C₆Alkoxy, -NR_7-2R_7-34-8 membered heterocycloalkyl, or R_7-4Substituted with a substituent of a substituted 4-8 membered heterocycloalkyl group; wherein R is_7-4Is C₁-C₆Alkyl or C₆-C₁₀An aryl group; r_7-2And R_7-3Independently selected from hydrogen or C₁-C₆An alkyl group; said heterocycloalkyl is independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; wherein R is_7-5Selected from hydroxy, cyano, C₁-C₆Alkoxy, -NR_7-5aR_7-5b5-10 membered heteroaryl, R_7-5cSubstituted 5-10 membered heteroaryl, or 3-8 membered cycloalkyl; r_7-6、R_7-7、R_7-5aAnd R_7-5bIndependently selected from hydrogen or C₁-C₆An alkyl group; r_7-5cIs C₁-C₆An alkyl group;

n is selected from 0 to 4;

R₈、R₉and R₁₀Independently selected from hydrogen, halogen, cyano, C₁-C₆Alkyl, or C₁-C₆alkylene-NR_8-1R_8-2(ii) a One or more hydrogen atoms on any of the above groups are optionally substituted with halogen; r_8-1And R_8-2Independently is hydrogen or C₁-C₆An alkyl group.

in the formula (I), the compound is shown in the specification,

R₁and R₂Independently selected from halogen, or C₁-C₆An alkoxy group;

R₃and R₄Independently selected from halogen, or C₁-C₆An alkoxy group;

R₅is hydrogen;

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

m is selected from CH or N;

R₇selected from hydrogen, halogen, C₁-C₆Alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl, or 4-8 membered heterocycloalkyl; wherein R is_7-5Is a 3-8 membered cycloalkyl group; r_7-6And R_7-7Independently is C₁-C₆An alkyl group;

n is selected from 0, 1 or 2;

R₈selected from hydrogen, halogen, cyano, or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens;

R₉and R₁₀Independently selected from hydrogen, or C₁-C₆alkylene-NR_8-1R_8-2；R_8-1And R_8-2Independently is C₁-C₆An alkyl group.

in the formula (I), the compound is shown in the specification,

R₁and R₂Independently is halogen;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

y is N and 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;

R₉and R₁₀Is hydrogen.

in the formula (I), the compound is shown in the specification,

R₁and R₂Independently is halogen;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

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

m is selected from CH or N;

cy is selected from 5-8 membered aryl, or 5-8 membered heteroaryl;

R₇selected from hydrogen, C₁-C₆Alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl, or 4-8 membered heterocycloalkyl; wherein R is_7-5Is a 3-8 membered cycloalkyl group; r_7-6And R_7-7Independently is C₁-C₆An alkyl group;

n is selected from 0, 1 or 2;

R₈selected from hydrogen, halogen, or C₁-C₆An alkyl group;

R₉and R₁₀Is hydrogen.

in the formula (I), the compound is shown in the specification,

R₁and R₂Independently is halogen;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

y is N and 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;

R₇selected from hydrogen, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3C₁-C₆Alkyl substituted;

n is selected from 0, 1 or 2;

R₈is hydrogen;

R₉and R₁₀Is hydrogen.

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

wherein R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀Cy, M and n are as defined above.

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

the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps of a-d:

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

b) carrying out substitution reaction or coupling reaction on the compound with the general formula (B) and a nitro-substituted amine compound under the reaction condition of the presence of acid, alkali or a transition metal catalyst to obtain a compound with the general formula (C); and

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

d) in the presence of alkali or a condensation reagent, carrying out condensation reaction on a compound (D) with a general formula and acrylic acid or an acryloyl chloride compound to prepare a compound shown in a formula (I);

wherein LG represents a leaving group conventionally used in such reactions in the art, such as a halogen, sulfone group, sulfoxide group, sulfonate group, etc., and the other groups are as defined above.

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

Preferably, each of the steps a), b), c), d) is carried out in a solvent, and each of the solvents is independently selected from one or more of water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-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, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]One or more of palladium dichloride, bis (triphenylphosphine) palladium dichloride, and 1, 2-bis (diphenylphosphino) ethane palladium dichloride; the ligand of the transition metal catalyst is selected from one or more of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine and tri-o-phenylmethylphosphine.

Preferably, the condensing agent 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 one or more of sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate; the organic base is selected from one or more of pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide and lutidine.

Preferably, the acid is selected from one or more of hydrochloric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, toluenesulphonic acid, trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulphonic 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, which comprises the compound shown as the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, can be in a therapeutically effective amount.

The pharmaceutical composition is preferably a pharmaceutical composition for treating tumors, and consists of a compound shown as a formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.

The invention also provides application of the compound shown as the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition in preparation of medicines. The medicament is preferably a medicament for preventing and/or treating tumors or a medicament for treating diseases related to FGFR kinase. Wherein, the tumors include but are not limited to non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer, nasopharyngeal carcinoma and the like, in particular liver cancer or bile duct cancer; the FGFR kinase is preferably FGFR1 and/or FGFR4, more preferably FGFR 4.

The invention also provides application of the compound shown as the formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition in preparing FGFR kinase inhibitors. The FGFR kinase is preferably FGFR1 and/or FGFR4, more preferably FGFR 4.

The present invention also provides 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 of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition thereof; the tumor includes, but is not limited to, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymph cancer, nasopharyngeal carcinoma, etc., especially liver cancer or bile duct cancer.

Term(s) for

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 claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.

Definitions for the terms of the standardization sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical 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 reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH 2O-is equivalent to-OCH 2-.

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

Certain chemical groups defined herein are preceded by a shorthand notation 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 shorthand notation excludes carbons that may be present in a substituent of the group.

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

In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group; "carbonyl" refers to a-C (═ O) -group; "nitro" means-NO₂(ii) a "cyano" means-CN; "amino" means-NH₂(ii) a "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" means-COOH.

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

In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting 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 being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

In the present application, the term "alkynyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by single bonds, 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, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups 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-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 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, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.

In this application, the term "heterocyclyl" or "heterocycloalkyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

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

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

In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by 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 may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from 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 groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [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-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.

In the present 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 subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.

"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"tautomer" refers to an isomer 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 are also intended to be included within the scope of the invention.

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

Conventional techniques for the preparation/separation of individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, as described, for example, in Gerald Gubitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; m. Stalcup, Chiral Separations, Annu. Rev. anal. chem.3:341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; heller, acc, chem, res, 1990,23,128.

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

"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain 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, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.

"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain 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: primary, secondary and tertiary amines, substituted amines including naturally occurring 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, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, 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 of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.

Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods for preparing prodrugs can be found in 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, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., 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 an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.

The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(ii) inhibiting the disease or disorder, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or

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

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.

It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, 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 carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups may 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 described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. The space is not described herein in a repeated fashion.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

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

The positive progress effects of the invention are as follows: the fused ring triazole compound is a novel specific FGFR kinase irreversible inhibitor, has good target selectivity and can be used for treating tumors.

Detailed Description

The invention prepares a compound with a novel structure shown in formula I through long-term and intensive research, and finds that the compound has better FGFR kinase inhibition activity, and the compound generates specific irreversible inhibition effect on FGFR kinase under extremely low concentration (which can be as low as less than or equal to 10nmol/L), and has quite excellent inhibition activity, thereby being capable of being used for treating 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 invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

The application claims priority from a chinese patent application CN201810965291.6 with application date of 2018, 8 and 23, a chinese patent application CN201811283207.9 with application date of 2018, 10 and 31, and a chinese patent application CN201811498192.8 with application date of 2018, 12 and 7. The present application refers to the above-mentioned chinese patent application in its entirety. Reference is made to the above patent application text for information regarding the compounds of the present invention, which are not specifically disclosed herein.

Preparation of intermediates

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

The first step is as follows: 1, 3-dimethoxy-5-methylbenzene (30g,0.20mol) and dichloromethane (900mL) were charged into a dry round-bottomed flask (1L), and to the above solution was added dropwise sulfone dichloride (52.5g,0.40mol) under cooling in an ice bath, and after completion of the dropwise addition, the mixture was stirred at room temperature overnight. After the reaction is finished, NaHCO is added dropwise₃The pH of the aqueous solution was adjusted to 8, dichloromethane was extracted, washed with dilute hydrochloric acid and distilled water, respectively, dried, and concentrated under reduced pressure to give the compound 2, 4-dichloro-1, 5-dimethoxy-3-methylbenzene (31g, white solid) which was used in the next reaction.

The second step is that: 2, 4-dichloro-1, 5-dimethoxy-3-methylbenzene (31g,0.14mol) was dissolved in CCl₄(600mL) was placed in a dry round bottom flask (1000mL) and azobisisobutyronitrile (3.0g,0.018mol) and NBS (27.6g,0.154mol) were added sequentially at room temperature. Reacting for 3h at 80 ℃, and adding NaHCO₃The reaction was quenched with aqueous solution, extracted with dichloromethane, the organic phase dried, concentrated, and crystallized from methyl tert-butyl ether to give the compound 3-bromomethyl-2, 4-dichloro-1, 5-dimethoxybenzene (30g, white solid).

The third step: in a dry 1000mL round bottom flask was charged the compound 3-bromomethyl-2, 4-dichloro-1, 5-dimethoxybenzene (30g,0.1mol) and acetonitrile (500mL), and at room temperature was added trimethylsilylcyanide (12g,0.34mmol) and tetrabutylammonium fluoride (100mL,1 mol/L). Stir at rt for 1h and TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, the organic phase was washed with water and saturated brine, respectively, dried and concentrated, and the concentrate was slurried with ethyl acetate to give the compound (2, 6-dichloro-3, 5-dimethoxy-phenyl) -acetonitrile (20g, white solid).

The fourth step: to a dry 250mL round bottom flask was added (2, 6-dichloro-3, 5-bis)Methoxy-phenyl) -acetonitrile (10.4g,0.028mol) and DMF (100mL) were added 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (5g,0.02mol) and potassium carbonate (12.25g,0.06mol) in sequence at room temperature and the reaction stirred overnight until completion. The reaction solution was extracted with ethyl acetate, the organic phase was washed with distilled water and saturated brine, dried, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with an eluent system (DCM: MeOH ═ 30:1) to give compound 6- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -2-methylsulfanyl-pyridine [2,3-d ═]Pyrimidin-7-ylamine (3.7g, yellow solid). LC-MS ESI [ M + H ]]⁺＝399.0；1H-NMR(400MHz,CDCl₃)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 250mL round bottom flask, 4-amino-6-chloro-pyridine-3-carbaldehyde (2g,0.013mol) and NMP (20mL) were added followed by the addition of the compound (2, 6-dichloro-3, 5-dimethoxy-phenyl) -acetonitrile (4.4g,0.018mol), potassium carbonate (5.27g,0.039mol), and the reaction stirred at 80 degrees. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, the organic phase was washed successively with distilled water and saturated brine, dried, filtered, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with an eluent system (DCM: MeOH ═ 30:1) to give the compound 7-chloro-3- (2, 6-dichloro-3, 5-dimethoxy-phenyl) - [1,6]]Naphthyridin-2-ylamine (0.8g, yellow solid). LC-MS ESI [ M + H ]]⁺＝383.9；1H-NMR(400MHz,DMSO-d6)δ8.71(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

The first step is as follows: 4- (4-methyl-piperazin-1-yl) -aniline (5g) and triethylamine (5g) were dissolved in dry ethyl acetate (20mL) and cooled in an ice bathAcetic anhydride (5mL) was added dropwise thereto. After the completion of the dropwise addition, the reaction was carried out at room temperature for 3 hours. Separating out solid from the reaction solution, filtering under reduced pressure, leaching with ethyl acetate, and drying to obtain N- [4- (4-methyl-piperazine-1-yl) -phenyl]-acetamide solid (4 g). LC-MS ESI [ M + H ]]⁺＝234.3。

The second step is that: reacting N- [4- (4-methyl-piperazin-1-yl) -phenyl]-acetamide (4g) was dissolved in concentrated sulfuric acid (10mL), and concentrated nitric acid (3mL) was added dropwise slowly under cooling in an ice bath, and stirring was continued for 1 hour after completion of the dropwise addition. Pouring the reaction liquid into ice cubes, separating out solid, filtering under reduced pressure, drying, and recrystallizing ethyl acetate to obtain the N- [4- (4-methyl-piperazine-1-yl) -2-nitro-phenyl]Acetamide solid (2.8 g). LC-MS ESI [ M + H ]]⁺＝279.1。

The third step: reacting N- [4- (4-methyl-piperazin-1-yl) -2-nitro-phenyl]-acetamide (2.5g) was dissolved in methanol (10mL), and 4N hydrochloric acid solution (10mL) was added and heated under reflux for 1 hour. After the reaction is finished, diluting the reaction solution with water, adjusting the pH value to 8-9 by using ammonia water under the cooling of an ice bath, extracting by using ethyl acetate, washing by using water, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the 4- (4-methyl-piperazine-1-yl) -2-nitro-aniline. LC-MS ESI [ M + H ]]⁺＝237.2。

With reference to the same synthetic procedures and procedures, 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＝7.2Hz,1H),3.11(t,J＝4.0Hz,4H),2.67(t,J＝4.0Hz,4H),2.51-2.55(m,2H),1.69(t,J＝6.0Hz,3H)。

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

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)δ8.28(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- (pyrrolin-1-yl) piperidin-1-yl) aniline

LC-MS:ESI[M+H]+＝291.2。1H-NMR(400MHz,DMSO-d6)δ8.23(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] triazolo [1',5':1,6] pyrid [2,3-d ] pyrimidine

The first step is as follows: reacting 6- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -2-methylthio-pyrido [2,3-d]Dissolving pyrimidin-7-ylamine (4g, 10mmol) in methanol (300mL), adding N, N-dimethylformamide dimethyl acetal (2.4g, 20mmol), heating to 80 deg.C, stirring overnight, concentrating under reduced pressure, pulping with ethyl acetate for purification, filtering and drying to obtain the compound N' - (6- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -2- (methylthio) pyridine [2, 3-d%]Pyrimidin-7-yl) -N, N-dimethylformimide (3.6g, yellow solid) was used directly in the next reaction. LC-MS ESI [ M + H ]]⁺＝452.1。

The second step is that: n' - (6- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -2- (methylthio) pyridine [2, 3-d)]Pyrimidin-7-yl) -N, N-dimethylcarboximide (2.3g, 5mmol) was dissolved in methanol (50mL), pyridine (0.8g, 10mmol) and hydroxylammonium hydrochloride (417mg, 6mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature overnight. LCMS monitor reaction completion and concentrate under reduced pressure. Dissolving the residue in tetrahydrofuran (50mL), adding trifluoroacetic anhydride (10mL), stirring at room temperature for 12 hr, concentrating under reduced pressure to precipitate solid, and filtering to obtain compound 4- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -8- (methylthio) - [1,2,4]]Triazole [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%]Triazole [1',5':1,6]Pyridine [2,3-d ]]Pyrimidine (1.1g,2.6mmol) was dissolved in chloroform (100mL), and m-CPBA (1.6g,7.8mmol) was added and reacted at room temperature for 3 h. Washing the reaction solution with saturated sodium bicarbonate solution and water in sequence, extracting with dichloromethane, drying with anhydrous sodium sulfate, and filtering to obtain the compound 4- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -8- (methylsulfonyl) - [1,2,4]]Triazole [1',5':1,6]Pyridine [2,3-d ]]Pyrimidine (1.1g, yellow solid). LC-MS ESI [ M + H ]]⁺＝454.0。

The following intermediates 4A-4D were prepared using the same synthetic procedures and methods.

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

LC-MS:ESI[M+H]⁺＝421.3。1H-NMR(400MHz,CDCl₃)δ9.08(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] triazole [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] triazole [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] triazolo [4',3':1,6] pyrid [2,3-d ] pyrimidine

The first step is as follows: reacting 7-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d]Pyrimidine (1.2g,2.88mmol) was dissolved in ethanol (100mL), hydrazine hydrate (4mL) was added, the mixture was heated to 80 ℃ for overnight reaction, and concentrated under reduced pressure to give the compound 6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -7-hydrazino-2- (methylthio) pyrido [2, 3-d%]Pyrimidine (1.2g, yellow solid), was used directly in the next reaction. LC-MS ESI [ M + H ]]⁺＝412.0。

The second step is that: mixing 6- (2, 6-dichloro-3, 5-diMethoxyphenyl) -7-hydrazino-2- (methylthio) pyrido [2,3-d]Pyrimidine (1.2g,2.88mmol) was dissolved in formic acid (30mL) and heated to 100 ℃ for reaction overnight. Cooling the reaction liquid to room temperature, pouring the reaction liquid into cold water, separating out solid, filtering, and drying a filter cake to obtain the compound 6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) - [1,2,4]]Triazolo [4',3':1,6]Pyrido [2,3-d]Pyrimidine (1.1g, yellow solid). LC-MS ESI [ M + H ]]⁺＝421.8。

The third step: mixing 6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) - [1,2,4]Triazolo [4',3':1,6]Pyrido [2,3-d]Pyrimidine (1.1g,2.6mmol) was dissolved in chloroform (100mL), and m-CPBA (1.6g,7.8mmol) was added and reacted at room temperature for 3 h. Washing the reaction solution with saturated sodium bicarbonate solution and water in sequence, extracting with dichloromethane, drying with anhydrous sodium sulfate, and filtering to obtain the compound 4- (2, 6-dichloro-3, 5-dimethoxy-phenyl) -8- (methylsulfonyl) - [1,2,4]]Triazole [1',5':1,6]Pyridine [2,3-d ]]Pyrimidine (1.2g, yellow solid). LC-MS ESI [ M + H ]]⁺＝453.8。

The intermediate 4E is 8-chloro-4- (2, 6-dichloro-3, 5-dimethoxyphenyl) - [1,2,4] triazole [4,3-a ] [1,6] naphthyridine

LC-MS:ESI[M+H]⁺＝409.7/411.7。

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

The first step is as follows: triethylamine (2.5mL,17.3mmol) was added to a solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6g,8.64mmol) in DMF (15mL) and tert-butanol (5mL) cooled in an ice bath, followed by DPPA (3.6g,12.97mmol) and the reaction was heated to 80 ℃ and stirred for 4H. After the reaction was completed, part of the solvent was removed under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g, 90%).

The second step is that: 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g,7.8mmol) was dissolved in DCM (10mL) and trifluoroacetic acid (6mL) was slowly added dropwise thereto with cooling on an ice bath. After the addition was complete, the reaction solution was stirred overnight at room temperature. After the reaction was complete, concentration under reduced pressure gave 1-methyl-4-nitro-3-amino-pyrazole (1g, 80%). ESI-MS: M/z ═ 157(M + H)⁺。

The general method comprises the following steps: amino-substituted methylsulfonyl group

Dissolving the methylsulfonyl intermediate (1eq.) and the raw material amine (2eq.) in anhydrous DMF, adding potassium tert-butoxide (2eq.) and then heating to 100 ℃ by microwave for 2 hours. After the reaction is finished, dichloromethane is added for extraction, the organic phase is washed by saturated sodium bicarbonate solution and water in sequence, dried by anhydrous sodium sulfate, filtered, decompressed, concentrated, separated and purified by column chromatography to obtain the intermediate of the nitro compound.

The general method II comprises the following steps: amino-substituted aryl chlorides

Dissolving the chloro aryl intermediate (1eq.) and the raw material amine (2eq.) in anhydrous DMF, bubbling nitrogen for ten minutes, and sequentially adding Pd under the protection of nitrogen₂(dba)₃(0.1eq.), XantPhos (0.2eq.), and cesium carbonate (2 eq.). The reaction is carried out for 1 hour by microwave heating to 100 ℃. After the reaction is finished, dichloromethane is added for extraction, the organic phase is washed by saturated sodium bicarbonate solution and water in sequence, dried by anhydrous sodium sulfate, filtered, decompressed, concentrated, separated and purified by column chromatography to obtain an intermediate compound.

The general method is three: reduction of nitro groups

The nitro compound (1eq.) was dissolved in methanol, and a saturated sodium thiosulfate solution (2eq.) and a sodium carbonate solution (2eq.) were added, followed by stirring at room temperature overnight. After the reaction is finished, adding ethyl acetate for extraction, washing saturated sodium bicarbonate solution and water, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and recrystallizing by ethyl acetate to obtain the amino intermediate.

The general method comprises the following steps: acylation of propenoic acid

The amino compound intermediate (1eq.) and DIPEA (2eq.) were dissolved in dry DMF and acryloyl chloride (1.2eq.) was added slowly dropwise with cooling on an ice bath. After the addition, the reaction was carried out at room temperature overnight. And (3) quenching the reaction liquid by using dichloromethane and saturated sodium bicarbonate solution, separating an organic phase, washing the organic phase by using water and saturated sodium chloride respectively, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, concentrating the organic phase under reduced pressure, and separating and purifying the residue by using preparative HPLC or Biotage Flash column chromatography to obtain the target compound.

Examples preparation

The following compounds of examples were prepared and synthesized in sequence by general methods one to four, using intermediates 1-5 as starting materials, and other commercial reagents such as piperazine, tetrahydropyrrole, N-methylpiperazine, etc:

test example 1 determination of FGFR1-4 kinase inhibitory Activity of the Compounds of the present invention

1. The test method comprises the following steps: (1) a1 XKinase buffer was prepared. (2) Preparation of compound concentration gradient: test compounds were tested at 10uM starting concentration, 3-fold diluted 10 concentrations, duplicate wells tested, and serially diluted in 96-well plates to 100-fold final concentration of 10 different concentration solutions. Each concentration of compound was then further diluted with 1 x Kinase buffer to 5-fold final concentration of intermediate dilution solution. (3) Respectively adding 5 mu L of the prepared compound solution into compound holes of a 384-hole plate, and testing each concentration single hole; mu.L of 5% DMSO was added to each of the negative and positive control wells. (4) A2.5 fold final concentration of Kinase solution was prepared using a 1 XKinase buffer. (5) Add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 XKinase buffer was added to the negative control wells. (6) The mixture was centrifuged at 1000rpm for 30 seconds, shaken and mixed, and then incubated at room temperature for 10 minutes. (7) A2.5 fold final ATP and Kinase substrate22 mixture was made up using 1 XKinase buffer. (8) The reaction was initiated by adding 10. mu.L of a 2.5 fold final ATP and substrate mixture. (9) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at 28 ℃ for the corresponding time, respectively. (10) Add 30. mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix. (11) The conversion was read using Caliper EZ Reader ii. (12) Sample (I)The inhibition ratio of (d) was determined by the following formula, wherein (%) inhibition ratio was (OD negative control well-OD administration well)/OD negative control well × 100%. Analysis of results, IC₅₀The values were determined by regression with a four parameter method using a microplate reader random plus software.

2. Results the majority of examples provided by the invention have IC for the inhibitory activity of FGFR4₅₀Values were all less than 100nM, and the inhibitory activity IC of most of the examples₅₀Less than 20nM, and even less than 1nM in some examples, showing strong enzyme inhibitory activity; the inhibitory activity of the compounds on FGFR1 is weak, and the inhibitory activity IC of most of the compounds of the examples on FGFR1₅₀Greater than 20nM, and even greater than 1000nM in some examples, show higher kinase subtype selectivity. The specific results are shown in table one.

Table one: inhibitory Activity of some example Compounds on FGFR kinases

Meanwhile, compared with comparative compounds 1-3, the compounds of the embodiment of the invention have higher activity on FGFR4 kinase or subtype selectivity on FGFR1, and have obvious advantages. The specific results are shown in table two.

Table two: the kinase activity and selectivity of some of the example compounds was compared to the control compounds.

Test example 2: test of Effect of embodiments of the present invention on the proliferative Capacity of FGFR-mediated tumor cells

1. The test method comprises the following steps: hep3B cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density of 100. mu.L per well, incubated overnight, then added with compounds at various concentrations for 72hr, and a solvent control group (negative control) was set and incubated at 37 ℃ under 5% CO 2. Adding 10mM compound stock solution into cells, and using the compound to influence cell proliferation after the compound acts on the cells for 72h

And (Promega) adding 30 mu L of CTG reagent into each well, placing the mixture in a 37-degree culture box for 2-4 hours, reading by using an Envision of a full-wavelength microplate reader, and measuring the wavelength at 450 nm. The inhibition rate (%) of the compound on the growth of tumor cells was calculated by the following formula (OD negative control well-OD administration well)/OD negative control well × 100%. IC (integrated circuit)₅₀Values were determined by four parameter regression using Graphpad Prism 5 software.

2. As a result, the present invention provides some examples 1 to 50 showing proliferation inhibitory activity, IC, against Hep3B cells₅₀Values were all less than 500nM, IC for inhibitory activity of some of the example compounds₅₀Values even less than 100nM show strong cell proliferation inhibitory activity. The specific results are shown in table three:

table three: some of the example compounds have inhibitory activity on Hep3B cell proliferation.

Test example 3: EXAMPLES test of Compounds without differential kinase inhibitory Activity

The inhibitory activity of the compounds of the invention on different kinases such as EGFR, VEGFR, PDGFR, FGFR1-3, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, FGFR1, FGFR2, FGFR3, FGFR gated mutant V550L, CSF1R, etc. were also tested, and some of the example compounds such as example 3, example 7, example 11, example 35, example 47, etc. showed better FGFR4 kinase selectivity (IC)₅₀<5nM) for VEGFR, FGFR3, CDK, etc. (IC)₅₀>500nM) is greater than 100-fold; whereas for FGFR1, FGFR2, CSF1R, FGFR4 gated mutant kinases (20 nM)<IC₅₀<400nM) and the like in a selectivity of 10 to 100 times; in contrast, some of the examples show higher FGFR1, FGFR2 inhibitory activity (IC)₅₀<50nM) against FGFR4 kinase (IC)₅₀>1000nM) greater than 100-fold, as in example 43.

Test example 4: examples proliferation inhibitory Activity of Compounds of examples on different tumor cells

A variety of tumor cells, such as BaF3-FGFR4, BaF3-FGFR V550L, HuH-7, JH7, 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, kappa-299, SK-OV-3, U87MG, BT474, LNCAP, A, KYSE140, HUCC-T1, PANC-1, etc., were tested by SRB staining or CCK8 or CTG, and the proliferation inhibitory activity of the compounds of examples 3, 34, or the like, the compound shows better antitumor activity, the proliferation inhibition activity on various tumor cells is less than 1000nM, particularly the proliferation inhibition activity on cell strains positive to FGFR1, FGFR2 and FGFR4 is less than 500nM, and the IC50 of some embodiments such as example 3, example 7, example 32 and the like is even less than 50 nM.

Test example 5: ADME testing of the Compounds of the examples

(1) Metabolic stability test: the system is 150 mu L liver microsome (final concentration is 0.5mg/mL) for metabolic stability incubation, the system contains NADPH (final concentration is 1mM), 1 mu M test compound and positive control midazolam or negative control atenolol, the reaction is stopped by acetonitrile containing tinidazole at 0min, 5min, 10min and 30min respectively, vortex for 10min, centrifuge for 10min at 15000rmp, and 50 mu L supernatant is taken to be injected into a 96-well plate. The metabolic stability of the compounds was calculated by determining the relative decrease of the bulk drug.

(2) Direct inhibition assay (DI assay): the incubation was directly inhibited with 100. mu.L of human liver microsomes (final concentration 0.2mg/mL), which contained NADPH (final concentration 1mM), 10. mu.M of compound, cococktail (ketoconazole 10. mu.M, quinidine 10. mu.M, sulfaphenazole 100. mu.M, alpha-naphthoflavone 10. mu.M, tranylcypromine 1000. mu.M), negative control (BPS with 0.1% DMSO), and mixed probe substrate (midazolam 10. mu.M, testosterone 100. mu.M, dextromethorphan 10. mu.M, diclofenac 20. mu.M, phenacetin 100. mu.M, and mefenton 100. mu.M), and the reaction was terminated after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative production of the metabolite.

Some of the compounds of the examples, such as example 3, example 4, example 5, example 32, have high stability to microsomal metabolism and T_1/2All above 30min, has no direct inhibition effect on main metabolic enzyme, and IC₅₀All are larger than 20uM, showing better drug property.

Test example 6: examples in vivo pharmacokinetic parameter testing of Compounds in rats and mice

6 male SPF-grade SD rats (Shanghai Spill-Bikea laboratory animals) were divided into two groups, and the test compounds were formulated into appropriate solutions or suspensions; one group was administered intravenously (1mg/kg dose) and one group was administered orally (5mg/kg dose). Blood is collected by jugular venipuncture, about 0.2 mL/time point of each sample is collected, heparin sodium is anticoagulated, and the blood collection time points are as follows: pre-and post-dose 5, 15 and 30min, 1,2,4, 6, 8 and 24 h; blood samples were collected and placed on ice, plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 min, 2-8 ℃) and collected plasma was stored at-80 ℃ before analysis. Plasma samples were analyzed by LC-MS/MS.

According to the data of the blood concentration of the drug, pharmacokinetic parameters of the test sample, such as AUC0-T, AUC0- ∞, MRT0- ∞, Cmax, Tmax, T1/2 and Vd, and the average value and standard deviation thereof are respectively calculated by using a pharmacokinetic calculation software WinNonlin5.2 non-atrioventricular model. In addition, the bioavailability (F) will be calculated by the following formula.

For samples with concentrations below the lower limit of quantitation, in performing pharmacokinetic parameter calculations, samples taken before Cmax was reached should be calculated as zero values and samples taken at points after Cmax was reached should be calculated as non-quantifiable (BLQ).

Some of the compounds of the examples, such as example 3, example 4, example 5, example 32, were better potent when administered by gavage with Cmax greater than 200nM, AUC greater than 2000hr nM, and F% greater than 15%.

Test example 7: test of the Compounds of examples for growth inhibition of nude mouse Hep3B transplanted tumors

Cutting tumor tissue in vigorous growth stage into 1.5mm³And left and right, under aseptic conditions, inoculated subcutaneously in the right axilla of nude mice. Measuring the diameter of the transplanted tumor by using a vernier caliper in the nude mouse subcutaneous transplanted tumor until the average tumor volume reaches 130mm³Animals were randomized into groups. The compound of the example (prepared to the required concentration with water for injection containing 1% Tween 80) was administered orally at the given dose daily for three weeks with the solvent control group given an equal amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b²Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV is Vt/V0. Where V0 is the tumor volume measured at the time of caged administration (i.e., d0) and Vt is the tumor volume at each measurement. The evaluation index of the antitumor activity is 1) the relative tumor proliferation rate T/C (%), and the calculation formula is as follows: T/C (%) (TRTV/CRTV) × 100%, TRTV: treatment group RTV; CRTV: negative control group RTV; 2) the tumor volume increase inhibition rate GI% is calculated according to the following formula: GI% ([ 1- (TVt-TV0)/(CVt-CT 0))]X 100%, TVt is the tumor volume measured for each treatment group; TV0 is the tumor volume obtained when therapeutic components were administered in cages; CVt is the tumor volume measured in each time in the control group; CV0 is the tumor volume obtained when the control component was administered in cages; 3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio (% Wc-WT)/Wc × 100%, Wc: tumor weight of control group, WT: the treated group had heavy tumor.

The compound of some examples of the invention shows better effect of inhibiting tumor growth, such as example 3, example 7, etc. under 40mg/kg dose, the compound is continuously orally taken for 21 days, T/C is less than 10%, and part of experimental animal groups have tumor fading.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

in the formula (I), the compound is shown in the specification,

R₁and R₂Independently selected from halogen or C₁-C₆An alkoxy group;

R₃and R₄Independently selected from halogen or C₁-C₆An alkoxy group;

R₅is hydrogen;

y is N and 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;

the 3-8 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl of which the heteroatom is O and the heteroatom number is 1;

the 5-8-membered aryl is phenyl;

the 5-8 membered heteroaryl is a 5-membered heteroaryl with 1-3 heteroatoms as N;

R₇selected from hydrogen, halogen, C₁-C₆Alkyl or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl group is independentlyOptionally 1-3 of them are selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl or 4-8 membered heterocycloalkyl; wherein R is_7-5Is a 3-8 membered cycloalkyl group; r_7-6And R_7-7Independently is C₁-C₆An alkyl group;

the 4-11 membered heterocycloalkyl is 5-7 membered monocyclic heterocycloalkyl with 1-3 heteroatoms as N or 9-membered bicyclic heterocycloalkyl with 1-3 heteroatoms as N; the 4-8 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl of which the heteroatom is selected from one or more of N, O or S and the number of the heteroatoms is 1-3;

n is selected from 0, 1 or 2;

R₈selected from hydrogen, halogen, cyano or C₁-C₆An alkyl group; said C₁-C₆Alkyl is optionally substituted with 1-3 halogens;

R₉and R₁₀Independently selected from hydrogen.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein when R is₁And R₂When independently halogen, said halogen is fluorine or chlorine;

and/or when R₃And R₄When independently halogen, said halogen is fluorine;

and/or when R₃And R₄Independently is C₁-C₆At alkoxy, said C₁-C₆Alkoxy is C₁-C₄An alkoxy group;

and/or when R₇Is C₁-C₆When alkyl, said C₁-C₆Alkyl is C₁-C₄An alkyl group;

and/or, R₇When said 4-11 membered heterocycloalkyl group is optionally substituted with 1-3C₁-C₆When substituted by alkyl, said C₁-C₆Alkyl is C₁-C₄An alkyl group;

and/or when R₈Is C₁-C₆Alkyl radical, said C₁-C₆Alkyl is C₁-C₄An alkyl group;

and/or, R₈When said C is₁-C₆When alkyl is substituted with 1 or 3 halogens, said halogens are fluorine;

and/or, R₈Wherein when said alkyl group is substituted with 1 to 3 halogens, the number of said halogens is 3.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 2 wherein when R is₃And R₄Independently is C₁-C₄At alkoxy, said C₁-C₄Alkoxy is methoxy;

and/or, when Cy is 3-8 membered heterocycloalkyl, said 3-8 membered heterocycloalkyl is tetrahydrofuranyl, tetrahydropyranyl or tetrahydropyranyl;

and/or, when Cy is 5-8 membered heteroaryl, said 5-8 membered heteroaryl is pyrazolyl;

and/or when R₇Is C₁-C₆Alkyl radical, said C₁-C₆Alkyl is methyl, ethyl, n-propyl or isobutyl;

and/or, when the 4-11 membered heterocycloalkyl group is a 5-7 membered monocyclic heterocycloalkyl group having 1-3 heteroatoms as "heteroatom N", or a 9 membered bicyclic heterocycloalkyl group having 1-3 heteroatoms as "heteroatom N"; the 5-7 membered monocyclic heterocycloalkyl is piperidyl, piperazinyl or homopiperazinyl; the 9-membered bicyclic heterocycloalkyl is

And/or, R₇When said 4-11 membered heterocycloalkyl group is optionally substituted with 1-3C₁-C₆When substituted by alkyl, said C₁-C₆Alkyl is methyl, ethyl or isopropyl;

and/or, R₇When saidWhen the 4-to 11-membered heterocycloalkyl group of (a) is optionally substituted with 1 to 3 4-to 8-membered heterocycloalkyl groups, said 4-to 8-membered heterocycloalkyl group is a tetrahydropyrrolyl group;

and/or when R₈Is C₁-C₆Alkyl radical, said C₁-C₆The alkyl group is a methyl group.

4. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 3, wherein when Cy is 3-8 membered heterocycloalkyl, said 3-8 membered heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl;

and/or when R₇Is C₁-C₆Alkyl radical, said C₁-C₆The alkyl group is a methyl group.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R is₁And R₂Independently selected from halogen;

and/or, R₃And R₄Independently selected from C₁-C₆An alkoxy group;

and/or Cy is selected from 5-8-membered aryl or 5-8-membered heteroaryl, the 5-8-membered aryl is phenyl, and the 5-8-membered heteroaryl is 5-membered heteroaryl with 1-3 heteroatoms as N;

and/or, R₇Selected from hydrogen, C₁-C₆Alkyl or 4-11 membered heterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is 5-7 membered monocyclic heterocycloalkyl having 1-3 heteroatoms as N or 9-membered bicyclic heterocycloalkyl having 1-3 heteroatoms as N;

and/or, R₈Selected from hydrogen, halogen or C₁-C₆An alkyl group.

6. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 5 wherein Cy is selected from 5-8 membered aryl, said 5-8 membered aryl being phenyl;

and/or, R₇Is selected from hydrogen or 4-11 membered heterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is 5-7 membered monocyclic heterocycloalkyl with 1-3 heteroatoms as a "heteroatom of N, or 9 membered bicyclic heterocycloalkyl with 1-3 heteroatoms as a" heteroatom of N ".

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R is₁And R₂Independently selected from fluorine or chlorine;

and/or, R₃And R₄Independently selected from fluoro or methoxy;

and/or, Cy is selected from

And/or, R₇Selected from H, F, Me,

And/or, the structure in the compound shown as formula (I)

Is selected from

And/or, R₈Selected from H, F, Cl, CN, Me or CF₃。

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 7 wherein R is₃And R₄Independently selected from methoxy;

and/or, Cy is selected from

And/or, R₇Selected from H, F, Me,

And/or, the structure in the compound shown as formula (I)

Is selected from

And/or, R₈Is selected from H.

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula (I) is according to any one of the following schemes:

scheme 1:

R₁and R₂Independently of halogenA peptide;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

y is N and 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; the 3-8 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl of which the heteroatom is O and the heteroatom number is 1; the 5-8-membered aryl is phenyl; the 5-8 membered heteroaryl is a 5-membered heteroaryl with 1-3 heteroatoms as N;

R₇selected from hydrogen, halogen, C₁-C₆Alkyl or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl or 4-8 membered heterocycloalkyl; wherein R is_7-5Is a 3-8 membered cycloalkyl group; r_7-6And R_7-7Independently is C₁-C₆An alkyl group; the 4-11 membered heterocycloalkyl is 5-7 membered monocyclic heterocycloalkyl with 1-3 heteroatoms as N or 9-membered bicyclic heterocycloalkyl with 1-3 heteroatoms as N; the 4-8 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl of which the heteroatom is selected from one or more of N, O or S and the number of the heteroatoms is 1-3;

n is selected from 0, 1 or 2;

R₉and R₁₀Is hydrogen;

scheme 2:

R₁and R₂Independently is halogen;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

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

m is selected from CH or N;

cy is selected from 5-8 membered aryl or 5-8 membered heteroaryl; the 5-8-membered aryl is phenyl; the 5-8 membered heteroaryl is a 5-membered heteroaryl with 1-3 heteroatoms as N;

R₇selected from hydrogen, C₁-C₆Alkyl or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3 substituents selected from C₁-C₆Alkyl radical, R_7-5Substituted C₁-C₆Alkyl, -NR_7-6R_7-7Carbonyl or 4-8 membered heterocycloalkyl; wherein R is_7-5Is a 3-8 membered cycloalkyl group; r_7-6And R_7-7Independently is C₁-C₆An alkyl group; the 4-11 membered heterocycloalkyl is 5-7 membered monocyclic heterocycloalkyl with 1-3 heteroatoms as N or 9-membered bicyclic heterocycloalkyl with 1-3 heteroatoms as N; the 4-8 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl of which the heteroatom is selected from one or more of N, O or S and the number of the heteroatoms is 1-3;

n is selected from 0, 1 or 2;

R₈selected from hydrogen, halogen or C₁-C₆An alkyl group;

R₉and R₁₀Is hydrogen;

scheme 3:

R₁and R₂Independently is halogen;

R₃and R₄Independently is C₁-C₆An alkoxy group;

R₅is hydrogen;

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

m is selected from CH or N;

cy is 5-8-membered aryl, and the 5-8-membered aryl is phenyl;

R₇selected from hydrogen or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3C₁-C₆Alkyl substituted; the 4-to 11-membered heterocyclic ringThe alkyl is a 5-7 membered monocyclic heterocycloalkyl of which the heteroatom is N and the number of the heteroatoms is 1-3 or a 9-membered bicyclic heterocycloalkyl of which the heteroatom is N and the number of the heteroatoms is 1-3;

n is selected from 0, 1 or 2;

R₈is hydrogen;

R₉and R₁₀Is hydrogen.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1,

when R is_7-5When the alkyl is 3-8 membered cycloalkyl, the 3-8 membered cycloalkyl is 3-6 membered cycloalkyl;

and/or, when said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3R_7-5Substituted C₁-C₆When substituted by alkyl, said C₁-C₆Alkyl is C₁-C₄An alkyl group.

11. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 10,

and/or when R_7-5When the alkyl is 3-8 membered cycloalkyl, the 3-8 membered cycloalkyl is cyclopropyl;

and/or, when said 4-11 membered heterocycloalkyl is independently optionally substituted with 1-3R_7-5Substituted C₁-C₆When substituted by alkyl, said C₁-C₆The alkyl group is a methyl group.

12. A compound as shown below or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds:

13. a pharmaceutical composition comprising a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a pharmaceutical composition for treating a tumor.

15. Use of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 13 or 14 for the manufacture of a medicament; the medicine is a medicine for preventing and/or treating tumors or a medicine for treating diseases related to FGFR kinase.

16. The use of claim 15, wherein the tumor is non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma or nasopharyngeal carcinoma; the FGFR kinase is FGFR 4.

17. The use of claim 16, wherein the tumor is liver cancer or cholangiocarcinoma.

18. Use of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 13 or 14 for the preparation of an FGFR kinase inhibitor.

19. The use of claim 18, wherein the FGFR kinase is FGFR1 and/or FGFR 4.

20. The use of claim 19, wherein the FGFR kinase is FGFR 4.