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 a pharmaceutically acceptable form thereof, wherein
Cy is phenyl substituted by 0-1 occurrences of R 3 and 0-3 occurrences or 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 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 is —(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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, nitro or —C(═O)R 17 ; wherein each of the above substituents can be substituted with 0, 1, 2, or 3 R 13 ;
R 17 is hydrogen, hydroxyl or heterocyclyl;
each R 5 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;
each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl or heteroalkyl; and
W d is
wherein X 1 is N or CR 10 ; and
each R 10 , R 11 , R 12 , and R 13 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 phenyl substituted with 1 occurrence of R 3 and 0-3 occurrences of R 5 .
3. The compound of claim 1 , wherein Cy is phenyl substituted with 0 occurrence of R 3 and 0-3 occurrences of R 5 .
4. The compound of claim 1 , wherein Cy is phenyl substituted with 1 occurrence of R 3 and 0 occurrence of R 5 .
5. The compound of claim 1 , wherein the compound of Formula (I) has a structure of Formula (XV):
wherein W a 2 is CH or CR 5 ; W a 3 is CH or CR 5 ; and W a 4 is CH or CR 5 .
6. The compound of claim 5 , wherein each R 3 is independently CH 3 , OCH 3 , CF 3 , or halo.
7. The compound of claim 5 , wherein the compound of Formula (XV) has a structure of Formula (IIa) or (IIb):
8. The compound of claim 5 , wherein the compound of Formula (XV) has a structure of Formula (IIIa) or (IIIb):
9. The compound of claim 5 , wherein R 3 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, heteroaryl, hydroxyl, or nitro; wherein each of the above substituents can be substituted with 0, 1, 2, or 3 R 13 .
10. The compound of claim 9 , wherein R 3 is halo, alkyl, alkoxy, or cycloalkyl.
11. The compound of claim 10 , wherein R 3 is CH 3 , CF 3 , or Cl.
12. The compound of claim 5 , wherein R 3 is 5-10 membered heteroaryl substituted with 0, 1, 2 or 3 R 13 .
13. The compound of claim 12 , wherein R 3 is 6-membered heteroaryl substituted with 0, 1, 2 or 3 R 13 .
14. The compound of claim 13 , wherein R 3 is pyridyl or pyrimidyl substituted with 0, 1, 2 or 3 R 13 .
15. The compound of claim 14 , wherein the compound has a structure of Formula (IIIb-1):
wherein X 3 is CR 13 or N; and p is 0, 1, 2, or 3.
16. The compound of claim 15 , wherein p is 1 or 2.
17. The compound of claim 15 , wherein B is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0-4 R 2 .
18. The compound of claim 17 , wherein B is 5-6 membered heteroaryl substituted with 0-4 R 2 .
19. The compound of claim 18 , wherein B is isoxazolyl.
20. The compound of claim 17 , wherein B is alkyl or cycloalkyl substituted with 0-4 occurrences or R 2 .
21. The compound of claim 20 , wherein B is isopropyl.
22. The compound of claim 15 , wherein X 1 is N.
23. The compound of claim 15 , wherein R 8 is hydrogen.
24. The compound of claim 15 , wherein R 9 is methyl.
25. The compound of claim 15 , wherein Y is NH.
26. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
27. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.
28. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable form thereof.
29. The compound of claim 28 , wherein the compound is
or a pharmaceutically acceptable form thereof.
30. The compound of claim 28 , wherein the compound is
or a pharmaceutically acceptable form thereof.
31. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
32. A compound, which is
or a pharmaceutically acceptable form thereof.