Azaindoles as inhibitors of HPK1

Patent metadata

Field	Value
Publication number	US-10952995-B2
Application number	US-201916568459-A
Country	US
Kind code	B2
Filing date	Sep 12, 2019
Priority date	Mar 15, 2017
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

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.

First claim

We claim:

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.

Assignees

• Genentech Inc

Inventors

• Heffron Timothy
• Malhotra Sushant
• Wei Binqing
• Chan Bryan
• Gazzard Lewis
• Gancia Emanuela
• Lainchbury Michael
• Madin Andrew
• SEWARD Eileen
• Hu Yonghan

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title