Heterocyclic compounds and uses thereof
Provided herein are compounds of Formula (I″) or (A″), pharmaceutical compositions comprising the compounds, and methods of use thereof. The compounds provided herein modulate kinase activity, including PI3 kinase activity, and are useful for treating diseases and conditions associated with kinase activity, including PI3 kinase activity.
1. A compound of Formula (I″):
wherein:
R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —COR 2 ;
B is hydrogen, alkyl, cycloalkyl, or aryl;
wherein R 2 is hydrogen;
R 1c is hydrogen, alkyl, alkenyl, or alkynyl;
R 2c is hydrogen, alkyl, alkenyl, or alkynyl;
W d is:
wherein
X 1 , X 2 and X 3 are each independently C, CR 13 , or N; and
R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, unsubstituted alkyl, or amino;
X is N;
wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halo, OH, alkoxy, NH 2 , NH(alkyl), N(alkyl) 2 , C(O)H, CO(alkyl), COOH, COO(alkyl), CONH 2 , CONH(alkyl), CON(alkyl) 2 , S(O)(alkyl), S(O) 2 (alkyl), cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
wherein each cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more halo, alkyl, alkenyl, alkynyl, OH, alkoxy, oxo, NH 2 , NH(alkyl), N(alkyl) 2 , C(O)H, CO(alkyl), COOH, COO(alkyl), CONH 2 , CONH(alkyl), CON(alkyl) 2 , S(O)(alkyl), or S(O) 2 (alkyl);
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or mixture of stereoisomers thereof.
2. The compound of claim 1 , wherein the compound is a compound of Formula (I′):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or mixture of stereoisomers thereof.
3. The compound of claim 2 , wherein the compound is a compound of Formula (I):
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
4. The compound of claim 1 , wherein
R 1 is branched alkyl, 6-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl,
cyclopropyl, or methyl,
wherein R A is OH, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
x is 1, 2, 3, 4, 5, or 6; and
R 7 , R 8 , and R 9 are each, independently, hydrogen, OH, alkoxy, NH 2 , NH(alkyl), N(alkyl) 2 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
5. The compound of claim 4 , wherein
R 1 is: methyl,
6. The compound of claim 1 , wherein R 1 is a 5- to 10-membered heteroaryl.
7. The compound of claim 6 , wherein R 1 is a 6-membered heteroaryl.
8. The compound of claim 7 , wherein R 1 is a pyridinyl or pyrimidinyl.
9. The compound of claim 6 , wherein R 1 is a 5-membered heteroaryl.
10. The compound of claim 9 , wherein R 1 is a thiazolyl, pyrazolyl, or imidazolyl.
11. The compound of claim 6 , wherein the heteroaryl is substituted with one or more alkyl.
12. The compound of claim 1 , wherein B is aryl or cycloalkyl.
13. The compound of claim 12 , wherein B is aryl or 3- to 6-membered cycloalkyl.
14. The compound of claim 13 , wherein B is phenyl substituted with 0, 1, 2, or 3 occurrence(s) of R Z , wherein each instance of R Z is independently halo or alkyl.
15. The compound of claim 14 , wherein B is unsubstituted phenyl.
16. The compound of claim 13 , wherein B is
17. The compound of claim 1 , wherein W d is
18. The compound of claim 1 , wherein W d is
wherein one of X 1 and X 2 is C and the other is N.
19. The compound of claim 1 , wherein W d is
wherein X 3 is N or CR 13 .
20. The compound of claim 1 , wherein W d is
wherein one of X 1 and X 2 is N and the other is CR 13 .
21. The compound of claim 1 , wherein the compound is a compound of formula IV, VII, VIII, X, or XI:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or mixture of stereoisomers thereof.
22. The compound of claim 1 , wherein the compound is in an (S)-stereochemical configuration.
23. The compound of claim 1 , wherein the compound is the S-enantiomer having an enantiomeric purity greater than 75%.
24. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient, diluent, or carrier.
25. A compound, which is
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
26. A compound, which is
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.