Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof

Patent metadata

Field	Value
Publication number	US-10370360-B2
Application number	US-201515521107-A
Country	US
Kind code	B2
Filing date	Oct 21, 2015
Priority date	Oct 22, 2014
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

Compounds of formula (I), their pharmaceutically acceptable salts and stereoisomers thereof, as well as application in effectively inhibiting the enzymatic activity of discoidin domain receptor 1 and can be used as new therapeutic agents for preventing and treating e.g. inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scar, atherosclerosis, and cancer. The compound of formula I is: wherein the variables are as defined herein.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
A is —NR 8 C(O)— or —C(O)NR 8 —; wherein:
R 8 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;

R 1 is aryl (C≤12 ) , heteroaryl (C≤12) , or a substituted version of either of these groups;
R 2 , R 3 , and R 3 ′ are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ;
R 4 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , substituted alkyl (C≤12) , substituted cycloalkyl (C≤12) , or substituted aryl (C≤12) ,
R 5 is
—X—R 9 , wherein:

X is a covalent bond, alkanediyl (C≤8) , or substituted alkanediyl (C≤8) ;
R 9 is amino or heterocycloalkyl (C≤12) , heteroaryl (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , or a substituted version of any of these groups; or a group of the formula:

wherein:
R 10 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ; and
p and q are each 0, 1, or 2;

R 6 and R 7 are each independently amino, cyano, halo, hydroxy, hydroxysulfonyl, nitro, sulfonamide; or
substituted or unsubstituted alkyl (C≤8) , acyl (C≤8) , alkoxy (C≤8) , amido (C≤8) , acyloxy (C≤8) , alkylamino (C≤8) , or dialkylamino (C≤8) ; and

m and n are each independently 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is further defined as:

wherein: A, R 1 , R 3 , R 3 ′, R 4 , R 5 , R 6 , and n are as defined above;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is further defined as:

wherein: A, R 1 , R 3 , R 3 ′, R 4 , R 5 , R 6 , and n are as defined above;
or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein R 1 is heteroaryl (C≤12) .

5. The compound according to claim 1 , wherein R 3 is alkyl (C≤12) .

6. The compound according to claim 1 , wherein R 3 is hydrogen.

7. The compound according to claim 1 , wherein R 3 ′ is hydrogen.

8. The compound according to claim 1 , wherein R 4 is alkyl (C≤12) or substituted alkyl (C≤12) .

9. The compound according to claim 1 , wherein R 4 is cycloalkyl (C≤12) or substituted cycloalkyl (C≤12) .

10. The compound according to claim 1 , wherein R 4 is aryl (C≤12 ) .

11. The compound according to claim 1 , wherein m is 0.

12. The compound according to claim 1 , wherein m is 1.

13. The compound according to claim 1 , wherein R 7 is alkyl (C≤8) or substituted alkyl (C≤8) .

14. The compound according to claim 1 , wherein R 7 is halo.

15. A compound of the formula:
4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(quinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4,4-dimethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-chloro-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(4-methyl-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(2-(4-methylpiperazin-1-yl)ethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-((4-methyl-1,4-diazepan-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-ethyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-isopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclohexyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-tert-butyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(5-((4-methylpiperazin-1-yl)methyl)biphenyl-3-yl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
3-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclopentyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-cyclohexylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin

Assignees

• Univ Texas
• Guangzhou Inst Biomed & Health

Inventors

• Brekken Rolf A
• Ding Ke
• Ren Xiaomei
• Tu Zhengchao
• Wang Zhen
• Aguilera Kristina Y

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title