Analogs for the treatment of disease
The disclosure provides TNIK and/or MAP4K4 kinases inhibitors for the treatment of disease. In one aspect, disclosed herein are kinase inhibitors having a structure of Formula (A), (A*), (I), (IIA), or (IIB). Further described herein are pharmaceutical composition comprising these compounds and methods of using these compounds. In one aspect, disclosed herein are methods of treating a disease or condition by administering the kinases inhibitors described herein.
1. A compound represented by Formula (IIA),
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected at each occurrence from oxo and C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and —NH 2 ;
R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogen; and
R 4 is
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is piperazine substituted with one or more C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogen.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. A method of treating a fibrotic disease or condition, comprising administering a compound of claim 6 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the fibrotic disease or condition is kidney fibrosis.
14. The method of claim 13 , wherein the fibrotic disease or condition is associated with TNIK kinase.
15. A pharmaceutical composition comprising (i) a compound represented by Formula (IIA),
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected at each occurrence from oxo and C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and —NH 2 ;
R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogen; and
R 4 is
and
(ii) a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15 , wherein R 1 is piperazine substituted with one or more C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogen.
17. The pharmaceutical composition of claim 15 , wherein:
R 1 is selected from
and
R 3 is selected from
18. The pharmaceutical composition of claim 15 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is
30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is