Selective HDAC3 inhibitors
Provided herein are HDAC3 inhibitors, as well as methods of treatment comprising administering these compounds to a subject in need thereof.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein
A is bicyclic heteroaryl or bicyclic heterocycloalkyl;
R 1 and R 2 are each independently selected from H or halo;
R 3 is H, heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl, wherein the heterocycloalkyl or C 1-6 -alkyl-heterocycloalkyl groups are optionally substituted;
R 4 and R 5 are each independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cyclo alkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 6 R 7 , O—C 1-6 -alkyl-OR 8 , C 1-6 -alkyl-OR 8 , aryl, C 1-6 -alkyl-aryl, heteroaryl, C 1-6 -alkyl-heteroaryl, C(O)N(R 6 )-heteroaryl, C(O)N(R 6 )-heterocycloalkyl, C(O)N(R 6 )-aryl, C(O)—NR 6 R 7 , C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 -heteroaryl, CO 2 -heterocycloalkyl, CO 2 -aryl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally substituted;
R 6 and R 7 are each independently selected from H, C 1-6 -alkyl, C 1-6 -alkyl-OR 8 , CO 2 R 8 , or C 1 -C 6 -alkyl-aryl; and
R 8 is H or C 1-6 -alkyl.
2. The compound of claim 1 ,
wherein
the heterocycloalkyl or C 1-6 -alkyl-heterocycloalkyl groups of R 3 are optionally substituted with C 1-4 -alkyl; and
the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups of R 4 and R 5 are optionally substituted with C 1-4 -alkyl, CO 2 R 8 , C(O)R 8 , or C 1-6 -alkyl-OR 8 .
3. The compound of claim 1 ,
wherein
A is a bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of
4. The compound of claim 1 ,
wherein
A is a bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of
5. The compound of claim 1 , wherein R 1 is halo.
6. The compound of claim 1 , wherein R 1 is fluoro.
7. The compound of claim 1 , wherein R 2 is halo.
8. The compound of claim 1 , wherein R 2 is chloro.
9. The compound of claim 1 , wherein R 3 is heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl wherein the heterocycloalkyl or C 1-6 -alkyl-heterocycloalkyl groups are optionally substituted with C 1-4 -alkyl.
10. The compound of claim 1 , wherein R 3 is piperazinyl or piperazinyl-CH 3 .
11. The compound of claim 1 , wherein R 3 is CH 2 CH 2 -morpholinyl.
12. The compound of claim 1 ,
wherein
R 4 is independently selected from H, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl.
13. The compound of claim 1 , wherein R 4 is H or C 3-6 -cycloalkyl.
14. The compound of claim 1 , wherein R 4 is H.
15. The compound of claim 1 , wherein R 4 is cyclopropyl.
16. The compound of claim 1 , wherein R 5 is H.
17. The compound of claim 1 , of Formula III:
or a pharmaceutically acceptable salt thereof,
wherein
A is bicyclic heteroaryl or bicyclic heterocycloalkyl;
R 1 and R 2 are halo;
R 3 is H, heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl;
R 4 and R 5 are each independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cyclo alkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, NR 6 R 7 , O—C 1-6 -alkyl-OR 8 , C 1-6 -alkyl-OR 8 , aryl, C 1-6 -alkyl-aryl, heteroaryl, C 1-6 -alkyl-heteroaryl, C(O)N(R 6 )-heteroaryl, C(O)N(R 6 )-heterocycloalkyl, C(O)N(R 6 )-aryl, C(O)—NR 6 R 7 , C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 -heteroaryl, CO 2 -heterocycloalkyl, CO 2 -aryl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally substituted;
R 6 and R 7 are each independently selected from H, C 1-6 -alkyl, C 1-6 -alkyl-OR 8 , CO 2 R 8 , or C 1 -C 6 -alkyl-aryl; and
R 8 is H or C 1-6 -alkyl.
18. The compound of claim 17 , wherein R 1 is chloro and R 2 is fluoro.
19. The compound of claim 17 , wherein R 3 is H, R 4 is H, and R 5 is H.
20. The compound of claim 1 , selected from the following:
or pharmaceutically acceptable salts thereof.
21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
22. A method of inhibiting the activity of HDAC3 in a subject in need thereof, comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
23. A method of treating a disease mediated by HDAC3 in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 21 .