Heterocyclic compounds and uses thereof
Provided herein are compounds of Formula (I″) or (A″), 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 PI3 kinase activity.
1. A compound of Formula (I):
wherein:
R 1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —COR 2 ;
B is hydrogen, alkyl, cycloalkyl, or aryl;
wherein R 2 is hydrogen;
W d is:
wherein
X 1 , X 2 and X 3 are each independently C, CR 13 , or N; and
R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, unsubstituted alkyl, or amino;
X is CR 1a ;
wherein R 1a is hydrogen, halo, alkyl, alkenyl, alkynyl, or CN;
wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halo, OH, alkoxy, NH 2 , NH(alkyl), N(alkyl) 2 , C(O)H, CO(alkyl), COOH, COO(alkyl), CONH 2 , CONH(alkyl), CON(alkyl) 2 , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more halo, alkyl, alkenyl, alkynyl, OH, alkoxy, oxo, NH 2 , NH(alkyl), N(alkyl) 2 , C(O)H, CO(alkyl), COOH, COO(alkyl), CONH 2 , CONH(alkyl), or CON(alkyl) 2 ;
wherein each heterocycloalkyl is independently a 5- to 10-membered heterocycloalkyl having one to three ring heteroatoms independently selected from nitrogen, oxygen, and sulfur;
wherein each heteroaryl is independently a 5- to 10-membered heteroaryl having one to three ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
wherein in Formula (I), when X is CH, B is unsubstituted phenyl, and W d is
then R 1 is not methyl, (CH 2 )NH 2 , (CH 2 ) 2 NH 2 ;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
2. The compound of claim 1 , wherein
R 1 is branched alkyl, 6-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl,
cyclopropyl, or methyl,
wherein R A is OH, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
x is 1, 2, 3, 4, 5, or 6; and
R 7 , R 8 , and R 9 are each, independently, hydrogen, OH, alkoxy, NH 2 , NH(alkyl), N(alkyl) 2 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein each alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted.
3. The compound of claim 2 , wherein
R 1 is: methyl,
4. The compound of claim 1 , wherein R 1 is a 5- to 10-membered heteroaryl, which is optionally substituted.
5. The compound of claim 4 , wherein R 1 is a 6-membered heteroaryl, which is optionally substituted.
6. The compound of claim 5 , wherein R 1 is a pyridinyl or pyrimidinyl, each of which is optionally substituted.
7. The compound of claim 4 , wherein R 1 is a 5-membered heteroaryl, which is optionally substituted.
8. The compound of claim 7 , wherein R 1 is a thiazolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted.
9. The compound of claim 4 , wherein the heteroaryl is substituted with one or more alkyl.
10. The compound of claim 1 , wherein B is aryl or cycloalkyl, each of which is optionally substituted.
11. The compound of claim 10 , wherein B is aryl or 3- to 6-membered cycloalkyl, each of which is optionally substituted.
12. The compound of claim 11 , wherein B is phenyl substituted with 0, 1, 2, or 3 occurrence(s) of R Z , wherein each instance of R Z is independently halo or alkyl.
13. The compound of claim 12 , wherein B is unsubstituted phenyl.
14. The compound of claim 11 , wherein B is
15. The compound of claim 1 , wherein W d is
16. The compound of claim 1 , wherein W d is
wherein one of X 1 and X 2 is C and the other is N.
17. The compound of claim 1 , wherein W d is
wherein X 3 is N or CR 13 .
18. The compound of claim 1 , wherein W d is
wherein one of X 1 and X 2 is N and the other is CR 13 .
19. The compound of claim 1 , wherein X is CH.
20. The compound of claim 1 , wherein the compound is a compound of formula II, III, V, VI, VIII, IX, or XII:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
21. The compound of claim 1 , wherein the compound is the S-enantiomer having an enantiomeric purity greater than 75%.
22. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient, diluent, or carrier.
23. The compound of claim 8 , wherein R 1 is a pyrazolyl, which is optionally substituted.
24. The compound of claim 23 , wherein R 1 is a pyrazolyl, and wherein the pyrazolyl is substituted with one or more alkyl.
25. The compound of claim 24 , wherein R 1 is
26. The compound of claim 1 , wherein the compound is a compound of formula III:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
27. The compound of claim 26 , wherein R 1 is 5- or 6-membered heteroaryl, which is optionally substituted.
28. The compound of claim 27 , wherein R 1 is a pyrazolyl, which is optionally substituted.
29. The compound of claim 28 , wherein R 1 is a pyrazolyl, and wherein the pyrazolyl is substituted with one or more alkyl.
30. The compound of claim 29 , wherein R 1 is
31. The compound of claim 30 , wherein R 1 is
32. The compound of claim 1 , wherein the compound is a compound of formula VI:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
33. The compound of claim 32 , wherein R 1 is 5- or 6-membered heteroaryl, which is optionally substituted.
34. The compound of claim 33 , wherein R 1 is a pyrazolyl, which is optionally substituted.
35. The compound of claim 34 , wherein R 1 is a pyrazolyl, and wherein the pyrazolyl is substituted with one or more alkyl.
36. The compound of claim 1 , wherein the compound is a compound of formula XIV:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
37. The compound of claim 1 , wherein the compound is a compound of formula XV:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
38. The compound of claim 15 , wherein W d is
39. The compound of claim 1 , which is
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
40. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
41. A pharmaceutical composition comprising a compound of claim 40 , and a pharmaceutically acceptable excipient, diluent, or carrier.
42. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
43. A pharmaceutical composition comprising a compound of claim 42 , and a pharmaceutically acceptable excipient, diluent, or carrier.