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 (XXV):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein
W b 1 and W b 2 are each independently CR 3 , S, O, N or NR 13 , wherein at least one of W b 1 and W b 2 is CR 3 , N or NR 13 ;
p is 0, 1, 2 or 3;
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, heterocyclylalkyl, aryl or heteroaryl, each of which is substituted with 0-4 occurrences of R 2 ;
X is absent or —(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;
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;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, heteroaryl, aryl, hydroxyl, or nitro;
each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl or heteroalkyl;
W d is selected from:
wherein each R b is independently hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, amino, heteroalkyl, or heterocyclyl;
each R 12 is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, phosphate, urea, carboxylic acid, carbonate, oxo, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety; and
each R 13 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl or heteroalkyl.
2. The compound of claim 1 , wherein W b 5 is CR 8 and R 8 is hydrogen.
3. The compound of claim 1 , wherein p is 1 and R 3 is hydrogen.
4. The compound of claim 1 , wherein the compound of Formula (XXV) has a structure of formula:
5. The compound of claim 1 , wherein the compound of Formula (XXV) has a structure of formula:
6. The compound of claim 1 , wherein B is aryl substituted with 0-4 occurrences of R 2 .
7. The compound of claim 6 , wherein B is phenyl substituted with 0 or 1 occurrences of R 2 .
8. The compound of claim 1 , wherein X is —(CH(R 9 )) z —, z is 1, and R 9 is C 1-10 alkyl.
9. The compound of claim 1 , wherein Y is —N(R 9 )— and R 9 is hydrogen.
10. The compound of claim 1 , wherein X—Y is (S)—CH(CH 3 )—NH—.
11. The compound of claim 1 , wherein W d is
12. The compound of claim 1 , wherein W d is selected from:
13. The compound of claim 12 , wherein R 12 is hydrogen, alkyl, halo, cyano, amino or amido.
14. A compound of Formula (XII):
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 aryl or heteroaryl substituted by 0-1 occurrences of R 3 and 0-3 occurrences 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 0-4 R 2 ;
R 2 is 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 —(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 ) z —;
each z is independently an integer of 1, 2, 3, or 4;
R 3 is alkyl, cycloalkyl, heterocyclyl, haloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro; wherein each of the above substituents can be substituted with 0, 1, 2, or 3 R 17 ;
each R 5 is independently alkyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;
each R 9 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; and
W d is
wherein one of X 5 and X 2 is N and one of X 5 and X 2 is C;
X 3 and X 4 are each independently CR 13 or N;
X 2 and X 3 are not both N; and
each R 10 , R 11 , R 12 , R 13 , and R 17 is 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.
15. The compound of claim 14 , wherein Cy is phenyl substituted with 1 occurrence of R 3 and 0 occurrences of R 5 .
16. The compound of claim 14 , wherein Cy is 5-membered heteroaryl substituted with 0-1 occurrences of R 3 and 0-3 occurrences of R 5 .
17. The compound of claim 14 , wherein the compound of Formula (XII) has the structure of formula:
18. The compound of claim 14 , wherein the compound of Formula (XII) has the structure of Formula:
19. The compound of claim 14 , wherein R 3 is halo or heteroaryl.
20. The compound of claim 14 , wherein X is —(CH(R 9 )) z —, z is 1, and R 9 is C 1-10 alkyl.
21. The compound of claim 14 , wherein Y is —N(R 9 )— and R 9 is hydrogen.
22. The compound of claim 14 , wherein X—Y is (S)—CH(CH 3 )—NH—.
23. The compound of claim 14 , wherein B is phenyl substituted with 0 or 1 occurrences of R 2 .
24. The compound of claim 14 , wherein B is cycloalkyl substituted with 0-4 occurrences of R 2 .
25. The compound of claim 14 , wherein R 10 is hydrogen or alkyl, R 11 is hydrogen, and R 12 is hydrogen or halo.
26. The compound of claim 14 , wherein W d is selected from:
27. The compound of claim 1 , which is
or a pharmaceutical acceptable form thereof.
28. The compound of claim 14 , which is
or a pharmaceutical acceptable form thereof.
29. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.
30. A pharmaceutical composition comprising a compound according to claim 14 and one or more pharmaceutically acceptable excipients.