Azaindoles as inhibitors of HPK1
Azaindole compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the azaindole compounds.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein,
G 1 is N or C—R x1 ;
G 2 is N or C—R x2 ;
G 3 is N or C—R x3 ;
G 4 is N or C—R x4 ;
wherein, 0, 1 or 2 of G 1 , G 2 , G 3 , and G 4 is N;
R x1 , R x2 , R x3 and R x4 , if present, in each instance, is independently selected from the group consisting of hydrogen, halo, C 6 -C 20 aryl optionally substituted with one or two R 1a , C 1 -C 20 heteroaryl optionally substituted with one or two R 1a , —CONR 6 R 7 , —NR 6 R 7 , and —N(R 8 )—CO(R 9 ), provided that at least one of R x1 , R x2 , R x3 and R x4 is other than hydrogen;
wherein, R 6 and R 7 taken together with the N to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 6 and R 7 are independently hydrogen or alkyl;
wherein, R 8 and R 9 taken together with the N or the carbonyl to which each is bound form a 4-, 5-, 6- or 7-member cyclic or heterocyclic ring, wherein said heterocyclic ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O, said ring may be optionally substituted with one or two R 1a ; or
R 8 and R 9 are independently hydrogen or alkyl;
wherein, in each instance, R 1a is independently taken together with the carbon to which it is bound to form a carbonyl; or R 1a is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;
R 1 is hydrogen, alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl;
R 2 is alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SOR 5 , or cycloalkyl; and
R 3 and R 4 , in each instance, is independently hydrogen, alkyl, alkoxy, halo, haloalkyl-, haloalkoxy-, —R 5 —O—R 5 , —SO 2 R 5 , —SO 2 R 5 , or cycloalkyl;
wherein R 5 , in each instance, is independently an unsubstituted alkyl;
provided that R 1 and R 4 are not both hydrogen.
2. The compound of claim 1 , wherein one or both of G 1 and G 3 are N; G 2 is C—R x2 ; and G 4 is C—R x4 .
3. The compound of claim 1 , wherein G 1 is N and G 3 is C—R 3 .
4. The compound of claim 1 , wherein R 1 and R 2 , in each instance, is independently alkyl, haloalkyl or halo.
5. The compound of claim 4 , wherein the haloalkyl is —CF 3 or —CF 2 R 5 .
6. The compound of claim 4 , wherein R 1 and R 2 , in each instance, is independently halo or alkyl.
7. The compound of claim 1 , wherein G 1 is C—R x1 ; G 2 is C—R x2 ; G 3 is C—R x3 ; and G 4 is C—R x4 .
8. The compound of claim 7 , wherein R 1 and R 2 , in each instance, is independently alkyl, haloalkyl or halo.
9. The compound of claim 7 , wherein the haloalkyl is —CF 3 .
10. The compound of claim 8 , wherein R 1 and R 2 , in each instance, is independently halo or alkyl.
11. The compound of claim 1 , wherein two of R x1 , R x2 , R x3 and R x4 are hydrogen.
12. The compound of claim 1 , wherein R x2 is selected from:
wherein, t is 1 or 2.
13. The compound of claim 12 , wherein R x1 is hydrogen or halo; R x3 is hydrogen or —NH 2 ; R x4 is hydrogen or —NH 2 , wherein at least one of R x1 , R x3 and R x4 is hydrogen.
14. The compound of claim 1 , having Formula Ia:
15. The compound of claim 14 , wherein R 8 and R 9 , in each instance, is independently a C 1-4 alkyl; and R 6 and R 7 are both hydrogen.
16. The compound of claim 15 , wherein R 8 and R 9 are both methyl.
17. The compound of claim 1 , wherein R 1 is alkyl, hydroxyl, hydroxyalkyl, halo or haloalkyl; and R 3 and R 4 are each hydrogen.
18. The compound of claim 17 , wherein R 1 is alkyl, halo or haloalkyl; R 2 is hydrogen, alkyl, alkoxy, halo or haloalkyl.
19. The compound of claim 17 , wherein R 1 is alkyl, halo or haloalkyl; R 2 is hydrogen, alkyl, alkoxy, halo or —CF 3 .
20. The compound of claim 14 , wherein R 1 is C 1-4 alkyl.
21. The compound of claim 14 , wherein R 1 is chloro.
22. The compound of claim 14 , wherein R 2 is hydrogen, C 1-4 alkyl or —CF 3 .
23. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
25. The pharmaceutical composition of claim 24 , wherein said composition further comprises a chemotherapeutic agent.
26. The pharmaceutical composition of claim 25 , wherein said chemotherapeutic agent is an immunotherapeutic agent.
27. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 23 , which is
or a pharmaceutically acceptable salt thereof.