Chemical compounds, compositions and methods for kinase modulation
Provided herein are compounds of formula (I), pharmaceutical compositions comprising the compounds, and methods of use thereof The compounds provided herein modulate kinase activity, including PI3 kinase activity, and are useful for treating diseases and conditions associated with kinase activity, including diseases and conditions associated with PI3 kinase activity.
1. A compound of formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein
B is hydrogen, or a moiety of Formula II:
wherein W c is 6-membered aryl or cycloalkyl;
q is an integer of 0, 1, 2, 3, or 4;
X is absent or —(CH(R 9 )) z —, and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —C(═O)—, —C(═O)(CHR 9 ) z —, —N(R 9 )—, —N(R 9 )—C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —, and z is an integer of 1, 2, 3, or 4;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
each R 2 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is a 5-membered heteroaryl, a 5-membered nonaromatic heterocyclyl, a 6-membered heteroaryl, or a 6-membered nonaromatic heterocyclyl, each of which comprises at least one ring nitrogen, and each of which can be substituted with 0, 1, 2, or 3 R 13 ;
R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, cyano, alkyl, or amino;
each R 9 is independently hydrogen, alkyl, or heterocycloalkyl;
W d is
R 11 is hydrogen, alkyl, halo, amino, amido, hydroxy, alkoxy, phosphate, urea, or carbonate;
R 12 is hydrogen, alkyl, haloalkyl, alkynyl, alkenyl, halo, —C(O)NH 2 , NH 2 , cyano, aryl, heteroaryl, nonaromatic heterocyclyl, or cycloalkyl;
R a is methyl;
R a′ is hydrogen, alkyl, —NH 2 , cyano, or halogen; and
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen.
2. The compound of claim 1 , wherein R 3 is
3. The compound of claim 1 , wherein B is:
4. The compound of claim 3 , wherein q is 0 or 1.
5. The compound of claim 4 , wherein R 1 is hydrogen, alkyl, alkoxy, amido, halo, cyano, or nitro.
6. The compound of claim 4 , wherein q is 1 and R 2 is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro.
7. The compound of claim 1 , wherein Y is —O—, —S(═O) 2 —, —C(═O)—, —N(R 9 )—, or —N(R 9 )—C(═O)—.
8. The compound of claim 1 , wherein X is —(CH(R9)) z —.
9. The compound of claim 8 , wherein z is 1, 2 or 3.
10. The compound of claim 8 , wherein R 9 is hydrogen or alkyl.
11. The compound of claim 1 , wherein W d is
12. The compound of claim 1 , wherein R 6 is hydrogen, halo, cyano or alkyl.
13. The compound of claim 1 , wherein R 7 is hydrogen, halo, cyano or alkyl.
14. The compound of claim 1 , wherein R 8 is hydrogen, halo, cyano or alkyl.
15. The compound of claim 2 , wherein B is:
16. The compound of claim 15 , wherein q is 0 or 1.
17. The compound of claim 16 , wherein R 1 is hydrogen, alkyl, alkoxy, amido, halo, cyano, or nitro.
18. The compound of claim 16 , wherein q is 1 and R 2 is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro.
19. The compound of claim 2 , wherein Y is —O—, —S(═O) 2 —, —C(═O)—, or —N(R 9 )—.
20. The compound of claim 2 , wherein X is —(CH(R 9 )) z —.
21. The compound of claim 20 , wherein z is 1, 2 or 3.
22. The compound of claim 20 , wherein R 9 is hydrogen or alkyl.
23. The compound of claim 2 , wherein W d is
24. The compound of claim 2 , wherein R 6 is hydrogen, halo, cyano or alkyl.
25. The compound of claim 2 , wherein R 7 is hydrogen, halo, cyano or alkyl.
26. The compound of claim 2 , wherein R 8 is hydrogen, halo, cyano or alkyl.
27. The compound of claim 11 , wherein B is:
28. The compound of claim 27 , wherein q is 0 or 1.
29. The compound of claim 28 , wherein R 1 is hydrogen, alkyl, alkoxy, amido, halo, cyano, or nitro.
30. The compound of claim 28 , wherein q is 1 and R 2 is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro.
31. The compound of claim 11 , wherein Y is —O—, —S(═O) 2 —, —C(═O)—, or —N(R 9 )—.
32. The compound of claim 11 , wherein X is —(CH(R 9 )) z —.
33. The compound of claim 32 , wherein z is 1, 2 or 3.
34. The compound of claim 32 , wherein R 9 is hydrogen or alkyl.
35. The compound of claim 11 , wherein R 6 is hydrogen, halo, cyano or alkyl.
36. The compound of claim 11 , wherein R 7 is hydrogen, halo, cyano or alkyl.
37. The compound of claim 11 , wherein R 8 is hydrogen, halo, cyano or alkyl.
38. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
39. The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
40. The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
41. The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
42. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.