Pyrazolopyridine compounds and uses thereof
Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C(O)NR c R d and NR c C(O)R b ;
Cy A is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more ring-forming carbon atoms and 1 or 2 ring-forming N heteroatoms; wherein the N is optionally oxidized; wherein a carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the 5-10 membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R 20 ;
R 2 is H;
each R 10 is morpholinyl, 4-methylpiperazin-1-yl, 4-ethoxycarbonylpiperazin-1-yl, 4-methoxypiperidin-1-yl, 3-aminopiperidin-1-yl, 3-methoxypiperidin-1-yl, 1-propylamino, 2-methoxyethylamino, or 3-difluoropyrrolidin-1-yl;
each R 20 is independently selected from C 1-6 alkyl and OR a2 ;
each R c and R d is independently selected from H and C 6-10 aryl; wherein said C 6-10 aryl is optionally substituted with 1 or 2 substituents independently selected from R 10 ;
R b is C 6-10 aryl; wherein said C 6-10 aryl is optionally substituted with 1 or 2 substituents independently selected from R 10 ; and
each R a2 is independently selected from H and C 1-6 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)NR c R d .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NR c C(O)R b .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R b is phenyl optionally substituted with 1 or 2 substituents independently selected from R 10 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy A is pyridyl or pyrazolyl; wherein said pyridyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R 20 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 20 is independently selected from C 1-6 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 20 is OR a2 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 20 is independently selected from methyl and methoxy.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy A is 4-methylpyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or 4-methoxypyridin-3-yl.
10. The compound of claim 1 having Formula III:
wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 having Formula IV:
wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 having Formula Ma or Formula IIIb:
wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 having Formula IVa or Formula IVb:
wherein n is 1 or 2; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 selected from:
N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide;
4-(4-Methylpiperazin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;
Ethyl 4-(4-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate;
4-(4-Methoxypiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;
4-(3-Aminopiperidin-1-yl)-N-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide;
Ethyl 4-(4-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methoxypiperidin-1-yl)benzamide;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-methoxypiperidin-1-yl)benzamide;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(propylamino)benzamide;
N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(2-methoxyethylamino)benzamide;
4-(3,3-Difluoropyrrolidin-1-yl)-N-(5-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide;
N-(5-(4-methoxypyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide;
N-(4-(4-methylpiperazin-1-yl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; and
5-(4-Methoxypyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
16. A method of inhibiting HPK1 activity, said method comprising administering to a patient a compound of claim 1 , or a pharmaceutically acceptable salt thereof.