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 (Ia):
or a pharmaceutically acceptable form thereof, wherein:
W 5 is CR 4 ;
R 4 is hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
Cy is aryl substituted by 0-4 occurrences of R 3 ;
R 1 is -(L) n -R 1′ ;
each L is independently a bond, alkylene, heteroalkylene, —N(R 2 )—, —S(═O)—, —S(═O) 2 —, —S—, —C(═O)—, —P(═O)R 2 —, or —O—;
R 1′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, heterocycloalkyloxy, amino, amido, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, nitro, phosphate, urea, carbonate, —(C═O)—NR a1 R a2 , or NR a1 R a2 ;
R a1 and R a2 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or R a1 and R a2 are taken together with nitrogen to form a cyclic moiety;
R 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl;
each R 3 is independently alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
X is —(CH(R 10 )) z —;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—(CHR 10 ) z —, —C(═O)—, —N(R 9 )—C(═O)—, —C(═O)—N(R 9 )—, —N(R 9 )—C(═O)NH—, —N(R 9 )C(R 10 ) 2 —, —C(═O)—N(R 9 )—(CHR 10 ) z —, or —P(═O)R 2 —;
each z is an integer of 1, 2, 3, or 4;
n is an integer of 0, 1, 2, 3, or 4;
each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, aryl, or heteroaryl;
W d is
each R b is independently hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl; and
each R 10 , R 11 , and R 12 is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl, 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 , wherein n is 1, 2, or 3.
3. The compound of claim 1 , wherein each L is —O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —S—, alkylene, or a bond.
4. The compound of claim 1 , wherein R 1′ is alkyl, hydroxy, aryl, heteroaryl, aralkyl, —(C═O)—NR a1 R a2 , or NR a1 R a2 .
5. The compound of claim 4 , wherein R a1 is hydrogen or alkyl.
6. The compound of claim 4 , wherein R a2 is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, acyl, or heterocycloalkylalkyl.
7. The compound of claim 4 , wherein R a1 and R a2 are taken together with the nitrogen to which they are attached to form a cyclic moiety.
8. The compound of claim 1 , wherein W 5 is CH.
9. The compound of claim 1 , wherein X is —(CH(R 10 )) z — and z is 1 or 2.
10. The compound of claim 1 , wherein Y is absent, —O—, —NH(R 9 )—, or —S(═O) 2 —.
11. The compound of claim 1 , wherein Cy is phenyl substituted with 0-4 occurrences of R 3 .
12. The compound of claim 1 , wherein Cy is phenyl substituted with 1 occurrence of R 3 .
13. The compound of claim 1 , wherein R 3 is halo, alkyl, haloalkyl, acyl, or heteroaryl.
14. The compound of claim 1 , wherein R 10 is hydrogen.
15. The compound of claim 1 , wherein R 12 is hydrogen, halo, haloalkyl, cyano, amino, or amido.
16. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (II):
or a pharmaceutically acceptable form thereof, wherein:
W 1 is CR 14 , W 2 is CR 6 , W 3 is CR 7 , and W 4 is CR 8 ; and
R 6 , R 7 , R 8 and R 14 are independently hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
17. The compound of claim 16 , wherein R 1′ is hydrogen, amino, alkoxy, alkyl, heterocycloalkyl, aryl, or NR a1 R a2 , wherein R a1 and R a2 are taken together with nitrogen to form a cyclic moiety.
18. The compound of claim 16 , wherein R 1′ is amino, alkoxy, alkyl, or NR a1 R a2 , wherein R a1 and R a2 are taken together with nitrogen to form a cyclic moiety.
19. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (IIIa):
or a pharmaceutically acceptable form thereof, wherein:
W 1 is CR 14 , W 2 is CR 6 , W 3 is CR 7 , and W 4 is CR 8 ; and
R 6 , R 7 , R 8 and R 14 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
20. The compound of claim 19 , wherein R a1 and R a2 are taken together with nitrogen to form a cyclic moiety.
21. The compound of claim 20 , wherein the cyclic moiety is 5- or 6-membered.
22. The compound of claim 19 , wherein n is 1 and L is alkylene.
23. The compound of claim 22 , wherein L is methylene or ethylene.
24. The compound of claim 19 , wherein L is alkylene substituted by aryl, heteroaryl or halo.
25. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (IV):
or a pharmaceutically acceptable form thereof, wherein:
W 1 is CR 14 , W 2 is CR 6 , W 3 is CR 7 , W 4 is CR 8 , and W 5 is CR 4 ; and
R 6 , R 7 , R 8 and R 14 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR/R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
26. The compound of claim 16 , wherein R 8 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
27. The compound of claim 26 , wherein R 8 is hydrogen or alkyl.
28. The compound of claim 27 , wherein R 8 is alkyl substituted with one or more fluoro.
29. The compound of claim 1 , wherein X is —CH 2 —, —CH(CH 3 )—, —CH(C 6 H 5 )—, or —CH(CH 2 CH 3 )—.
30. The compound of claim 29 , wherein the CH carbon of —CH(CH 3 )— or —CH(CH 2 CH 3 )— has a predominately (S) stereochemical configuration.
31. The compound of claim 1 , wherein Y is absent, —O—, —N(R 9 )—, N(R 9 )C(R 10 ) 2 —, or —S(═O) 2 —.
32. The compound of claim 31 , wherein R 9 and R 10 are independently hydrogen, methyl or ethyl.
33. The compound of claim 1 , wherein X is —(CH(R 10 ) z —, is 1, Y is —N(R 9 )—, and R 9 is hydrogen.
34. The compound of claim 1 , wherein Y is —N(CH 2 CH 3 )CH 2 — or —N(CH 3 )CH 2 —.
35. The compound of claim 1 , wherein X—Y is —CH 2 —N(CH 3 )—, or —CH 2 —N(CH 2 CH 3 )—.
36. The compound of claim 1 , wherein W d is
37. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (V):
or a pharmaceutically acceptable form thereof.
38. The compound of claim 37 , or a pharmaceutically acceptable form thereof, wherein:
R 1 is -(L) n -R 1′ ;
each L is —O—, —C(═O)—, —S(═O) 2 —, —S—, or alkylene;
R 1′ is alkyl, hydroxy, aryl, heteroaryl, aralkyl, —(C═O)—NR a1 R a2 , or NR a1 R a2 ;
W d is:
R 10 is hydrogen;
R 12 is hydrogen, halo, haloalkyl, cyano, amino, or amido; and
n is 0, 1, 2, 3, or 4.
39. The compound of claim 38 , wherein L is —O— or alkylene; and n is 0, 1, or 2.
40. A pharmaceutical composition comprising a compound according to claim 1 , and one or more pharmaceutically acceptable excipients.
41. The compound of claim 1 , wherein the compound of Formula (Ia) is:
or a pharmaceutically acceptable form thereof.
42. The pharmaceutical composition of claim 40 , 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. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable form thereof.
46. A compound, which is:
or a pharmaceutically acceptable form thereof.
47. The compound of claim 1 , wherein W d is
48. The compound of claim 1 , wherein W d is
49. The compound of claim 1 , wherein W d is
50. The compound of claim 1 , wherein W d is
51. A pharmaceutical composition comprising a compound according to claim 43 , 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.