CN108794453A

CN108794453A - It is a kind of targeting degradation FAK albumen compound and its application

Info

Publication number: CN108794453A
Application number: CN201810730844.XA
Authority: CN
Inventors: 饶燏; 周光飚; 孙永汇; 吴越; 高红英
Original assignee: Tsinghua University
Current assignee: Tsinghua University
Priority date: 2018-07-05
Filing date: 2018-07-05
Publication date: 2018-11-13

Abstract

The present invention proposes a kind of compound, is compound or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug shown in Formulas I：Wherein, X indicates that the ligand of FAK albumen, Z indicate that the ligand of E3 ligases, Y indicate the chain of connection X and Z to X-Y-Z Formulas I.

Description

It is a kind of targeting degradation FAK albumen compound and its application

Technical field

The present invention relates to biomedicine fields, in particular it relates to target the compound of degradation FAK albumen and its answer With.

Background technology

FAK albumen is also known as PTK2, by PTK2 gene codes.FAK kinases plays an important role in cell adherence, including thin The interaction of adherency and cell and ambient enviroment between born of the same parents, and FAK in cell in the movement to ambient enviroment Play important function.Evidence suggests when the function of FAK kinases is obstructed, the metastatic of breast cancer is greatly reduced.

The high expression in about 37% ovarian cancer cell and about 26% breast cancer cell of the mRNA level in-site of FAK.Since FAK joins With the regulation and control of kinds of tumors, also it is developed in succession for the inhibitor of FAK at present.Include the PF- of exploitation in 2012 228, PF-271, Y15 (1,2,4,5-benzenetetraamine tetrahydrochloride) and PND-1186.

2014, a variety of Fak inhibitors came into clinical experimental stage, including ATP competitive inhibitor VS-6062, Defactinib and PND-1186.Defactinib comes into non-small cell of the phase II clinical trials for treating KRAS mutation Lung cancer.

Can effectively it inhibit or the drug for FAK albumen of degrading is also to be developed however, new.

Invention content

One of the technical issues of the present invention is directed to solve the prior art at least to a certain extent：

Inventor has found that current FAK micromolecular inhibitors are broadly divided into two major classes：ATP dependent forms and non ATP rely on Type.ATP dependent form FAK micromolecular inhibitors can interfere the activity of FAK catalysis regions, and it is logical may to influence multiple downstream signals Relatively broad side effect is caused on road, and can block spy if non ATP dependent form FAK micromolecular inhibitors such as allosteric Fak inhibitor Fixed protein-protein interaction (interaction of such as p53 and FAK), to inhibit the activity of FAK.Therefore, although mesh It is preceding to have developed many FAK micromolecular inhibitors for being directed to both the above type, but due to the complexity and limitation of organism Property, it is really considerably less for clinical micromolecular inhibitor.

Discovery based on problem above inventors herein proposes a kind of new compound, and the compound is using double target spots Molecular structure, structure is as shown in Figure 1, the structure targeting of such molecule one end combines E3 ligases, the structure targeting knot of the other end FAK albumen is closed, the structure at both ends is connected by chain (linker), forms a complete compound molecule, and the compound is logical It crosses E3 ubiquitinations target protein and guiding target albumen enters degradation access, the selective degradation of target protein is acted on strong.It should Compound can selective degradation FAK, therefore have potential application value in antitumor and reproductive system field.

For this purpose, in the first aspect of the present invention, the present invention proposes a kind of compound, be Formulas I shown in compound or its Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, can pharmaceutically connect geometric isomer The salt or prodrug received：

X-Y-Z

Formulas I

Wherein, X indicates the ligand of FAK albumen (Focal Adhesion Kinase-Related Nonkinase), Z tables Show that the ligand of E3 ligases, Y indicate the chain of connection X and Z.

According to an embodiment of the invention, above compound can also further comprise at least one following additional technical feature：

According to an embodiment of the invention, the X is compound shown in Formula II -1 or II-2,

Cy¹Or Cy²It is separately phenyl ring, C_6-12Aryl, the heteroaryl of 5-12 annular atom composition, C_3-12Naphthenic base Or the heterocycle of 3-12 annular atom composition；

L¹For-(CR^mR^w)_g-O-(CR^mR^w)_g,-(CR^mR^w)_g-S-(CR^mR^w)_g,-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g,- (CR^mR^w)_n,-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g,-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g,-(CR^mR^w)_g-S (=O)_p-(CR^mR^w)_g,-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g,-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g,-(CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g,-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_g-；

Each Cy¹Or Cy²Separately by 1,2,3,4,5 or 6 R^h1Replaced；

Each L¹Separately by 1,2,3,4,5 or 6 R^h2Replaced；

Each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle of 3-12 annular atom composition, 5-12 The heteroaryl of a annular atom composition, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N (R^1a)-(CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle of 3-12 annular atom composition, 5-12 The heteroaryl of a annular atom composition, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N (R^1a)-(CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^gIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each R^g1It is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each R^1aIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5- of 3-12 annular atom composition The heteroaryl of 10 annular atoms composition；

Each R^mOr R^wIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Halogen Substituted alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle that aryl, 3-12 annular atom form Or the heteroaryl of 5-10 annular atom composition；

Each n is separately 1,2,3 or 4；

Each g is separately 0,1,2,3 or 4；

Each p is separately 1 or 2.

According to an embodiment of the invention, Cy¹Or Cy²It is separately phenyl ring, C_6-10Aryl, 5-10 annular atom composition Heteroaryl, C_3-6The heterocycle of naphthenic base or 3-12 annular atom composition.

According to an embodiment of the invention, each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, 3-12 The heterocycle of annular atom composition, the heteroaryl of 5-10 annular atom composition, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle of 3-12 annular atom composition, 5-10 The heteroaryl of a annular atom composition, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N (R^1a)-(CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mRw)_g- C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^gIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each R^g1It is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition.

According to an embodiment of the invention, each R^1aIt is separately H, deuterium, F, Cl, Br, I, CN, NO₂, OH, amino, carboxylic Base, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, 3-12 ring The heteroaryl of former molecular heterocycle or 5-10 annular atom composition；

Each R^mOr R^wIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Halogen Substituted alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle that aryl, 3-12 annular atom form Or the heteroaryl of 5-10 annular atom composition.

According to an embodiment of the invention, Cy¹Or Cy²It is separately

According to an embodiment of the invention, each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl ,-CH₂F ,-CHF₂,-CF₃,-CH₂Cl ,- CHCl₂,-CCl₃,-CH₂Br ,-CHBr₂,-CBr₃,-CH₂CHF₂,-CH₂CF₃,-CHFCF₃,-CF₂CHF₂,-CF₂CF₃,- CH₂CH₂CF₃,-CH₂CF₂CHF₂, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group or tertiary butyl；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group, tertiary butyl ,-R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group or tertiary butyl；

Each R^gIt is separately

Each R^g1It is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

According to an embodiment of the invention, each R^1aIt is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group or tertiary butyl；

Each R^m、R^wOr R^gIt is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or uncle Butyl.

According to an embodiment of the invention, the X is formula III -1, shown in III-2, III-3, III-4, III-5 or III-6 Compound,

According to an embodiment of the invention, the Z is compound shown in formula IV,

Wherein, Q is N or CR²；

M is C (R^eR^f), N (R^1b), O or S；

W, K are separately C (R^eR^f), N (R^1b), O or S；

R²For hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl or C_2-6Alkynyl；

Each R^2a、R^2bIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, oxo, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 annular atom form miscellaneous The heteroaryl of ring group or 5-12 annular atom composition；

Each R^2cIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle or 5- of 3-12 annular atom composition The heteroaryl of 12 annular atoms composition；

Each R^e、R^fIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6It is halogenated Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, 3-12 annular atom composition heterocycle or The heteroaryl of 5-10 annular atom composition；

Each R^1bIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle or 5- of 3-12 annular atom composition The heteroaryl of 12 annular atoms composition；

n₁、n₂It is separately 0,1,2 or 3；

n₃It is 0,1,2,3,4 or 5.

According to an embodiment of the invention, R²For hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4 Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl or C_2-4Alkynyl.

According to an embodiment of the invention, each R^2a、R^2bIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, oxo, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, 3- The heteroaryl of heterocycle or 5-10 annular atom composition that 12 annular atoms form；

Each R^2cIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5- of 3-12 annular atom composition The heteroaryl of 10 annular atoms composition.

According to an embodiment of the invention, each R^e、R^fIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, Carboxyl, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, 3-12 The heterocycle of annular atom composition or the heteroaryl of 5-10 annular atom composition；

Each R^1bIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5- of 3-12 annular atom composition The heteroaryl of 10 annular atoms composition.

According to an embodiment of the invention, R²For hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or Tertiary butyl.

According to an embodiment of the invention, each R^2a、R^2bIt is separately hydrogen, deuterium, oxo, methyl, ethyl, n-propyl is different Propyl, normal-butyl, isobutyl group or tertiary butyl；

Each R^2cIt is separately hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

According to an embodiment of the invention, each R^e、R^fIt is separately hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group or tertiary butyl；

Each R^1bIt is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

According to an embodiment of the invention, the Z be Formula V -1, compound shown in V-2, V-3, V-4 or V-5,

According to an embodiment of the invention, the Y is the group containing 1~30 atom, and the atom includes former selected from carbon At least one of son, sulphur atom, oxygen atom, nitrogen-atoms, selenium atom.

According to an embodiment of the invention, the Y is C_1-20Alkyl, C_1-20Halogenated alkyl, C_1-20Alkoxy, C_2-20Alkenyl, C_2-20Alkynyl, C_3-12Naphthenic base, C_6-12The heteroaryl of heterocycle or 5-12 annular atom composition that aryl, 3-12 annular atom form The group that at least one of base is constituted.

According to an embodiment of the invention, the Y is Wherein, x₁-x₂₃It is separately a key,

R^1dFor H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl or C_1-4Alkyl.

According to an embodiment of the invention, the Y is compound shown in Formula IV -1 or VI-2,

Each r is separately the integer between 0~12；

Each k is separately the integer between 0~12；

Each j is separately the integer between 0~12；

Each t¹Or t³It is separately key,

Each t²Or t⁴It is separately key,

t⁵For key or

R^1dFor H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

In the second aspect of the present invention, the present invention proposes a kind of compound, is compound shown in 1~38 any one of formula Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,

In the third aspect of the present invention, the present invention proposes a kind of pharmaceutical composition.According to an embodiment of the invention, described Pharmaceutical composition includes compound described in any one of the above embodiments.

According to an embodiment of the invention, aforementioned pharmaceutical compositions can also further comprise following additional technical feature at least it One：

According to an embodiment of the invention, described pharmaceutical composition further comprises auxiliary material.

According to an embodiment of the invention, described pharmaceutical composition further comprise for contraception drug or other treatment or The drug of pre- preventing tumor or the related disease of reproductive system.

According to an embodiment of the invention, the tumour or the related disease of reproductive system include selected from breast cancer, oophoroma, At least one of cervical carcinoma, lung cancer, liver cancer, gastric cancer, colorectal cancer, cutaneum carcinoma, the cancer of the brain, osteosarcoma.

According to an embodiment of the invention, the other treatment or pre- preventing tumor or the drug packet of the related disease of reproductive system It includes selected from non-at least one of Buddhist nun, Afatinib, Cetuximab, Gamendazole, testosterone.

In the fourth aspect of the present invention, the present invention proposes compound described in any of the above-described or described in any one of the above embodiments The purposes of pharmaceutical composition in medicine preparation, the drug is for FAK albumen of degrading.

In the fifth aspect of the present invention, the present invention proposes described in any one of above-mentioned compound or any of the above-described Pharmaceutical composition purposes in medicine preparation, the drug is for treating or preventing tumour or the related disease of reproductive system Disease.

According to some embodiments of the present invention, the tumour or the related disease of reproductive system include selected from breast cancer, ovum At least one of nest cancer, cervical carcinoma, lung cancer, liver cancer, gastric cancer, colorectal cancer, cutaneum carcinoma, the cancer of the brain, osteosarcoma.

In the sixth aspect of the present invention, the present invention proposes a kind of method of degradation FAK albumen.Implementation according to the present invention Example, the method includes：Make FAK albumen and compound described in any one of the above embodiments or pharmaceutical composition described in any one of the above embodiments Contact.

In the seventh aspect of the present invention, the present invention proposes a kind for the treatment of or prevention tumour or the related disease of reproductive system Method according to an embodiment of the invention, the method includes giving patient's compound described in any one of the above embodiments or any of the above-described Pharmaceutical composition described in.

Description of the drawings

Fig. 1 is to be illustrated according to the basic fundamental route of the PROTACs (protein cleavage targeting chimera) of the embodiment of the present invention Figure；

Fig. 2 is to prepare the compounds of this invention by click chemistry (click-reaction) according to the embodiment of the present invention Schematic diagram；

Fig. 3 is to be tied according to the synthetic route schematic diagram and PF-562271 of the ends the PF-562271 derivative of the embodiment of the present invention Structure；

Fig. 4 is compound shown in the formula 1- formulas 4 according to the embodiment of the present invention to the degradation schematic diagram of FAK；

Fig. 5 is compound shown in the formula 5- formulas 10 according to the embodiment of the present invention to the degradation schematic diagram of FAK；

Fig. 6 is compound shown in the formula 2 according to the embodiment of the present invention to the half degradation rate of FAK in different tumor cell lines Schematic diagram；

Fig. 7 is compound shown in the formula 2 according to the embodiment of the present invention to FAK in mouse ovarian and testis relevant cell system Degradation schematic diagram；

Fig. 8-1 is compound shown in the formula 2 according to the embodiment of the present invention to the drop of FAK in the primary sertoli cell of mouse testis Solve effect curves schematic diagram；And

Fig. 8-2 is compound shown in the formula 2 according to the embodiment of the present invention to the drop of FAK in the primary sertoli cell of mouse testis Solve exercising result schematic diagram.

Specific implementation mode

The embodiment of the present invention is described below in detail, the embodiments described below is exemplary, it is intended to for explaining this Invention, and be not considered as limiting the invention.

Term used in herein " give the foregoing chemical combination of patient or its stereoisomer, geometric isomer, Tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug are noted earlier Pharmaceutical composition " refer to the substance of predetermined amount introduced into patient by certain suitable mode.Formulas I, Formula II, the formula of the present invention Compound or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, water described in III, formula IV, Formula V or Formula IV It closes object, solvate, metabolite, pharmaceutically acceptable salt or prodrug or pharmaceutical composition can be by any common Approach is administered, as long as it can reach expected tissue.The various modes of administration are expected, including peritonaeum, vein, Muscle, subcutaneously, cortex take orally, part, nasal cavity, lung and rectum, but the present invention is not restricted to these illustrated to prescription Formula.

The administration frequency and dosage of the pharmaceutical composition of the present invention can be determined by multiple correlative factors, the factor packet Include the disease type to be treated, administration route, patient age, gender, weight and the severity of disease and as activity The drug type of ingredient.

Term " treatment " obtains desired pharmacology and/or physiologic effect for referring to.The effect is with regard to complete or partial It can be preventative for prevention disease or its symptom, and/or just partially or completely cure caused by disease and/or disease not Can be therapeutic for good action." treatment " used herein covers the treatment of mammal, particularly the disease of people, packet It includes：(a) prevent disease in easy illness but in not yet making a definite diagnosis the individual fallen ill or illness occurs；(b) inhibit disease；Or (c) Alleviate disease, such as mitigates and the relevant symptom of disease." treatment " used herein, which is covered, gives drug or compound to individual With treatment, healing, alleviation, improvement, mitigation or any medication for inhibiting individual disease, will including but not limited to contain described herein Formulas I~Formula IV or 1~18 compound of formula or pharmaceutical composition give individual in need.

According to an embodiment of the invention, the auxiliary material includes pharmaceutical excipient well known to formulation art, lubricant, fills out Agent, diluent, disintegrant, stabilizer, preservative, emulsifier, cosolvent, colorant, sweetener are filled, tablet, pill, glue is made The different dosage forms such as wafer, injection.

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.

It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.

There is apparent conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.

Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.

" stereoisomer " refers to having identical chemical constitution, but atom or the group spatially different change of arrangement mode Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.

" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Many organic compounds exist with optical active forms, i.e., they, which have, makes the plane of linearly polarized light rotate Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains, there are one double bonds, and substituent group may be E or Z configurations；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is can refer to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".In general, art " substituted " expression of language is replaced to one or more of structure hydrogen atom by specific substituent group.Unless other aspect tables Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not Only a position can be replaced by one or more substituent groups selected from specific group, then substituent group can identical or differently Replace at various locations.

As described in the present invention, substituent R ' it is keyed to the member ring systems formed on the ring at center by one and represents substituent group R ' can be replaced any commutable position on the ring.For example, formula a represents any possible substituted position on B ' rings It can be replaced by R ', as shown in formula b, formula c and formula d.

As described in the present invention, the attachment point on ringCan on the ring any attachable position and molecule its remaining part Divide connection.For example, formula i, which represents any possible connected position on B ' rings, can be used as tie point, as shown in formula d, e and f.

As described in the present invention, two attachment points on the same ringIt can any attachable two not on the ring Same remaining two parts of position and molecule are separately connected, and the connection type at both ends can be interchanged.Take up an official post for example, formula j represents D rings What may connected two different positions can be used as tie point and molecule remaining two parts and be separately connected, such as formula g, h and k It is shown.

As described in the present invention, if can be connected with molecule rest part there are two tie point in chain structure, both ends Connection type can be interchanged.As described in the invention, for example, "-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g" or "- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g" connection type at both ends can be interchanged.

It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.For another example 0~12 it Between integer include endpoint 0 and any one integer between 12 and 0~12, such as 1,2,3,4,5,6,7,8,9,10 or 11.

In each section of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is respectively represented it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Unless otherwise indicated, term " alkyl " indicates that 1-20 carbon atom or 1-10 carbon atom or 1-8 carbon are former The univalence hydrocarbyl of the saturated straight chain or branch of son or 1-6 carbon atom or 1-4 carbon atom or 1-3 carbon atom, wherein alkane Base can be independent and optionally be replaced by one or more substituent groups described in the invention, and substituent group includes but not limited to, Deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, sulfydryl, nitro, oxo (=O) etc..The example of alkyl includes, but and unlimited In methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,-CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tertiary butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyls (- CH (CH₃) CH₂CH₂CH₃), 3- amyls (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl-1s-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), just Hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyls (- CH (CH₃)CH₂CH₂CH₂CH₃), 3- hexyls (- CH (CH₂CH₃) (CH₂CH₂CH₃)), 2- methyl -2- amyls (- C (CH₃)₂CH₂CH₂CH₃), 3- methyl -2- amyls (- CH (CH₃)CH(CH₃) CH₂CH₃), 4- methyl -2- amyls (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- amyls (- C (CH₃)(CH₂CH₃)₂), 2- first Base -3- amyls (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- Butyl (- CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl etc..Term " alkyl " and its prefix " alkane " use here, all wrap Saturated carbon chains containing straight chain and branch.Term " alkylene " uses here, indicates to eliminate from linear chain or branched chain saturation hydrocarbons The saturated divalent hydrocarbon radical that two hydrogen atoms obtain, such example include, but is not limited to, methylene, ethylidine, secondary isopropyl Etc..

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-15 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention The substituent group stated is replaced comprising the positioning of " cis " and " tans ", or " E " and " Z " positioning.In one embodiment, Alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH₂)、 Allyl (- CH₂CH=CH₂) etc..

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-15 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one tri- keys of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention The substituent group stated is replaced.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyls (- C ≡ C-CH₃) etc..

Term " naphthenic base ", " alicyclic group ", " annular aliphatic base ", " carbocyclic ring " or " carbocylic radical " refers to monovalence or more Valence, non-aromatic, saturation or the undersaturated ring in part, and do not include hetero atom, monocycle including 3-12 carbon atom or Two rings of 7-12 carbon atom.Bicyclic carbocyclic with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] System, while it can be two rings [5,6] or [6,6] system to have the bicyclic carbocyclic of 9 or 10 atoms.Suitable annular aliphatic Base includes, but is not limited to, naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of annular aliphatic base includes, but is not limited to, ring Propyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- Cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl Base, cyclodecyl, ring undecyl, cyclo-dodecyl etc..And " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " naphthenic base " can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyanogen Base, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, hydroxyl substitution Alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)₂, hydroxyl Alkyl-the S (=O) of substituted alkyl-S (=O)-, hydroxyl substitution₂, carboxyl substitution alkoxy etc..

Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " is used interchangeably here, all refer to monocycle, Bicyclic or three-ring system, one or more carbon atoms are independent in middle ring and optionally replaced by hetero atom, the hetero atom With meaning as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, but be definitely not virtue The fragrant same clan, and there are one or multiple tie points be connected to the other parts of molecule.One or more ring hydrogen atoms it is independent and Optionally replaced by one or more substituent groups described in the invention.Some of embodiments are " heterocycle ", " heterocycle Base ", " heteroalicyclic " or " heterocycle " group be 3-7 membered rings monocycle (1-6 carbon atom and 1-3 selected from N, O, P, S it is miscellaneous Atom optionally replaces to obtain such as SO, SO in this S or P by one or more oxygen atoms₂、PO、PO₂Group, when described Ring when being three-membered ring, only one of which hetero atom) or 7-10 members bicyclic (4-9 carbon atom and selected from N, O, P, S 1-3 hetero atom optionally replaces to obtain such as SO, SO in this S or P by one or more oxygen atoms₂、PO、PO₂Base Group).

Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and close be formed by group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thioalkyl, thiazolidinyl, oxazolidine radicals, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- Methoxy-piperidin -1- bases, 1,2,3, 6- tetrahydropyridine -1- bases, oxygen azepineBase, diazaBase, sulphur azepineBase, pyrrolin -1- bases, 2- pyrrolinyls, 3- pyrroles Cough up quinoline base, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxacyclohexyl, 1,3- dioxymyls, pyrazolinyl, two thiophenes Alkyl, dithienyl group, dihydrothiophene, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 1, 2,6- thiadiazine alkane 1,1- dioxo -2- bases, 4- hydroxyl -1,4- azepine phosphine 4- oxide -1- bases, 2- hydroxyl -1- (piperazines - 1- yls) ethyl ketone -4- bases, 2- hydroxyls -1- (- 1 (4H)-yl of 5,6- dihydro -1,2,4- triazines) ethyl ketone -4- bases, 5,6- dihydros -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyls -1- (5,6- dihydropyridines -1 (2H)-yl) ethyl ketone -4- bases, 3- azabicyclos [3.1.0] Hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- methyl -5,6,7,8- tetrahydrochysenes-[1.2.4] three Azoles [1,5-c] pyrimidine -6- bases, 4,5,6,7- tetrahydrochysene isoxazoles [4,3-c] pyridine -5- bases, 3H- indyl 2- oxygen -5- azepines are double Ring [2.2.1] heptane -5- bases, 2- oxygen -5- azabicyclos [2.2.2] octane -5- bases, quinazinyl and N- pyridyl ureas.Heterocycle The example of group further includes that two carbon atoms are replaced by oxygen atom such as pyrimidine on 1,1- dioxothiomorpholinyl and its middle ring Diketo.And the heterocycle can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitre Base, aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, The alkoxy that alkyl-S (=O) 2-, the alkyl-S (=O)-of hydroxyl substitution, alkyl-S (=O) 2- of hydroxyl substitution, carboxyl replace Etc..

Term " hetero atom " indicates one or more O, S, N, P and Si atom, includes the form of any oxidation state of N, S and P； The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N (such as 3,4- bis- N in hydrogen -2H- pyrrole radicals), NH (such as NH in pyrrolidinyl) or NR (such as NR in the pyrrolidinyl of N- substitutions).

Term " aryl " can be used alone or as " aralkyl ", " aralkoxy " or " aryloxy alkyl " a big portion Point, indicate monocycle altogether containing 6-14 membered rings, bicyclic and tricyclic carbocyclic ring system, wherein at least one member ring systems are aromatic series , wherein each member ring systems include 3-7 membered rings, and there are one or multiple attachment points be connected with the rest part of molecule.Term " aryl " can be exchanged with term " aromatic rings " and be used, if aromatic rings may include phenyl, naphthalene and anthryl.And the aryl Can be substituted or unsubstituted, wherein substituent group can be, but be not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, Heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, hydroxyl substitution alkoxy, Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, the alkyl-S (=O) of hydroxyl substitution₂, hydroxyl substitution alkane Alkyl-the S (=O) that base-S (=O)-, hydroxyl replace₂, carboxyl substitution alkoxy etc..

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate monocycle altogether containing 5-14 membered rings, bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one A member ring systems include one or more hetero atoms, and wherein hetero atom has meaning of the present invention, wherein each member ring systems Including 3-7 membered rings, and there are one or multiple attachment points be connected with molecule rest part.Term " heteroaryl " can be with term " virtue Heterocycle " or " heteroaromatics ", which exchange, to be used.And the heteroaryl can be substituted or unsubstituted, and wherein substituent group can It to be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynes Base, heterocycle, sulfydryl, nitro, aryloxy group, hydroxyl substitution alkoxy, hydroxyl substitution alkyl-C (=O)-, alkyl-C (= O)-, alkyl-S (=O)-, alkyl-S (=O)₂, hydroxyl substitution alkyl-S (=O)-, hydroxyl substitution alkyl-S (=O)₂-、 The alkoxy etc. of carboxyl substitution.

Other embodiment is that heteroaromatic includes monocycle below, but is not limited to these monocycles：2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazoles Base, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- Pyridyl group, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazinyl (such as 3- pyridazinyls), 2- thiophenes Oxazolyl, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazolyls), 2- thiophene Base, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- Oxadiazolyl, 1,2,3- triazolyls, 1,2,3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, 1,3, 4- thiadiazoles -2- bases, pyrazinyl, pyrazine -2- bases, cyanuro 1,3,5, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyrrole Pyridine -6- bases；Also include below bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, Indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls) and isoquinolyl (such as 1- Isoquinolyl, 3- isoquinolyls or 4- isoquinolyls).

Term " prodrug " used in the present invention represents a compound and is converted into Formulas I, Formula II, formula III, formula in vivo IV, Formula V or Formula IV compound represented.Such conversion is hydrolyzed or in blood or tissue by pro-drug through enzyme in blood It is converted into the influence of precursor structure.Pro-drug compounds of the present invention can be ester, and ester can conduct in existing invention Pro-drug has phenyl ester class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino Esters of gallic acid.Such as a compound in the present invention includes hydroxyl, you can be acylated to obtain the chemical combination of prodrug form Object.Other prodrug forms include phosphate, if these phosphate compounds are obtained through the di on parent It arrives.Following documents can be referred to by completely being discussed about pro-drug：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche, ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry, 2008,51,2328-2345。

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stablizes body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.

Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can obtain the inorganic base of salt by its derivative includes, for example, the I races of ammonium salt and periodic table to XII races metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

It includes primary amine, secondary amine and tertiary amine that can obtain the organic base of salt by its derivative, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid of metered amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it needs to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the other suitable for salt can be found in.

In addition, compound disclosed by the invention, includes their salt, in the form of their hydrate or it can also be included The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, and is used for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as³H,¹⁴C and¹⁸Those of F compounds, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for being metabolized research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound shown in the Formulas I of isotope enrichment, Formula II, formula III, formula IV, Formula V or Formula IV It can be by using conjunction described by the embodiment and preparation process in routine techniques or the present invention familiar to the person skilled in the art Suitable isotope labeling reagent substitutes original used unmarked reagent to prepare.

In addition, higher isotope especially deuterium (that is,²H or D) substitution certain treatment advantages can be provided, these advantages are It is brought by metabolic stability higher.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.The concentration of such higher isotope especially deuterium can be defined with isotope enrichment factor.If the compounds of this invention Substituent group be designated as deuterium, which has for each specified D-atom at least 3500 (at each specified D-atom 52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% Deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuteriums Incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuteriums Incorporation) isotope enrichment factor.The pharmaceutical solvate of the present invention includes that wherein recrystallisation solvent can be isotope substitution Such as D₂O, acetone-d₆、DMSO-d₆Those of solvate.

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention, pharmacy Upper acceptable carrier, excipient, diluent, adjuvant, solvent or combination thereof.In some embodiments, pharmaceutical composition Can be liquid, solid, semisolid, gel or spray-type.

The embodiment of the present invention is described more fully, the embodiment is exemplary, it is intended to for explaining The present invention, and be not considered as limiting the invention.

Experimental method used in following embodiments is conventional method unless otherwise specified.

The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.

The micromolecular compound of the embodiment of the present invention can be derived by the ends Pomalidomide or the ends Lenalidomide Click chemistry (click-reaction) between object and the ends PF-562271 derivative are formed by connecting, as shown in Figure 2, wherein The preparation method of the ends Pomalidomid or the ends Lenalidomide derivative can refer to document Chemistry&Biology 22, 755-763 (2015) and J.Med.Chem.61,462-481 (2018)

The ends PF-562271 (structure the is as follows) derivative used in following embodiments is prepared as follows, instead Answer equation as shown in Figure 3：An Amino End Group of p-phenylenediamine and corresponding acetylenic acid are formed into amido bond first；Secondly by cyano fluoro The nitrogen-atoms of the fluorine atom of pyridine sulfonamide analog replaces, and benzylamine analog is obtained after restoring cyano；Finally with above-mentioned benzyl Amine analog replaces 2,4-, bis- 4 chlorine atoms of chloro- 5- trifluoromethyl pyrimidines, replaces 2 with the amino of above-mentioned p-phenylene diamine derivative Position chlorine atom is up to the ends PF-562271 derivative.Specific preparation process is as follows：

(1) preparation of intermediate 1a

2 grams of p-phenylenediamine, 954 microlitres of propiolic acids, 15 milliliters of chloroforms are added in 250 milliliters of round-bottomed flasks, are added anhydrous DMF is cooled to zero degree, 20 milliliters of chloroformic solutions containing 3.18 grams of DCC is added up to being completely dissolved.Zero degree stirs 1 hour, mistake Filter obtains clear filtrate, then uses DCM：MeOH=20：1, which crosses silicagel column, obtains intermediate 1a.¹H-NMR(400MHz,DMSO-d₆, ppm):10.35 (s, 1H), 7.24 (d, J=8.60Hz, 2H), 6.50 (d, J=8.64Hz, 2H), 4.97 (s, 2H), 4.25 (s, 1H).LC-MS:calculated for C₉H₉N₂O[M+H]⁺:161.06,found 161.28.

(2) preparation of intermediate 2a

2 grams of N- methylmethanesulfonamides, 30 milliliters of anhydrous DMFs and 2.1 grams of tert-butyl alcohols are added in 100 milliliters of round-bottomed flasks Potassium is stirred at room temperature after twenty minutes, 2.2 grams of fluoro- nicotinonitriles of 2- is added, and back flow reaction 3 hours is quenched with water reaction, is used in combination Ethyl acetate extracts, and then uses petroleum ether：Ethyl alcohol=2：1 crosses silicagel column, precipitates crystal to obtain 2a.¹H-NMR(400MHz, CDCl₃,ppm):8.65 (dd, J=1.88Hz, J=4.88Hz, 1H), 8.06 (dd, J=1.88Hz, J=7.76Hz, 1H), 7.41 (dd, J=4.88Hz, J=7.76Hz, 1H), 3.38 (s, 3H), 3.18 (s, 3H)¹³C-NMR(100MHz,CDCl₃, ppm):156.06,152.17,142.74,122.77,115.33,109.50,37.90,37.35.LC-MS:calculated for C₈H₁₀N₃O₂S[M+H]⁺:212.04,found 212.30.

(3) preparation of intermediate 3a

1 gram of intermediate 2a is added in 100 milliliters of round-bottomed flasks and is dissolved in methanol and anhydrous DMF in the mixed solvent, in argon 300 milligram 10% of Pd/C is added under gas shielded, argon gas in bottle is replaced with hydrogen, is inserted into hydrogen balloon, 40 degree to be stirred to react 16 small When, solvent is filtered and be spin-dried for, DCM is then used：Methanol=20：1 crosses silicagel column, obtains 3a.¹H-NMR(400MHz,DMSO-d₆, ppm):8.40 (dd, J=1.68Hz, J=4.64Hz, 1H), 8.06 (dd, J=1.40Hz, J=7.64Hz, 1H), 7.45 (dd, J=4.72Hz, J=7.68Hz, 1H), 3.85 (s, 2H), 3.13 (s, 3H), 3.12 (s, 3H), 2.89 (s, 2H)¹³C-NMR (100MHz,DMSO-d₆,ppm):152.24,146.88,138.16,124.03,54.90,40.67,37.31,36.06.LC- MS:calculated for C₈H₁₄N₃O₂S[M+H]⁺:216.07,found 216.38.

(4) preparation of intermediate 4a

In 100 milliliters of round-bottomed flasks be added 2.47 grams of intermediate 3a, 2.47 grams of bis- chloro- 5- trifluoromethyl pyrimidines of 2,4-, 3.16 grams of potassium carbonate, 50 milliliters of acetonitriles, 50 degree are stirred to react 2 hours, filter and are spin-dried for solvent, then use petroleum ether：Acetic acid second Ester=8：1 crosses silicagel column, and a small amount of DCM ultrasounds are added after being spin-dried for solvent, solid i.e. 4a is obtained by filtration.¹H-NMR(400MHz, DMSO-d₆,ppm):8.54 (t, J=5.60Hz, 1H), 8.45 (m, 2H), 7.76 (dd, J=1.48Hz, J=7.72Hz, 1H), 7.44 (dd, J=4.68Hz, J=7.72Hz, 1H), 4.73 (d, J=5.36Hz, 2H), 3.26 (s, 3H), 3.11 (s, 3H) .¹³C-NMR(100MHz,DMSO-d₆,ppm):162.58,158.36,155.74,155.69,152.30,147.69,137.24, 133.33,124.80,124.15,122.10,105.53,105.21,104.88,37.09,35.77.LC-MS:calculated for C₁₃H₁₄ClF₃N₅O₂S[M+H]⁺:396.04,found 396.41.

(5) preparation of intermediate 5a

100 milligrams of intermediate 4a, 41 milligrams of intermediate 1a, 2 milliliters of tertriary amylo alcohols, 3 drops are added in 25 milliliters of round-bottomed flasks Acetic acid, 90 degree of return stirrings react 4 hours, are spin-dried for solvent, then use DCM：MeOH=30：1 crosses silicagel column, obtains intermediate 5a。¹H-NMR(400MHz,CDCl₃,ppm):8.41 (d, J=3.44Hz, 1H), 8.12 (s, 2H), 7.98 (d, J=14.80Hz, 1H), 7.75 (d, J=7.40Hz, 1H), 7.49-7.42 (m, 4H), 7.27-7.23 (m, 1H), 6.13 (s, 1H), 4.93 (d, J =4.80Hz, 2H), 3.27 (s, 3H), 3.07 (s, 3H), 2.92 (s, 1H) .LC-MS:calculated for C₂₂H₂₁F₃N₇O₃S[M+H]⁺:520.13,found 520.59.

The preparation of compound shown in 1 formula 1~38 of embodiment

The ends 17mg Pomalidomide derivative, 20mg intermediates 5a, 7mg CuSO are added in 5ml round-bottomed flasks₄、 23mg sodium ascorbates, 0.1ml water and the 0.8ml tert-butyl alcohols.After 70 degrees Celsius are stirred 6 hours, washing, DCM extractions.Use dichloromethane Alkane：Methanol=30：1, which crosses silicagel column, obtains compound shown in formula 1, yield 61%.

¹H-NMR(400MHz,CDCl₃,ppm):8.88 (s, 1H), 8.43 (dd, J=1.80Hz, J=4.68Hz, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.81 (d, J=7.84Hz, 1H), 7.59-7.46 (m, 6H), 7.25 (m, 1H), 7.09 (d, J=7.04Hz, 2H), 6.86 (d, J=8.52Hz, 1H), 6.46 (t, J=5.28Hz, 1H), 6.04 (s, 1H), 4.95-4.88 (m, 3H), 4.65 (q, J=4.52Hz, 2H), 3.97 (t, J=4.68Hz, 2H), 3.71 (t, J=5.12Hz, 2H), 3.46 (q, J=5.48Hz, 2H), 3.28 (s, 3H), 3.07 (s, 3H), 2.76-2.60 (m, 3H), 2.10-2.00 (m, 1H) .LC-MS: calculated for C₃₉H₃₉F₃N₁₃O₈S[M+H]⁺:906.26,found 906.88.

According to compound shown in above-mentioned preparation method formula 2~38.

¹H-NMR(400MHz,CDCl₃,ppm):10.53 (s, 1H), 8.85 (s, 1H), 8.39 (d, J=4.12Hz, 2H), 8.15 (s, 2H), 7.78 (d, J=7.20Hz, 1H), 7.51-7.39 (m, 5H), 7.26-7.22 (m, 1H), 7.05 (d, J= 7.08Hz, 1H), 6.87 (d, J=8.56Hz, 1H), 6.51 (t, J=4.84Hz, 1H), 6.10 (s, 1H), 4.97-4.92 (m, 3H), 4.57 (d, J=4.36Hz, 2H), 3.90 (t, J=4.56Hz, 2H), 3.70 (t, J=4.76Hz, 2H), 3.62 (s, 4H), 3.45 (d, J=4.80Hz, 2H), 3.25 (s, 3H), 3.04 (s, 3H), 2.87-2.74 (m, 3H), 2.12-2.03 (m, 1H).¹³C-NMR(100MHz,CDCl₃,ppm):172.91,169.72,169.45,167.74,160.60,158.92, 157.85,154.48,152.77,148.21,146.73,143.29,139.19,136.05,135.51,133.88,132.93, 132.52,127.18,126.13,124.37,123.45,120.73,120.38,116.83,111.62,110.30,70.59, 70.53,69.27,50.71,48.95,42.30,40.59,37.64,35.51,31.95,31.53,29.72,29.39, 22.89,22.72,14.16.LC-MS:calculated for C₄₁H₄₂F₃N₁₃O₉S[M+H]⁺:950.29,found 950.77.

¹H-NMR(400MHz,CDCl₃,ppm):10.43(s,1H),8.90(s,1H),8.41(m,2H),8.19(s,2H), 7.77 (d, J=7.16Hz, 1H), 7.56 (d, J=8.80Hz, 2H), 7.48-7.42 (m, 3H), 7.26-7.22 (m, 1H), 7.08 (d, J=7.04Hz, 1H), 6.90 (d, J=8.56Hz, 1H), 6.43 (t, J=5.52Hz, 1H), 6.10 (s, 1H), 4.97-4.94 (m, 3H), 4.59 (t, J=4.48Hz, 2H), 3.89 (t, J=4.68Hz, 2H), 3.72-3.68 (m, 4H), 3.63-3.61 (m, 6H), 3.47 (q, J=5.60Hz, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.89-2.75 (m, 3H), 2.12-2.10(m,1H).LC-MS:calculated for C₄₃H₄₇F₃N₁₃O₁₀S[M+H]⁺:994.32,found 994.85.

¹H-NMR(400MHz,CDCl₃,ppm):10.25 (s, 1H), 8.92 (s, 1H), 8.40 (d, J=8.80Hz, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.77 (d, J=7.74Hz, 1H), 7.58 (d, J=8.72Hz, 2H), 7.48-7.43 (m, 3H), 7.26-7.22 (m, 1H), 7.08 (d, J=7.08Hz, 1H), 6.90 (d, J=8.52Hz, 1H), 6.45 (t, J=5.44Hz, 1H), 6.09 (s, 1H), 4.96-4.93 (m, 3H), 4.59 (t, J=4.56Hz, 2H), 3.88 (t, J =4.72Hz, 2H), 3.68-3.59 (m, 14H), 3.44 (q, J=5.20Hz, 2H), 3.27 (s, 3H), 3.05 (s, 3H), 2.88-2.72(m,3H),2.13-2.03(m,1H).LC-MS:calculated for C₄₅H₅₁F₃N₁₃O₁₁S[M+H]⁺: 1038.34,found 1038.84.

¹H-NMR(400MHz,CDCl₃,ppm):10.19 (s, 1H), 8.91 (s, 1H), 8.40 (dd, J=1.76Hz, J= 4.68Hz, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.77 (dd, J=1.24Hz, J=7.64Hz, 1H), 7.67 (d, J=7.08Hz, 1H), 7.59-7.51 (m, 4H), 7.47 (d, J=8.92Hz, 2H), 7.25 (dd, J=4.76Hz, J =7.68Hz, 1H), 6.10 (s, 1H), 5.01 (dd, J=5.28Hz, J=12.00Hz, 1H), 4.93 (d, J=4.96Hz, 2H), 4.61 (t, J=4.68Hz, 2H), 3.91 (t, J=4.88Hz, 2H), 3.62-3.53 (m, 4H), 3.51 (t, J= 6.20Hz, 2H), 3.26 (s, 3H), 3.14 (t, J=7.60Hz, 2H), 3.05 (s, 3H), 2.89-2.75 (m, 3H), 2.13- 2.10(m,1H),1.95-1.92(m,2H).LC-MS:calculated for C₄₂H₄₄F₃N₁₂O₉S[M+H]⁺:949.97, found 949.82.

¹H-NMR(400MHz,CDCl₃,ppm):10.45 (s, 1H), 8.94 (s, 1H), 8.39 (d, J=3.56Hz, 1H), 8.18 (m, 3H), 7.76 (d, J=7.40Hz, 1H), 7.58 (d, J=8.72Hz, 2H), 7.50-7.41 (m, 3H), 7.24 (dd, J=4.80Hz, J=7.60Hz, 1H), 7.06 (d, J=7.08Hz, 1H), 6.86 (d, J=8.56Hz, 1H), 6.22 (t, J= 5.36Hz, 1H), 6.12 (s, 1H), 4.96-4.92 (m, 3H), 4.40 (t, J=6.96Hz, 2H), 3.25 (s, 3H), 3.22 (m, 2H), 3.05 (s, 3H), 2.88-2.73 (m, 3H), 2.13-2.11 (m, 1H), 1.92 (m, 2H), 1.64 (t, J=6.60Hz, 2H),1.32-1.22(m,8H).LC-MS:calculated for C₄₃H₄₇F₃N₁₃O₇S[M+H]⁺:946.98,found 946.87.

¹H-NMR(400MHz,CDCl₃,ppm):10.16 (s, 1H), 8.88 (s, 1H), 8.40 (d, J=3.16Hz, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.79-7.63 (m, 4H), 7.55 (d, J=8.24Hz, 2H), 7.47 (d, J=8.12Hz, 2H), 7.25-7.22 (m, 1H), 6.09 (s, 1H), 5.05 (d, J=8.12Hz, 1H), 4.93 (m, 1H), 4.60 (m,2H),4.49(m,2H),3.92(m,2H),3.83(m,2H),3.70(m,2H),3.26(s,3H),3.05(s,3H), 2.89-2.77(m,3H),2.13-2.05(m,1H).LC-MS:calculated for C₄₂H₃₉F₃N₁₂O₉S[M+H]⁺: 945.26,found 945.92.

¹H-NMR(400MHz,CDCl₃,ppm):10.40 (s, 1H), 8.91 (s, 1H), 8.41 (d, J=3.84Hz, 1H), 8.15 (m, 3H), 7.82-7.68 (m, 4H), 7.57 (d, J=8.36Hz, 2H), 7.46 (d, J=8.56Hz, 2H), 7.26 (m, 1H), 6.11 (s, 1H), 5.11 (dd, J=4.88Hz, J=10.76Hz, 1H), 4.92 (s, 2H), 4.43 (m, 3H), 3.70 (t, J=6.12Hz, 2H), 3.26 (s, 3H), 3.06 (s, 3H), 2.92-2.81 (m, 3H), 2.16 (m, 1H), 2.03-1.97 (m, 3H),1.72-1.67(m,2H),1.50-1.45(m,2H).LC-MS:calculated for C₄₃H₄₂F₃N₁₂O₈S[M+H]⁺: 943.28,found 943.83.

¹H-NMR(400MHz,CDCl₃,ppm):10.04(s,1H),8.92(s,1H),8.41(s,1H),8.15-7.26 (m, 12H), 6.09 (s, 1H), 5.06-4.93 (m, 3H), 4.40 (m, 2H), 4.12 (d, J=6.56Hz, 1H), 3.26 (s, 3H),3.06(s,3H),2.87-2.84(m,3H),2.51(s,2H),2.14-1.25(m,10H).LC-MS:calculated for C₄₄H₄₄F₃N₁₂O₇S[M+H]⁺:941.31,found 941.84.

¹H-NMR(400MHz,CDCl₃,ppm):10.62(s,1H),8.92(s,1H),8.38(s,2H),8.21(s,2H), 7.83 (d, J=7.32Hz, 1H), 7.77 (d, J=6.48Hz, 1H), 7.59-7.55 (m, 3H), 7.49-7.41 (m, 3H), 7.24-7.21(m,1H),6.12(s,1H),5.26(m,1H),4.93(s,2H),4.58-4.32(m,6H),3.86(m,2H), 3.77(m,2H),3.64(m,6H),3.26(s,3H),3.05(s,3H),2.85(m,2H),2.37-2.33(m,1H),2.18- 2.16(m,1H).LC-MS:calculated for C₄₄H₄₆F₃N₁₂O₉S[M+H]⁺:975.31,found 975.85.

Degrading activity of 2 the compounds of this invention of embodiment to FAK

The compounds of this invention is stronger to the degrading activity of FAK, is carried out by taking micromolecular compound shown in formula 1~10 as an example below Test.

Cell inoculation and micromolecular compound processing：

Cell fusion degree is reached into 90% PA1 cells using 0.25% pancreatin at 37 DEG C, is digested 1 minute, addition contains Mycos ' the 5A culture mediums of 10%FBS, which terminate, digests and blows and beats into single cell suspension, and 15 milliliters of centrifuge tubes collections are unicellular, 800rpm is centrifuged 3 minutes, and cell is resuspended using fresh culture, and cell counting board counts number of cells.According to every hole 800k Cell number by cell inoculation in 24 orifice plates.

After 12-24 hours, micromolecular compound to be measured (1000x) processing is added, and in 37 degrees Celsius, 5%CO₂Incubator It is middle to be incubated 8 hours.After compound processing in 8 hours, cell is collected, extraction albumen carries out protein immunoblotting (Westernblot) it analyzes.

Total protein of cell extracts：

Will treated cell, discard upper layer culture medium, PBS is washed twice, and cell pyrolysis liquid is added, and is added per hole sample 100 microlitres of RIPA lysates are incubated 20 minutes on ice, using cell scraper, are scraped cell, are collected and managed with 1.5 milliliters of Eppendorf In, 4 degrees Celsius, 2,000rpm centrifugations 10 minutes.It takes in 90 microlitres of supernatants to 1.5 milliliters of new Eppendorf pipes.It is another take it is 2 micro- It goes up and is analyzed for albumen concentration quantitative clearly.30 microlitres of 4 × Loading is added into remaining 90 microlitres of protein extracts Buffer, 95 degrees Centigrades boil 10 minutes, preserve or be directly used in protein immunoblotting in -20 degrees Celsius (Westernblot) it detects.

The ingredient of RIPA buffer solutions is：The Tris-HCl pH 8.0 of final concentration 50mM, 150mM NaCl, 2mM MgCl₂, 0.1%SDS, 1.5%Nonidet-P40,0.5% deoxysodium cholate.Separately Pepstatin A, 10 μ g/ containing a concentration of 5 μ g/ml The Leupeptin of mL, the DTT of the PMSF of 5 μM of MG-132,1mM, 0.25mM.

The ingredient of 4 × Loading Buffer is：The SDS of final concentration 1%, 6% beta -mercaptoethanol, 30% glycerine, And suitable bromophenol blue.

Protein immunoblotting (Westernblot) detection is as follows：

1) the SDS-PAGE glue of 8% or 10% concentration is prepared.With reference to《Molecular Cloning:A Laboratory guide》(Science Press, the Two editions) the 883rd page table 18.3 prepares lower layer's separation gel of suitable concentration, with reference to the 883rd page table 18.4 prepare a concentration of 5% it is upper Layer concentration glue.

2) sample preparation.Protein sample is prepared according to requirement of experiment, takes the sample of 95 degrees Celsius of denaturation 10 minutes, centrifuge, Mixing is simultaneously splined in SDS-PAGE glue.According to protein quantification as a result, adjusting suitable loading volume, on usually each hole Sample volume is 10 microlitres.

3) electrophoresis.Power on, protein sample voltage in concentrating glue is 80 volts, waits for that protein sample enters separation gel When, voltage is adjusted to 125 volts of continuation electrophoresis by we.After the albumen Marker of purpose band is completely separable, electrophoresis is terminated.

4) transferring film.Gel is removed after electrophoresis, and membrane-transferring device is installed in the following order：(cathode), filter paper, gel, 0.45 μm of pvdf membrane, filter paper, (anode).Make sure to keep in mind cannot absolutely have bubble between gel and pvdf membrane.Then transfer device is clamped In transferring film slot, it is put into ice chest, transferring film buffer solution is added, is powered 1.5 hours in 4 degrees Celsius of freezer 100V constant pressures.

5) it closes.After transferring film, pvdf membrane is taken out, pvdf membrane is immersed in the 1x TBST containing 5% skimmed milk power and is delayed In fliud flushing, room temperature, shaking table is closed 1 hour.

6) it is incubated primary antibody.After closing, film is washed 3 times with 1x TBST buffer solutions, 10 minutes every time, appropriateness is then added The primary antibody of dilution ratio, 4 C overnights.Primary antibody is recycled, pvdf membrane is swung with 1x TBST buffer solutions and is washed 3 times, every time 10 points Clock.

7) it is incubated secondary antibody.1x TBST buffer solutions are discarded, it (is typically 1 that certain thinner ratio, which is added,：5000~1：10000) Secondary antibody (mouse resists or rabbit-anti, is determined by primary antibody), shaking table is incubated 1 hour at room temperature.Secondary antibody is discarded, by pvdf membrane 1x TBST Buffer solution, which is swung, to be washed 3 times, every time 10 minutes.

8) colour developing and tabletting.By ECL chromogenic substrate uniform folds on pvdf membrane, color development at room temperature 2~5 minutes.With fresh-keeping After film wraps film, is exposed in Chemiluminescence Apparatus and store image.

Micromolecular compound of the present invention is as follows to the degrading activity of FAK：

In PA1 cell lines, after 10 micromolecular compound of formula 1- formulas is handled 8 hours, protein immunoblotting (Westernblot) interpretation of result can obviously observe 10 micromolecular compound of formula 1- formulas at different dosages to FAK albumen Degradation effect.Degradation of the compound shown in formula 1- formulas 4 at 1,10,50nM to FAK albumen is as shown in figure 4, formula 5- formulas Compound shown in 10 (is as shown in Figure 5 sun with micromolecular compound shown in formula 2 to the degradation of FAK albumen at 1,10nM Property control).It can be degraded under certain concentration FAK, wherein formula 2 by majority of compounds it can be seen from above-mentioned test result It is most strong (the two under the concentration of 1nM degradable 50% or more FAK) with micromolecular compound degradation shown in formula 5.

It can be seen that the compounds of this invention has stronger degrading activity to FAK.

Half degradation concentration determination of 3 the compounds of this invention of embodiment to the tumor cell line of separate sources

The compounds of this invention all has stronger degradation effect to the FAK albumen of the tumor cell line of separate sources, below It is tested by taking micromolecular compound shown in formula 2 as an example.

Different tumor cell lines：People source ovarian cancer cell line PA1, SKOV3 are chosen in experiment；People source cervical cancer tumer line HeLa；People source breast cancer cell line MDA-MB-436, MDA-MB-453, MDA-MB-231, MCF-7；People source lung cancer cell line A549, H460, PC9 live to the half degradation rate of the tumor cell line of separate sources to investigate micromolecular compound shown in formula 2 Property.

Cell inoculation and micromolecular compound processing：Cell fusion degree is reached to 90% tumor cell line to be respectively adopted 0.25% pancreatin digests 1-2 minutes at 37 degrees Celsius, and the complete medium containing 10%FBS is added and terminates digestion and blows and beats into Single cell suspension, 15 milliliters of centrifuge tubes collections are unicellular, and 800rpm is centrifuged 3 minutes, cell is resuspended using fresh culture, carefully Born of the same parents' tally counts number of cells.According to the cell number of every hole 800k respectively by tumor cell inoculation in 24 orifice plates.

After 12-24 hours, be added 10 concentration gradient points (0.3,1,3,10,30,100,300,1000,3000, 10000nM) micromolecular compound (1000x) to be measured processing, and in 37 degrees Celsius, 5%CO₂It is incubated 8 hours in incubator.8 is small When compound processing after, collect cell, extraction albumen carry out protein immunoblotting (Westernblot) analyze.Protein is exempted from Epidemic disease trace (Westernblot) analysis implements specific steps with embodiment 2.

Micromolecular compound shown in formula 2 is as follows to the half degrading activity of FAK in different tumor cell lines：

Micromolecular compound shown in formula 2 to oophoroma PA1 cell lines and breast cancer MDA-MB-436, MDA-MB-453, The degradation of FAK albumen all has stronger activity in MDA-MB-231 cell lines, and half degrades concentration less than 2nM.To ovum The half degradation concentration (DC of FAK albumen in nest cancer SKOV3 cell lines, breast cancer MCF7 and lung cancer A549, H460 cell line₅₀) Less than 100nM, the results are shown in Figure 6.Thus result is it is found that micromolecular compound is in most of tumor cell line shown in formula 2 FAK albumen all have stronger degradation effect.

It can be seen that the compounds of this invention all has stronger degradation to the FAK albumen of the tumor cell line of separate sources Effect.

Degradation of 4 the compounds of this invention of embodiment to FAK in mouse ovarian and mouse testis relevant cell system

The compounds of this invention to the FAK albumen in mouse propagation relevant cell system have stronger degradation effect, below with It is tested for micromolecular compound shown in formula 2.

Cell inoculation and micromolecular compound processing：Specific implementation step is the same as embodiment 3.

Degrading activity of the micromolecular compound shown in formula 2 to mouse ovarian SRD15 and mouse testis TM3 cell lines It is as follows：

Under different gradient concentrations, micromolecular compound shown in formula 2 is at 10nM to FAK in mouse ovarian SRD15 cell lines Degradation rate about 46%.And to the degradation of FAK in mouse testis TM3 cell lines up to 70% or more at 1nM, as a result such as Shown in Fig. 7.Thus result it is found that micromolecular compound shown in formula 2 to the FAK albumen in mouse propagation relevant cell system have compared with Strong degradation effect.

It can be seen that the compounds of this invention imitates the FAK albumen in mouse propagation relevant cell system with stronger degradation Fruit.

Degradation of 5 the compounds of this invention of embodiment to FAK in the primary sertoli cell of mouse testis

The compounds of this invention has stronger degradation effect to the FAK in the primary sertoli cell of mouse testis, below with formula 2 It is tested for shown micromolecular compound.

The separation and culture of the primary sertoli cell of mouse testis：Primary sertoli cell is isolated by 16 days mouse.Disconnected neck After putting to death 16 days B6 mouse, testis is taken out, is put into the PBS of 3cm culture dishes, the white of testis tissue is removed under stereomicroscope Testis tissue is transferred in the 3cm culture dishes that another fills PBS by film；By the Qu Jing little of testis tissue under stereomicroscope Pipe scatter, and then testis tissue is transferred in 15 milliliters of centrifuge tubes containing appropriate digestive juice I, and room temperature digests 5 minutes, and It jiggles frequently；Room temperature 1500rpm is centrifuged 5 minutes, abandons supernatant；The digestive juice II that 5 times of volumes are added is precipitated to testis tissue, Room temperature digests 5 minutes, and acutely rocks；It is added suitable DMEM/F12, terminates digestion, with 70 mesh filter screens to the tissue that digested It is filtered, removes and digest incomplete tissue block；Cell liquid room temperature 800rpm is centrifuged after filtering, 5 minutes；Supernatant is abandoned, is used Cell precipitation is resuspended in DMEM/F12, and room temperature 1500rpm is centrifuged 5 minutes；Cell count after precipitation is resuspended with sertoli cell culture medium, With 0.5X 10⁶Cell/cm²Density be inoculated in 12 orifice plates (being covered with matrigel), in 5%CO₂, 37 degrees Celsius of cell incubator Culture；Liquid is changed after 24 hours, PBS washes away not adherent cell；The Tris-HCL PH7.4 that 20mM is used after 36 hours, clean 3 points Clock, then washed twice with PBS, culture medium is added and continues to cultivate.

The agent prescription used in above-mentioned experiment is as follows：

Digestive juice I:Type Ⅳ collagenase (2mg/ml, Sigma company)+DNaseI (75U/ml, Sigma company), uses DMEM/ F12 (invitrogen companies) is configured, and is filtered through 0.22 μm of Millipore syringe filters.

Digestive juice II:(2mg/ml, Sigma are public for IV Collagenase Types (2mg/ml, Sigma company)+IV types hyaluronidase Department)+DNaseI (75U/ml, Sigma company), DMEM/F12 (invitrogen companies) configurations, through 0.22 μm of Millipore Syringe filters filter.

Sertoli cell culture medium is:DMEM/F12 (invitrogen companies)+Bovine insulin (Sigma companies)+ Human transferring (R&D companies)+Epidermal growth factor (R&D companies)+1% is dual anti- (invitrogen companies)；

Micromolecular compound shown in formula 2 is as follows to the degrading activity of FAK in the primary sertoli cell of mouse testis：

Under different gradient concentrations, the half of FAK in the primary sertoli cell of mouse testis drops in micromolecular compound shown in formula 2 It solves concentration and reaches 1.31nM, there is stronger degradation effect, as a result as shown in Fig. 8-1 and 8-2.

It can be seen that the compounds of this invention has stronger degradation effect to the FAK in the primary sertoli cell of mouse testis.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office It can be combined in any suitable manner in one or more embodiments or example.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims

1. a kind of compound is compound or its stereoisomer, geometric isomer, tautomer, nitrogen oxidation shown in Formulas I Object, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug：

X-Y-Z

Formulas I

Wherein, X indicates that the ligand of FAK albumen, Z indicate that the ligand of E3 ligases, Y indicate the chain of connection X and Z.

2. compound according to claim 1, which is characterized in that the X is compound shown in Formula II -1 or II-2,

Cy¹Or Cy²It is separately phenyl ring, C_6-12Aryl, the heteroaryl of 5-12 annular atom composition, C_3-12Naphthenic base or 3-12 The heterocycle of a annular atom composition；

Each Cy¹Or Cy²Separately by 1,2,3,4,5 or 6 R^h1Replaced；

Each L¹Separately by 1,2,3,4,5 or 6 R^h2Replaced；

Each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6 Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle of 3-12 annular atom composition, 5-12 ring are former Molecular heteroaryl, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6 Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle of 3-12 annular atom composition, 5-12 ring are former Molecular heteroaryl, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6 Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6 Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^gIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5-10 that aryl, 3-12 annular atom form are a The heteroaryl of annular atom composition；

Each R^g1It is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5-10 that aryl, 3-12 annular atom form are a The heteroaryl of annular atom composition；

Each R^1aIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5-10 that 3-12 annular atom forms are a The heteroaryl of annular atom composition；

Each R^mOr R^wIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each n is separately 1,2,3 or 4；

Each g is separately 0,1,2,3 or 4；

Each p is separately 1 or 2.

3. compound according to claim 2, which is characterized in that

Cy¹Or Cy²It is separately phenyl ring, C_6-10Aryl, the heteroaryl of 5-10 annular atom composition, C_3-6Naphthenic base or 3-12 The heterocycle of a annular atom composition.

4. compound according to claim 2, which is characterized in that

Each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle of 3-12 annular atom composition, 5-10 ring are former Molecular heteroaryl, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle of 3-12 annular atom composition, 5-10 ring are former Molecular heteroaryl, R^g-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(CR^1a=CR^1a)_n-(CR^mR^w)_g, R^g-(CR^mR^w)_g-(C≡C)_n- (CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g-C (=O)-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g-(CR^mR^w)_g- S (=O)_p-N(R^1a)- (CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, R^g1-(CR^mR^w)_g-O-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-S- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-(CR^1a=CR^1a)_n- (CR^mR^w)_g, R^g1-(CR^mR^w)_g-(C≡C)_n-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, Rg¹-(CR^mR^w)_g- C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^gIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5-10 that aryl, 3-12 annular atom form are a The heteroaryl of annular atom composition；

Each R^g1It is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5-10 that aryl, 3-12 annular atom form are a The heteroaryl of annular atom composition.

5. compound according to claim 2, which is characterized in that

Each R^1aIt is separately H, deuterium, F, Cl, Br, I, CN, NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5-10 that aryl, 3-12 annular atom form are a The heteroaryl of annular atom composition；

Each R^mOr R^wIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition.

6. compound according to claim 2, which is characterized in that

Cy¹Or Cy²It is separately

7. compound according to claim 2, which is characterized in that

Each R^h1It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, tertiary butyl ,-CH₂F ,-CHF₂,-CF₃,-CH₂Cl ,-CHCl₂,-CCl₃,-CH₂Br ,-CHBr₂,- CBr₃,-CH₂CHF₂,-CH₂CF₃,-CHFCF₃,-CF₂CHF₂,-CF₂CF₃,-CH₂CH₂CF₃,-CH₂CF₂CHF₂, R^g-(CR^mR^w)_g-O- (CR^mR^w)_g, R^g-(CR^mR^w)_g-S-(CR^mR^w)_g, R^g-(CR^mR^w)_g-N(R^1a)-(CR^mR^w)_gOr R^g-(CR^mR^w)_g-；

Each R^h2It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group or tertiary butyl；

Each R^h1Separately by 1,2,3,4,5 or 6 R^h3Replaced；

Each R^h2Separately by 1,2,3,4,5 or 6 R^h4Replaced；

Each R^h3It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, tertiary butyl ,-R^g1-(CR^mR^w)_g- S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-O- (CR^mR^w)_g, R^g1-(CR^mR^w)_g- O-C (=O)-(CR^mR^w)_g, R^g1- (CR^mR^w)_g- S (=O)_p-N(R^1a)-(CR^mR^w)_g, R^g1-(CR^mR^w)_g-N(R^1a)-S (=O)_p-(CR^mR^w)_g, R^g1-(CR^mR^w)_g- C (=O)-N (R^1a)-(CR^mR^w)_gOr R^g1-(CR^mR^w)_g-N(R^1a)-C (=O)-(CR^mR^w)_g-；

Each R^h4It is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group or tertiary butyl；

Each R^gIt is separately

8. compound according to claim 1, which is characterized in that

Each R^1aIt is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；

Each R^m、R^wOr R^gIt is separately H, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

9. compound according to claim 1, which is characterized in that the X be formula III -1, III-2, III-3, III-4, Compound shown in III-5 or III-6,

10. compound according to claim 1, which is characterized in that the Z is compound shown in formula IV,

Wherein, Q is N or CR²；

M is C (R^eR^f), N (R^1b), O or S；

W, K are separately C (R^eR^f), N (R^1b), O or S；

R²For hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkene Base or C_2-6Alkynyl；

Each R^2aOr R^2bIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, oxo, C_1-6Alkyl, C_1-6Halogen Substituted alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle of 3-12 annular atom composition Or the heteroaryl of 5-12 annular atom composition；

Each R^2cIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6 Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle or 5-12 ring of 3-12 annular atom composition Former molecular heteroaryl；

Each R^e、R^fIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Alkyl halide Base, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each R^1bIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_6-12Aryl, the heterocycle or 5-12 that 3-12 annular atom forms are a The heteroaryl of annular atom composition；

n₁、n₂It is separately 0,1,2 or 3；

n₃It is 0,1,2,3,4 or 5.

11. compound according to claim 10, which is characterized in that

R²For hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkene Base or C_2-4Alkynyl.

12. compound according to claim 10, which is characterized in that

Each R^2a、R^2bIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, oxo, C_1-4Alkyl, C_1-4Halogen Substituted alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle of 3-12 annular atom composition Or the heteroaryl of 5-10 annular atom composition；

Each R^2cIt is separately hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO₂, NH₂, COOH, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5-10 ring of 3-12 annular atom composition Former molecular heteroaryl.

13. compound according to claim 10, which is characterized in that

Each R^e、R^fIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Alkyl halide Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10The heterocycle or 5- that aryl, 3-12 annular atom form The heteroaryl of 10 annular atoms composition；

Each R^1bIt is separately H, deuterium, F, Cl, Br, I, CN ,-NO₂, OH, amino, carboxyl, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_6-10Aryl, the heterocycle or 5-10 that 3-12 annular atom forms are a The heteroaryl of annular atom composition.

14. compound according to claim 10, which is characterized in that

R²For hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.

15. compound according to claim 10, which is characterized in that

Each R^2a、R^2bIt is separately hydrogen, deuterium, oxo, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary fourth Base；

16. compound according to claim 10, which is characterized in that

Each R^e、R^fIt is separately hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；

17. compound according to claim 10, which is characterized in that the Z is Formula V -1, V-2, V-3, V-4 or V-5 institute Show compound,

18. compound according to claim 1, which is characterized in that the Y is the group containing 1~30 atom, described Atom includes selected from least one of carbon atom, sulphur atom, oxygen atom, nitrogen-atoms, selenium atom.

19. compound according to claim 1, which is characterized in that the Y is C_1-20Alkyl, C_1-20Halogenated alkyl, C_1-20 Alkoxy, C_2-20Alkenyl, C_2-20Alkynyl, C_3-12Naphthenic base, C_6-12The heterocycle or 5-12 that aryl, 3-12 annular atom form are a The group that at least one of the heteroaryl of annular atom composition is constituted.

20. compound according to claim 1, which is characterized in that the Y is

Wherein, x₁-x₂₃Separately For a key,

21. compound according to claim 1, which is characterized in that the Y is compound shown in Formula IV -1 or VI-2,

Each r is separately the integer between 0~12；

Each k is separately the integer between 0~12；

Each j is separately the integer between 0~12；

Each t¹Or t³It is separately key,

Each t²Or t⁴It is separately key,

t⁵For key or

22. a kind of compound is compound or its stereoisomer, geometric isomer, mutually variation shown in 1~38 any one of formula Structure body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

23. a kind of pharmaceutical composition, which is characterized in that including claim 1~22 any one of them compound.

24. pharmaceutical composition according to claim 23, which is characterized in that further comprise auxiliary material.

25. pharmaceutical composition according to claim 23, which is characterized in that further comprise for the drug of contraception or its He treats or prevents the drug of tumour or the related disease of reproductive system；

Optionally, the tumour or the related disease of reproductive system include selected from breast cancer, oophoroma, cervical carcinoma, lung cancer, liver At least one of cancer, gastric cancer, colorectal cancer, cutaneum carcinoma, the cancer of the brain, osteosarcoma.

26. pharmaceutical composition according to claim 25, which is characterized in that the other treatment or pre- preventing tumor or reproduction The drug of the related disease of system include selected from Gefitinib, Afatinib, Cetuximab, Gamendazole, At least one of testosterone.

27. any one of the claim 1-22 compounds or claim 23~26 any one of them pharmaceutical composition exist The purposes in drug is prepared, the drug is for FAK albumen of degrading.

28. any one of the claim 1-22 compounds or claim 23~26 any one of them pharmaceutical composition exist The purposes in drug is prepared, the drug is for treating or preventing tumour or the related disease of reproductive system；

29. a kind of method of degradation FAK albumen, which is characterized in that including：Make any one of FAK albumen and claim 1-22 institute Compound or claim 23~26 any one of them pharmaceutical composition thereof stated.

30. a kind of method treating or preventing tumour or the related disease of reproductive system, which is characterized in that give Patient libraries and want Ask 1-22 any one of them compound or claim 23~26 any one of them pharmaceutical composition；