Heterocyclic compounds and uses thereof
Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
1. A compound of Formula (I):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or its pharmaceutically acceptable forms thereof, wherein
Cy is aryl or heteroaryl substituted by 0-1 occurrences of R 3 and 0-3 occurrences of R 5 ;
W b 5 is CR 8 or CHR 8 ;
R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;
B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with 0-4 occurrences of R 2 ;
each R 2 is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea or carbonate;
X is absent or —(CH(R 9 )) z —;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—(CHR 9 ) z —, —C(═O)—, —N(R 9 )—C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —;
each z is independently an integer of 1, 2, 3, or 4;
R 3 is unsubstituted alkyl, or
R 3 is alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl, hydroxyl, or nitro; wherein each of the above substituents can be substituted with 0, 1, 2, or 3 R 17 ;
each R 5 is independently unsubstituted alkyl, or
each R 5 is independently alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;
each R 9 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; an
W d is
wherein X 1 is N or CR 14 ;
wherein R 10 , R 11 R 12 , R 13 , R 14 , and R 17 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate, oxo, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
2. The compound of claim 1 , wherein Cy is aryl substituted with 0-1 occurrences of R 3 and 0-3 occurrences of R 5 .
3. The compound of claim 2 , wherein Cy is phenyl substituted with 1 occurrence of R 3 and 0 occurrences of R 5 .
4. The compound of claim 3 , wherein the compound of Formula (I) has a structure of Formula (IIa) or (IIb):
5. The compound of claim 4 , wherein the compound of Formula (I) has a structure of Formula (IIIa) or (IIIb):
6. The compound of claim 5 , wherein the compound of Formula (I) has a structure of Formula (IIIb-1):
7. The compound of claim 1 , wherein Cy is heteroaryl substituted with 0-1 occurrences of R 3 and 0-3 occurrences of R 5 .
8. The compound of claim 7 , wherein Cy is 5-membered heteroaryl substituted with 0-1 occurrences of R 3 and 0-3 occurrences of R 5 .
9. The compound of claim 8 , wherein Cy is isothiazolyl substituted with 0-1 occurrences of R 3 and 0 occurrence of R 5 .
10. The compound of claim 9 , wherein the compound of Formula (I) has the structure of Formula (IVa) or Formula (IVb):
11. The compound of claim 10 , wherein the compound of Formula (IVa) or Formula (IVb) has the structure of Formula (Va) or Formula (Vb):
12. The compound of claim 11 , wherein the compound of Formula (I) has a structure of Formula (Va-1):
13. The compound of claim 8 , wherein Cy is thiophenyl substituted with 0-1 occurrences of R 3 and 0 occurrence of R 5 .
14. The compound of claim 13 , wherein the compound of Formula (I) has the structure of Formula (VIa) or Formula (VIb):
15. The compound of claim 14 , wherein the compound of Formula (VIa) or Formula (VIb) has the structure of Formula (VIIa) or (VIIb):
16. The compound of claim 14 , wherein the compound of Formula (VIa) or Formula (VIb) has the structure of Formula (VIIIa) or Formula (VIIIb):
17. The compound of claim 16 , wherein the compound of Formula (VIIa) or Formula (VIIb) has the structure of Formula (IXa) or Formula (IXb):
18. The compound of claim 17 , wherein the compound of Formula (I) has a structure of Formula (IXa-1):
19. The compound of claim 1 , wherein each R 5 is independently selected from CH 3 , OCH 3 , and halo.
20. The compound of claim 1 . wherein R 3 is unsubstituted alkyl or R 3 is selected from cycloalkyl, halo, aryl, and heteroaryl.
21. The compound of claim 20 , wherein R 3 is selected from methyl, chloro, and pyrazolo.
22. The compound of claim 1 , wherein B is aryl substituted with 0-3 occurrences of R 2 .
23. The compound of claim 22 , wherein B is phenyl substituted with 0-3 occurrences of R 2 .
24. The compound of claim 23 , wherein B is unsubstituted phenyl.
25. The compound of claim 23 , wherein B is phenyl substituted with 1 occurrence of R 2 .
26. The compound of claim 1 , wherein R 2 is halo or alkyl.
27. The compound of claim 1 , wherein B is cycloalkyl.
28. The compound of claim 1 , wherein B is heterocyclyl.
29. The compound of claim 1 , wherein Y is absent, —O—, —N(R 9 )—, or —S(═O) 2 —.
30. The compound of claim 1 , wherein X-Y is —CH 2 —N(CH 3 )—.
31. The compound of claim 1 , wherein X-Y is (S)—CH(CH 3 )—NH—.
32. The compound of claim 1 , wherein X-Y is (R)—CH(CH 3 )—NH—.
33. The compound of claim 1 , wherein X 1 is N.
34. The compound of claim 1 , wherein R 10 , R 11 , R 12 , R 13 are independently selected from hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, and hydroxyl.
35. The compound of claim 34 , wherein R 10 , R 11 , R 12 , and R 13 are independently selected from hydrogen, amino, and chloro.
36. The compound of claim 35 , wherein R 10 is selected from amino and chloro.
37. The compound of claim 1 . wherein R 8 is hydrogen.
38. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
39. The compound of claim 1 , wherein the compounds is
or a pharmaceutically acceptable form thereof.
40. The compound of claim 1 , wherein the compounds is
or a pharmaceutically acceptable form thereof.
41. The compound of claim 1 , wherein the compounds is
or a pharmaceutically acceptable form thereof.
42. The compound of claim 1 , wherein the compounds is
or a pharmaceutically acceptable form thereof.
43. The compound of claim 1 , wherein the compounds is
or a pharmaceutically acceptable form thereof.
44. A compound selected from
or a pharmaceutically acceptable form thereof.
45. A compound selected from
or a pharmaceutically acceptable form thereof.
46. The compound of claim 45 , wherein the compound is
or a pharmaceutically acceptable form thereof.
47. The compound of claim 39 , wherein the compound is
or a pharmaceutically acceptable form thereof.
48. The compound of claim 39 , wherein the compound is
or a pharmaceutically acceptable form thereof.
49. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.
50. A pharmaceutical composition comprising a compound according to claim 38 and one or more pharmaceutically acceptable excipients.
51. A pharmaceutical composition comprising a compound according to claim 39 and one or more pharmaceutically acceptable excipients.
52. A pharmaceutical composition comprising a compound according to claim 44 and one or more pharmaceutically acceptable excipients.
53. A pharmaceutical composition comprising a compound according to claim 45 and one or more pharmaceutically acceptable excipients.
54. A pharmaceutical composition comprising a compound according to claim 46 and one or more pharmaceutically acceptable excipients.
55. A pharmaceutical composition comprising a compound according to claim 47 and one or more pharmaceutically acceptable excipients.
56. A pharmaceutical composition comprising a compound according to claim 48 and one or more pharmaceutically acceptable excipients.