Isoquinoline-5-carboxamide derivative having inhibitory activity for protein kinase

Patent metadata

Field	Value
Publication number	US-9388165-B2
Application number	US-201314413305-A
Country	US
Kind code	B2
Filing date	Jul 17, 2013
Priority date	Jul 19, 2012
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

A compound selected from the group consisting of an isoquinoline-5-carboxamide derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate and a solvate thereof is effective for the prevention or treatment of diseases associated with abnormal cell growth, which are caused by abnormal activation of a protein kinases.

First claim

What is claimed is:

1. A compound selected from the group consisting of an isoquinoline-5-carboxamide of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate and a solvate thereof:

wherein,
A is C 6-10 aryl or C 5-10 heteroaryl;
B is C 6-10 aryl or C 5-10 heteroaryl;
X is —NH—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(S)NH—, —NHC(S)—, —NHC(S)NH—, —NHSO 2 — or —SO 2 NH—;
Y is hydrogen, C 1-3 alkyl or NR 3 R 4 , wherein said R 3 and R 4 are each independently hydrogen, C 1-6 alkyl or —(CH 2 ) q —Z—, wherein said Z is NR 5 R 6 , C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl, wherein said R 5 and R 6 are each independently hydrogen, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being unsubstituted or substituted with one or more halogen atoms, q is an integer ranging from 0 to 3;
R 1 is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, wherein said alkyl or alkoxy is unsubstituted or substituted with one or more halogen atoms;
R 2 is hydrogen, halogen, —CF 3 , —NO 2 , —OH, C 1-6 alkoxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, —NR 7 R 8 , —NHSO 2 R 9 , —SO 2 R 10 , —C(O)R 11 , —NHC(O)R 12 , —NHC(O)OR 13 , C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl, C 6-10 aryloxy, C 5-10 heteroaryl or C 5-10 heteroaryloxy, wherein said R 2 is connected to B by —(CH 2 ) p — or may be substituted with halogen, cyano, C 1-4 alkyl or C 1-4 alkylcarbonyl, wherein said R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently hydrogen, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being unsubstituted or substituted with one or more halogen atoms, and p is 1 or 2;
m is an integer ranging from 0 to 5; and
n is an integer ranging from 0 to 2.

2. The compound of claim 1 , wherein A is phenyl or isoquinoline.

3. The compound of claim 1 , wherein X is —NH—, —C(O)NH—, —NHC(O)— or —NHC(O)NH—.

4. The compound of claim 1 , wherein Y is hydrogen, amino, —NHCH(CH 3 ) 3 , or

5. The compound of claim 1 , wherein A is phenyl or isoquinoline; X is —NH—, —C(O)NH—, —NHC(O)— or —NHC(O)NH—; and Y is hydrogen, amino, —NHCH(CH 3 ) 3 , or

6. The compound of claim 1 , wherein the isoquinoline-5-carboxamide of formula (I) is selected from the group consisting of:
1) 1-amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)isoquinoline-5-carboxamide;
2) 1-(t-butylamino)-N-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
3) 1-amino-N-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
4) 1-amino-N-(5-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)isoquinoline-5-carboxamide;
5) 1-amino-N-(5-((3-(2-cyanopropan-2-yl)phenyl)carbamoyl)-2-methylphenyl)isoquinoline-5-carboxamide;
6) 1-(t-butylamino)-N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)isoquinoline-5-carboxamide;
7) 1-amino-N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)isoquinoline-5-carboxamide;
8) 1-(t-butylamino)-N-(2-methyl-5-(phenylcarbamoyl)phenyl)isoquinoline-5-carboxamide;
9) 1-amino-N-(2-methyl-5-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
10) 1-amino-N-(5-((4,6-dimethylpyridin-2-yl)carbamoyl)-2-methylphenyl)isoquinoline-5-carboxamide;
11) 1-amino-N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
12) 1-(t-butylamino)-N-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)isoquinoline-5-carboxamide;
13) 1-amino-N-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)isoquinoline-5-carboxamide;
14) 1-amino-N-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)isoquinoline-5-carboxamide;
15) 1-(t-butylamino)-N-(5-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)isoquinoline-5-carboxamide;
16) 1-amino-N-(5-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)isoquinoline-5-carboxamide;
17) 1-amino-N-(3-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
18) 1-amino-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)isoquinoline-5-carboxamide;
19) 1-((5-methoxypyridin-2-yl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)isoquinoline-5-carboxamide;
20) 1-((5-methoxypyridin-2-yl)amino)-N-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)isoquinoline-5-carboxamide;
21) 1-((5-methoxypyridin-2-yl)amino)-N-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isoquinoline-5-carboxamide;
22) N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)isoquinoline-5-carboxamide; and
23) N-(1-((4-chlorophenyl)amino)-6-methylisoquinolin-5-yl)isoquinoline-5-carboxamide.

7. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient for the prevention or treatment of diseases associated with abnormal cell growth, which are caused by abnormal activation of protein kinases.

8. The pharmaceutical composition of claim 7 , wherein said kinases are selected from the group consisting of A-RAF, B-RAF, C-RAF, PDGFR alpha, PDGFR beta, VEGRF and a combination thereof.

9. The pharmaceutical composition of claim 7 , wherein said disease is selected from the group consisting of: gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophagus cancer, thyroid cancer, parathyroid cancer, renal cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma, fibroadenoma, inflammation, diabetes, obesity, psoriasis, rheumatoid arthritis, hemangioma, acute or chronic kidney disease, coronary restenosis, autoimmune diseases, asthma, neurodegenerative diseases, acute infection and ocular diseases caused by angiogenesis.

10. A method for treatment of a disease associated with abnormal cell growth, which is caused by abnormal activation of a protein kinase, which comprises administering to the subject in need thereof the compound of claim 1 .

11. A method for treating a disease associated with abnormal cell growth, which is caused by abnormal activation of a protein kinase, which comprises administering to the subject in need thereof the compound of claim 6 .

12. The method of claim 10 , wherein the protein kinase is selected from the group consisting of A-RAF, B-RAF, C-RAF, PDGFR alpha, PDGFR beta, VEGRF and a combination thereof.

13. The method of claim 11 , wherein the protein kinase is selected from the group consisting of A-RAF, B-RAF, C-RAF, PDGFR alpha, PDGFR beta, VEGRF and a combination thereof.

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Bae In Hwan
• Han Sang Mi
• Kwak Eun Joo
• Ahn Young Gil
• Suh Kwee Hyun

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title