Dihydroisoquinolinone and isoindolinone derivatives and uses thereof
A kinase inhibitor, comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. A method and a use for using the inhibitor for treatment of diseases related to CDK9 and/or mutagenic activity thereof.
1 . A kinase inhibitor, comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
wherein, A is selected from the group consisting of cyclohexyl, phenyl, pyridinyl and piperidyl;
X is CH or N;
Z is —NH— or —NH—C(═O)—;
n is 0 or 1;
R 1 is selected from the group consisting of hydrogen, halogen, cyano, (C1-C6)alkyl, and (C1-C6)haloalkyl;
R 2 are selected from the group consisting of hydrogen and (C1-C6)alkyl, or two R 2 together form a (C3-C6)cycloalkyl;
m is selected from the integer of 1-3, and each R 3 is independently selected from the group consisting of hydrogen, —NH—(C1-C3)alkyl-(C1-C3)alkoxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylacylamino, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclyl sulfonyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, carboxyl(C1-C3)alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclyl aminoacyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, heterocyclyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, —S(═O)(═NH)(C1-C3)alkyl, and —(C1-C3)alkyl-S(═O)(═NH)(C1-C3)alkyl;
R 4 is selected from the group consisting of hydrogen and (C1-C6)alkyl.
2 . The kinase inhibitor of claim 1 , comprising a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
wherein, R 3 is —NH—(C1-C3)alkyl-(C1-C3)alkoxy or carboxyl(C1-C3)alkyl.
3 . The kinase inhibitor of claim 1 , comprising a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
wherein, Y is CH or N;
m is selected from the integer of 1-3, and each R 3 is independently selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamido, aminosulfonyl, (C1-C6)alkylaminosulfonyl, heterocyclyl sulfonyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, aminosulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C1-C3)alkyl, (C1-C3)alkylsulfonyl(C3-C6)cycloalkyl, heterocyclyl aminoacyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, heterocyclyl with heteroatom(s) being optionally substituted by (C1-C6)alkyl, —S(═O)(═NH)(C1-C3)alkyl, and —(C1-C3)alkyl-S(═O)(═NH)(C1-C3)alkyl.
4 . The kinase inhibitor of claim 1 , comprising a compound of formula (Ic) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
wherein, R 3 is (C1-C6)alkylacylamino.
5 . The kinase inhibitor of claim 1 , comprising a compound of formula (Id) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
wherein, R 3 is (C1-C6)alkylsulfonyl.
6 . The kinase inhibitor of claim 1 , wherein X is N.
7 . The kinase inhibitor of claim 1 , comprising the following compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
Comp.
No.
Comp. Structure
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8 . A pharmaceutical composition, comprising the kinase inhibitor of claim 1 , and a pharmaceutically acceptable diluent or carrier, and optionally one or more other active ingredients.
9 . A method of treating a disease relating to CDK9 and/or CDK9 mutations, comprising administering the kinase inhibitor of claim 1 to a subject having said disease.
10 . A method of treating a disease selected from the group consisting of hyperproliferative diseases, virus induced infectious diseases and cardiovascular diseases, comprising administering the kinase inhibitor of claim 1 to a subject having said disease.
11 . The method of claim 10 , wherein the hyperproliferative disease is cancer.
12 . The method of claim 11 , wherein the cancer is selected from the group consisting of leukemia, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, gastrointestinal stromal tumor, and lymphoma.