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 II:
or a pharmaceutically acceptable salt thereof,
wherein
A is bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of
R 1 is halo;
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;
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 -cycloalkyl, 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 with C 1-4 -alkyl, CO 2 R 8 , C(O)R 8 , or C 1-6 -alkyl-OR 8 ;
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 R 3 is piperazinyl or piperazinyl-CH 3 .
3. The compound claim 1 , wherein R 3 is CH 2 CH 2 -morpholinyl.
4. 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.
5. The compound claim 4 , wherein R 4 is H or C 3-6 -cycloalkyl.
6. The compound of claim 5 , wherein R 4 is cyclopropyl.
7. A compound of Formula IV:
or a pharmaceutically acceptable salt thereof,
wherein
A is bicyclic heteroaryl or bicyclic heterocycloalkyl selected from the group consisting of
R 1 is H or halo;
R 3 is heterocycloalkyl, or C 1-6 -alkyl-heterocycloalkyl;
R 4 is selected from C 3-6 -cycloalkyl, C 1-6 -alkyl-C 3-6 -cycloalkyl, heterocycloalkyl, C 1-6 -alkyl-heterocycloalkyl, aryl, C 1-6 -alkyl-aryl, heteroaryl, C 1-6 -alkyl-heteroaryl wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally substituted with C 1-4 -alkyl, CO 2 R 8 , C(O)R 8 , or C 1-6 -alkyl-OR 8 ; and
R 8 is H or C 1-6 -alkyl.
8. The compound of claim 7 , wherein R 1 is halo.
9. The compound of claim 7 , wherein R 3 is heterocycloalkyl.
10. The compound of claim 7 , wherein R 4 is cycloalkyl.
11. The compound of claim 1 , selected from the following:
or pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
13. The compound of claim 1 , wherein R 1 is fluoro.
14. The compound claim 7 , wherein R 1 is fluoro.
15. The compound of claim 7 , wherein R 3 is piperazinyl.
16. The compound of claim 7 , wherein R 4 is cyclopropyl.
17. The compound of claim 7 , which is:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of claim 7 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.