Selective HDAC1 and HDAC2 inhibitors
Provided herein are compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with HDAC activity, particularly diseases or disorders that involve activity of HDAC1 and/or HDAC2. Such diseases include cancer, sickle-cell anemia, beta-thalassemia, and HIV.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof;
wherein
R 1 and R 2 are independently H, mono-, bi-, or tri- cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted;
or R 1 and R 2 are linked together to form a group of Formula:
R 3 and R 4 are 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 6 , O—C 1-6 -alkyl-OR 7 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted;
R 5 is H, C 1-6 -alkyl, CO 2 R 7 or C 1-6 -alkyl-OR 7 ;
R 6 is H, C 1-6 -alkyl, CO 2 R 7 or C 1-6 -alkyl-OR 7 ;
R 7 is H or C 1-6 -alkyl;
X 1 , X 2 , and X 3 are each independently CH, N, or S, wherein at least one of X 1 or X 2 is N or S;
a line denotes an optionally double bond;
p is 0 or 1.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is mono-, bi-, or tri-cyclic aryl or heteroaryl, wherein the mono-, bi-, or tri-cyclic aryl or heteroaryl is optionally substituted with halo, C 1-4 -alkyl, CO 2 R 7 , C(O)R 7 , or C 1-6 -alkyl-OR 7 ;
R 2 is H;
or R 1 and R 2 are linked together to form the following fused ring:
R 3 and R 4 are 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 5 R 6 , O—C 1-6 -alkyl-OR 7 , aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycloalkyl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, or C(O)—C 1-6 -alkyl-heterocycloalkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
R 1 is monocyclic aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with halo;
R 2 is H;
or R 1 and R 2 are linked together to form the following fused ring:
R 3 is H; and
R 4 is heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with C 1-4 -alkyl, CO 2 R 7 , C(O)R 7 , C 1-6 -alkyl-OR 7 .
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
p is 1; X 1 is N; and X 2 and X 3 are CH;
p is 1; X 1 and X 2 are CH; and X 3 is N;
p is 1; X 1 and X 3 are CH; and X 2 is N;
p is 0; X 1 is S; and X 2 and X 3 are CH; or
p is 0; X 1 and X 2 are CH; and X 3 is S.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or thienyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocycloalkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is piperazinyl.
11. The compound of claim 1 , wherein the compound of Formula II is:
or a pharmaceutically acceptable salt thereof.