Heterocyclic compounds and uses thereof
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the isoquinolone entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described herein.
1. A compound of Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein
W 1 is N or CR 5 , W 2 is N or CR 6 , W 3 is N or CR 7 , W 4 is N or CR 8 , wherein no more than two N atoms are adjacent;
R 1 is -(L) n —R 1 ;
L is —S—, —N(R 2 )—, —C(R 3 ) 2 —, or —O—;
n is 0 or 1;
R 1 ′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R 4 , R 5 , R 6 , R 7 and R 8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, 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 absent or is —(CH(R 10 )) z — and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—, —N(R 9 )—C(═O)—, —N(R 9 )—C(═O)NH—,)—N(R 9 )C(R 10 2 —, or —C(═O)—(CHR 10 ) z —;
each instance of R 2 and R 9 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, C 2 -C 10 heteroalkyl, aryl, or heteroaryl;
each instance of R 3 and R 10 is independently hydrogen, alkyl, aryl, heteroaryl, or halo; and
W d is
wherein each instance of R a is independently hydrogen or alkyl;
R 11 is H, alkyl, halo, amino, amido, hydroxyl, or alkoxy, and
R 12 is H, alkyl, cyano, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocyloalkyl, cycloalkyl, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amino.
2. A compound of Formula I-B:
or a pharmaceutically acceptable salt thereof, wherein
W 1 is N or CR 5 , W 2 is N or CR 6 , W 3 is N or CR 7 , W 4 is N or CR 8 , wherein no more than two N atoms are adjacent;
R 1 is —(L) n —R 1′ ;
L is —S—, —N(R 2 )—, —C(R 3 ) 2 —, or —O—;
n is 0or 1;
R 1′ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R 5 , R 6 , R 7 and R 8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, 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 absent or is —(CH(R 10 )) z — and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—, —N(R 9 )—C(═O)—, —N(R 9 )—C(═O)NH—,—N(R 9 )C(R 10 2 —,or —C(═O)—(CHR 10 ) z —;
each instance of R 2 and R 9 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, C 2 -C 10 heteroalkyl, aryl, or heteroaryl;
each instance of R 3 and R 10 is independently hydrogen, alkyl, aryl, heteroaryl or halo; and
W d is
wherein each instance of R a is independently hydrogen or alkyl;
R 11 is H, alkyl, halo, amino, amido, hydroxyl, or alkoxy, and
R 12 is H, alkyl, cyano, alkynyl, alkenyl , halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amino.
3. The compound of claim 1 or 2 wherein
W 1 is N, W 2 is CR 6 , W 3 is CR 7 , W 4 is CR 8 ;
W 1 is CR 5 , W 2 is N, W 3 is CR 7 , W 4 is CR 8 ;
W 1 is CR 5 , W 2 is CR 6 , W 3 is N, W 4 is CR 8 ;
W 1 is N, W 2 is CR 6 , W 3 is N, W 4 is CR 8 ;
W 1 is N, W 2 is N, W 3 is CR 7 , W 4 is CR 8 ;
W 1 is N, W 2 is CR 6 , W 3 is CR 7 , W 4 is N;
W 1 is CR 5 , W 2 is N, W 3 is N, W 4 is CR 8 ;
W 1 is CR 5 , W 2 is N, W 3 is CR 7 , W 4 is N;
W 1 is CR 5 , W 2 is CR 6 , W 3 is N , W 4 is N ; or
W 1 is CR 5 , W 2 is CR 6 , W 3 is CR 7 , w 4 is CR 8 .
4. The compound of claim 1 wherein the compound of Formula I-A is a compound of Formula XV-A:
5. The compound of claim 2 wherein the compound of Formula I-B is a compound of Formula XV-B:
6. The compound of claim 1 or 2 wherein n is 0 and R 1′ is hydrogen, amino, alkoxy, alkyl, heterocycloalkyl, aryl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
7. The compound of claim 1 or 2 wherein n is 1 and R 1′ is amino, alkoxy, alkyl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
8. The compound of claim 7 wherein n is 1 and R 1′ is alkyl which is substituted with heterocycloalkyl or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
9. The compound of claim 1 or 2 wherein R 8 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, sulfonamido, halo, cyano, hydroxy, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
10. The compound of claim 1 or 2 wherein R 8 is hydrogen or alkyl.
11. The compound of claim 10 wherein R 8 is alkyl substituted with one or more fluoro.
12. The compound of claim 1 or 2 wherein X is —CH 2— , —CH(CH 3 )—, —CH(C 6 H 5 )—,or —CH(CH 2 CH 3 )—.
13. The compound of claim 12 wherein —CH(CH 3 )—or —CH(CH 2 CH 3 )—has either a predominately (S) stereochemical configuration or a predominately (R) stereochemical configuration.
14. The compound of claim 1 or 2 wherein Y is absent, —O—, —N(R 9 )—, —N(R 9 )C(R 10 ) 2 —, or —S(═O) 2 —.
15. The compound of claim 14 wherein R 9 and R 19 are independently hydrogen, methyl, or ethyl.
16. The compound of claim 15 wherein the compound is a compound of Formula I-A, when R 1 is alkyl, X is —(CH(R 10 )) z —, z is 1, and Y is —N(R 9 )—, then R 9 is hydrogen.
17. The compound of claim 1 or 2 wherein Y is —N(CH 2 CH 3 )CH 2 —or —N(CH 3 )CH 2 —.
18. The compound of claim 1 or 2 wherein X-Y is —CH 2 —N(CH 3 )—, or —CH 2 —N(CH 2 CH 3 )—.
19. The compound of claim 1 or 2 wherein W d is of Formula XIV:
wherein R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, acyloxy, alkoxycarbonyl, or amido.
20. The compound of claim 1 or 2 wherein R 11 is amino.
21. The compound of claim 1 or 2 wherein R 12 is a monocyclic heteroaryl, a bicyclic heteroaryl, or a heterocycloalkyl.
22. The compound of claim 1 or 2 wherein R 12 is hydrogen.
23. The compound of claim 1 , wherein the compound is a compound of Formula XIX-A:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , wherein the compound is a compound of Formula XXI-A:
or a pharmaceutically acceptable salt thereof.
25. A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or 2 .
26. The composition of claim 25 wherein the composition is a liquid, solid, semi-solid, gel, or an aerosol form.
27. The compound of claim 2 , wherein the compound is a compound of Formula XIX-B:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 2 , wherein the compound is a compound of Formula XXI-B:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 29 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 31 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
33. The compound of claim 31 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 2 wherein the compound is:
or a pharmaceutically acceptable salt thereof.