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 6-membered aryl substituted by 1 occurrence of R 3 and 0, 1, 2, or 3 occurrence(s) 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, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) 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 —(CH(R 9 )) z —;
Y is —NH—C(═O)—, —C(═O)—N(R 9 )—, or —C(═O)—N(R 9 )—(CHR 9 )—;
z is an integer of 1, 2, 3, or 4;
R 3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;
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; or two adjacent occurrences of R 9 together with the atoms to which they are attached form a 4- to 7-membered ring;
W d is
X 1 , X 2 and X 3 are each independently C, CR 13 , or N;
X 4 , X 5 and X 6 are each independently N, NH, CR 13 , S, or O; and
wherein R 10 , R 11 , R 12 , and R 13 are each 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, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
2. The compound of claim 1 , having Formula (IIIb):
wherein R 8 is hydrogen, alkyl, cyano, or halo; R 9 is hydrogen or alkyl, and
Y is —NH—C(O)—.
3. The compound of claim 1 , having a structure of Formula (II):
4. The compound of claim 1 , having a structure of Formula (IIIa) or Formula (IIIb):
5. The compound of claim 1 , wherein R 3 is halo, cyano, hydroxy, alkyl, alkoxy, amino, acyl, heteroaryl, aryl, heterocyclyl, or cycloalkyl.
6. The compound of claim 5 , wherein R 3 is heteroaryl, aryl, alkyl, haloalkyl, OH, Cl, or F.
7. The compound of claim 6 , wherein R 3 is heteroaryl, phenyl, CH 3 , CF 3 , OH, or Cl.
8. The compound of claim 5 , wherein R 3 is CH 3 , OCH 3 , CF 3 , or halo.
9. The compound of claim 5 , wherein R 3 is OCF 3 , CN, cyclopropyl, CH 2 OH, amino, formyl, or heterocyclyl.
10. The compound of claim 1 , wherein R 8 is H, CH 3 , OCH 3 , CF 3 , CN, or halo.
11. The compound of claim 1 , wherein B is aryl, heteroaryl, alkyl, cycloalkyl, or heterocyclyl, each of which is substituted with 0, 1, 2, or 3 occurrence(s) of R 2 .
12. The compound of claim 1 , wherein B is phenyl substituted with 0, 1, 2, or 3 occurrence(s) of R 2 .
13. The compound of claim 1 , wherein B is unsubstituted phenyl.
14. The compound of claim 1 , wherein B is phenyl substituted with 1 or 2 occurrence(s) of R 2 .
15. The compound of claim 14 , wherein R 2 is halo or alkyl.
16. The compound of claim 1 , wherein B is methyl, isopropyl, or cyclopropyl.
17. The compound of claim 1 , wherein B is cyclohexyl or alkyl.
18. The compound of claim 1 , wherein W d is:
wherein one of X 1 and X 2 is N and one of X 1 and X 2 is C or CR 13 ; and X 3 is CR 13 or N.
19. The compound of claim 1 , wherein W d is:
20. The compound of claim 1 , wherein W d is:
21. The compound of claim 1 , wherein W d is:
22. The compound of claim 1 , wherein W d is:
23. The compound of claim 1 , wherein W d is:
24. The compound of claim 1 , wherein W d is
25. The compound of claim 18 , wherein R 10 is NH 2 .
26. The compound of claim 1 , wherein X is —CH 2 — or —CH(CH 3 )—.
27. The compound of claim 26 , wherein X is —CH(CH 3 )—.
28. The compound of claim 27 , wherein the CH carbon of the —CH(CH 3 )— moiety has an (S) stereochemical configuration.
29. The compound of claim 27 , wherein the CH carbon of the —CH(CH 3 )— moiety has an (R) stereochemical configuration.
30. The compound of claim 1 , wherein Y is —NH—C(O)—.
31. The compound of claim 1 , wherein —X—Y— is —CH 2 —N(CH 3 )—C(O)—.
32. The compound of claim 1 , wherein —X—Y— is (S)—CH(CH 3 )—NH—C(O)—.
33. The compound of claim 1 , wherein —X—Y— is (R)—CH(CH 3 )—NH—C(O)—.
34. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient, diluent, or carrier.
35. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
36. The compound of claim 35 , wherein the compound is
or a pharmaceutically acceptable form thereof.
37. The compound of claim 36 , wherein the compound is
Compound 116,
or a pharmaceutically acceptable form thereof.
38. The compound of claim 36 , wherein the compound is
or a pharmaceutically acceptable form thereof.
39. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
40. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
41. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
42. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
43. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
44. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
45. A compound of Formula (II):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof,
or a pharmaceutically acceptable form thereof, wherein
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, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) 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 —(CH(R 9 )) z —;
Y is —N(R 9 )—C(═O)—, —C(═O)—N(R 9 )—, or —C(═O)—N(R 9 )—(CHR 9 )—;
z is an integer of 1, 2, 3, or 4;
R 3 is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro;
each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two adjacent occurrences of R 9 together with the atoms to which they are attached form a 4- to 7-membered ring;
W d is
X 1 , X 2 and X 3 are each independently C, CR 13 , or N;
X 4 , X 5 and X 6 are each independently N, NH, CR 13 , S, or O; and
wherein R 10 , R 11 , R 12 , and R 13 are each 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, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
46. A pharmaceutical composition comprising a compound of claim 37 , and a pharmaceutically acceptable excipient, diluent, or carrier.
47. A pharmaceutical composition comprising a compound of claim 38 , and a pharmaceutically acceptable excipient, diluent, or carrier.
48. The compound of claim 45 , wherein the compound is
or a pharmaceutically acceptable form thereof.