Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof
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.
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-tetrahydroisoquinoline-7-carboxamide;
4-ethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(thiomorpholinomethyl)-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
3-((4-methylpiperazin-1-yl)methyl)-N-(2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(trifluoromethyl)benzamide;
(S)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
(R)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
(S)—N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
(R)—N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising:
(a) a compound according to claim 1 ; and
(b) a pharmaceutically acceptable carrier.
17. A method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 , wherein said disease or disorder is mediated by DDAR activation.
18. A method of inhibiting discoidin domain receptor (DDR) protein comprising contacting the protein with a compound according to claim 1 in an amount sufficient to inhibit the protein.
19. A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of:
(a) a compound according to claim 1 ; and
(b) a second chemotherapeutic compound.