阅读说明：本技术 用于治疗癌症的氮杂芳环酰胺衍生物 (Azaaromatic cyclic amide derivatives for the treatment of cancer ) 是由 朱程刚 杨铉 张朝春 塔利·约翰·J 陈超乐 包丽茗 徐良亮 于 2020-03-30 设计创作，主要内容包括：涉及用于治疗癌症的氮杂芳环酰胺衍生物。具体而言,涉及氮杂芳环酰胺衍生物的制备方法和用途。涉及式(I)、式(II)、式(III)、式(IV)、式(V)所示的氮杂芳环酰胺衍生物和苯胺基-嘧啶化合物及其药学上可接受的盐,所述化合物或其盐可通过调节某些突变形式的表皮生长因子受体而用于治疗或预防疾病或病症。还涉及包含所述化合物或其盐的药物组合物,以及使用所述化合物及其盐治疗由EGFR或HER2或HER4所介导的多种疾病的方法。(To nitrogen heteroaromatic amide derivatives useful in the treatment of cancer. In particular to a preparation method and application of nitrogen heterocyclic aromatic ring amide derivatives. To aza-aromatic cyclic amide derivatives of formula (I), formula (II), formula (III), formula (IV), formula (V) and anilino-pyrimidine compounds and their pharmaceutically acceptable salts, which compounds or salts can be used for the treatment or prevention of diseases or disorders by modulating certain mutated forms of epidermal growth factor receptors. Also relates to pharmaceutical compositions comprising the compounds or salts thereof, and methods of using the compounds and salts thereof to treat various diseases mediated by EGFR or HER2 or HER 4.)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

Y is selected from C, N, C-CF₃And C-Cl;

g is selected from aryl, heteroaryl or heterocyclyl, preferably C_6-10Aryl radical, C_5-10Heteroaryl or C_4-10Heterocyclyl, said aryl, heteroaryl or heterocyclyl being optionally substituted by one or more substituents independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, oxo, halogen or C_1-6Substituted with a substituent of haloalkyl;

R ¹selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, C_1-6Haloalkyl or C_1-6A haloalkoxy group;

R ²is selected from C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_6-10Aryl radical, C_5-10Heteroaryl group, C_4-10Heterocyclic group, C_6-10aryl-C_1-6Alkylene radical, C_5-10heteroaryl-C_1-6Alkylene, or C_4-10heterocyclyl-C_1-6Alkylene, wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di-C_1-6Alkylamino, oxo, halogen, C_1-6Haloalkyl, aminoacyl, C_1-6Alkylaminoacyl or di-C_1-6Substituted with a substituent of an alkylaminoacyl group;

R ³selected from hydrogen or C_1-6An alkyl group;

or R²And R³Together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl group, preferably C_3-10Heterocyclyl, wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di-C_1-6Alkylamino, oxo, halogen, C_1-6Haloalkyl, aminoacyl, C_1-6Alkylaminoacyl or di-C_1-6Substituted with a substituent of an alkylaminoacyl group;

R ⁴selected from hydrogen or C_1-6An alkyl group;

R ⁵selected from the following groups:

the compound according to claim 1, or a pharmaceutically acceptable salt thereof,

y is selected from C, N, C-CF₃And C-Cl;

g is selected from 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyridin-3-yl, 3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b ] pyridin-1-yl, 1H-indol-3-yl, 3-methyl-1H-indol-1-yl, 1H-benzo [ d ] imidazol-1-yl, 1H-indazol-1-yl, 1H-pyrrolo [3, 2-c ] pyridin-1-yl, 3-methyl-1H-indazol-1-yl, 5-fluoro-3-methyl-1H-indazol-1-yl, 3-methyl-1H-pyrrolo [3, 2-c ] pyridin-1-yl, 1H-benzo [ d ] [1, 2, 3] triazol-1-yl, 6-fluoro-3-methyl-1H-indazol-1-yl, 8-methyl-imidazo [1, 2-a ] pyridin-3-yl, 8-fluoro-imidazo [1, 2-a ] pyridin-3-yl, 8-trifluoromethyl-imidazo [1, 2-a ] pyridin-3-yl, 1H-pyrrolo [3, 2-c ] pyridin-1-yl, 3-fluoro-1H-indazol-1-yl, 1-methyl-1H-indol-3-yl, pyrazolo [1, 5-a ] pyridin-3-yl, 8-iodo-imidazo [1, 2-a ] pyridin-3-yl, 4-chloro-3-methoxyphenoxy, 5-methoxy-1-methyl-1H-indol-3-yl, 5-chloro-1-methyl-1H-indol-3-yl, 6-chloro-5-methoxy-1-methyl-1H-indol-3-yl, 5-fluoro-1-methyl-1H-indol-3-yl;

R ¹selected from methoxy, methyl, chloro, fluoro, difluoromethoxy, trifluoroethoxy, trifluoromethyl;

R ⁴is hydrogen;

R ⁵is the following group:

R ²and R³Together with the nitrogen atom to which they are attached form a group selected from: (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl]- (methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2, 5-diazaspiro [3.4]]Oct-2-yl, (3aR, 6aR) -5-methylhexahydro-pyrrolo [3, 4-b ]]Pyrrol-1 (2H) -yl, 1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -2-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino, 1-amino-1, 2, 3, 6-tetrahydropyridin-4-yl, or 4- [ (2S) -2-aminopropionyl]Piperazin-1-yl.

The compound according to claim 2, or a pharmaceutically acceptable salt thereof,

y is selected from C and N.

The compound according to claim 3, or a pharmaceutically acceptable salt thereof,

R ⁵selected from the following groups:

the compound according to claim 4, or a pharmaceutically acceptable salt thereof,

y is selected from N.

The compound according to claim 5, or a pharmaceutically acceptable salt thereof,

g is selected from 1H-pyrrolo [3, 2-c ] pyridin-1-yl, 3-fluoro-1H-indazol-1-yl, 8-fluoro-imidazo [1, 2-a ] pyridin-3-yl, 8-iodo-imidazo [1, 2-a ] pyridin-3-yl, 8-trifluoromethyl-imidazo [1, 2-a ] pyridin-3-yl, 4-chloro-3-methoxyphenoxy, 5-methoxy-1-methyl-1H-indol-3-yl, 5-chloro-1-methyl-1H-indol-3-yl, 6-chloro-5-methoxy-1-methyl-1H-indol-3-yl, and pharmaceutically acceptable salts thereof, 5-fluoro-1-methyl-1H-indol-3-yl.

The compound according to claim 6, or a pharmaceutically acceptable salt thereof,

R ¹selected from methoxy, difluoromethoxy, trifluoroethoxy, trifluoromethyl.

The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

The use according to claim 9, the cancer being selected from: ovarian cancer, non-small cell lung cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelocytic leukemia, multiple myeloma, melanoma, and mesothelioma.

The use of claim 10, wherein the cancer is non-small cell lung cancer.

Use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the EGFR or HER2 or HER4 pathway.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

The composition according to claim 13, for use in the treatment of cancer selected from the group consisting of: ovarian cancer, non-small cell lung cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelocytic leukemia, multiple myeloma, melanoma, and mesothelioma.

The composition of claim 14, wherein the cancer is non-small cell lung cancer.

The composition of claim 14 for use in inhibiting the EGFR or HER2 or HER4 pathway.

A compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein

Y is selected from C, N, C-CF3, and C-Cl;

x is selected from C and N;

g is selected from aryl, heteroaryl or heterocyclyl, preferably C6-10 aryl, C5-10 heteroaryl or C4-10 heterocyclyl, said aryl, heteroaryl or heterocyclyl being optionally substituted by one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, oxo, halogen, C6-C10 aryl, C5-10 heteroaryl or C4-10 heterocyclyl, C1-6 haloalkyl or C1-C6 aminoalkyl;

R ¹selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkyl or C1-6 haloalkoxy;

R ²a substituent selected from C1-6 alkyl, C1-6 heteroalkyl, C6-10 aryl, C5-10 heteroaryl, C4-10 heterocyclyl, C6-10 aryl-C1-6 alkylene, C5-10 heteroaryl-C1-6 alkylene, or C4-10 heterocyclyl-C1-6 alkylene, wherein said alkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di-C1-6 alkylamino, oxo, halogen, C1-6 haloalkyl, aminoacyl, C1-6 alkylaminoacyl, or di-C1-6 alkylaminoacyl;

R ³selected from hydrogen or C1-6 alkyl;

or R²And R³Together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl group, preferably a C3-10 heterocyclyl group, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di-C1-6 alkylamino, oxo, halogen, C1-6 haloalkyl, aminoacyl, C1-6 alkylaminoacyl, or di-C1-6 alkylaminoacyl;

R ⁴selected from hydrogen or C1-6An alkyl group;

R ⁵selected from the following groups:

a compound of formula (III) or a pharmaceutically acceptable salt thereof:

y is selected from C;

x is selected from CH₂NH, and O;

m forms a fused heteroaryl or heterocyclyl group with the pyrimidine ring (Y ═ C), M is selected from heteroaryl or heterocyclyl groups fused to the pyrimidine ring, preferably C5-C10 heteroaryl including the pyrimidine ring, C4-C10 heterocyclyl groups, said heteroaryl or heterocyclyl groups being optionally substituted by one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, oxo, halogen or C1-6 haloalkyl;

or when M does not form a fused heteroaryl or heterocyclyl group with a pyrimidine ring (Y ═ C), then Y is selected from C-C1 and C-CF₃；

R ¹Selected from the following groups:

R ³selected from hydrogen or C1-6 alkyl;

or R²And R³Together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl group, preferably a C3-10 heterocyclyl group, wherein the heteroaryl or heterocyclyl group is optionally substituted with one or more groups independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di-C1-6 alkylAmino, oxo, halogen, C1-6 haloalkyl, aminoacyl, C1-6 alkylaminoacyl, or di-C1-6 alkylaminoacyl;

R ⁴and R⁵Selected from hydrogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogen, C1-6 haloalkyl or C1-6 haloalkoxy, alkanoyl, C1-6 alkanoyl, alkoxyacyl, C1-C6 alkoxyacyl, aminoacyl or C1-6 alkylaminoacyl.

A compound of formula (IV) or a pharmaceutically acceptable salt thereof:

x and Y are selected from O, NH;

R ¹、R ²、R ³and R⁴Selected from hydrogen, nitro, cyano, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, alkanoyl, C1-6 alkanoyl, alkoxyacyl, C1-C6 alkoxyacyl, aminoacyl or C1-6 alkylaminoacyl;

R ⁵selected from C3-10 heterocyclyl, wherein the heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di-C1-6 alkylamino, oxo, halogen, C1-6 haloalkyl, aminoacyl, C1-6 alkylaminoacyl, or di-C1-6 alkylaminoacyl;

a compound of formula (V) or a pharmaceutically acceptable salt thereof

Wherein

X is selected from C and N;

R ¹、R ²、R ³、R ⁴and R⁵Selected from hydrogen, nitro, cyano, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy,

C1-6 haloalkyl or C1-6 haloalkoxy, alkanoyl, C1-6 alkanoyl, alkoxyacyl, C1-C6 alkoxyacyl, aminoacyl or C1-6 alkylaminoacyl;

n is selected from 1, 2, 3 and 4;

R ⁶selected from the following groups:

a pharmaceutical composition comprising a compound of formula (II), formula (III), formula (IV) and formula (V) as claimed in any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

A compound of formula (II), (III), (IV) and (V) as claimed in any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof, for use as a medicament.

Use of a compound of formula (II), (III), (IV) and (V) as claimed in any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

The use as claimed in claim 23, wherein the cancer is selected from: ovarian cancer, non-small cell lung cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelocytic leukemia, multiple myeloma, melanoma, and mesothelioma.

The use as claimed in claim 24, wherein the cancer is non-small cell lung cancer or small cell lung cancer.

Use of a compound of formula (II), (III), (IV) and (V) as defined in any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, and an additional anti-tumour agent, for the simultaneous, separate or sequential treatment of cancer.

An EGFR exon20 mutation inhibitor and/or a HER2exon 20 mutation inhibitor and/or a HER4 kinase inhibitor comprising a compound of any one of claims 17-20 or a pharmaceutically acceptable salt thereof.

Use of a compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, for the manufacture of an inhibitor of an EGFR20 exon mutation and/or an inhibitor of a HER2exon 20 mutation and/or an inhibitor of HER4 kinase.

The composition of claim 21 for use in the treatment of cancer selected from the group consisting of: ovarian cancer, non-small cell lung cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myelocytic leukemia, multiple myeloma, melanoma, and mesothelioma.

The composition of claim 29, wherein the cancer is non-small cell lung cancer or small cell lung cancer.

The composition of claim 21, for inhibiting the activity of a 20 exon mutated EGFR kinase, the activity of a 20 exon mutated HER2 kinase, and/or the activity of a 20 exon mutated HER4 kinase.