Piperidine derivatives as HDAC1/2 inhibitors
Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with HDAC1 and/or HDAC2 activity.
1. A method for treating a disease mediated by HDAC1 and/or HDAC2 in a subject comprising administering to the subject a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein,
X 1 is CR 7 or N;
X 2 is CH or N;
wherein X 1 and X 2 are each N, or X 1 and X 2 are each CH;
Y is selected from the group consisting of:
Z is selected from the group consisting of H, C 1 -C 6 -alkyl, C 6 -aryl, C(O)NR 4 R 5 , C(O)OR 6 , C(O)C 1 -C 6 -alkyl, C(O)C 0 -C 6 -alkyl-C 6 -aryl, C(O)—C 3 -C 6 -cycloalkyl, C(O)—C 2 -C 6 -heterocyclyl, and C(O)C 0-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, C 1 -C 6 -haloalkyl, hydroxy, or C 1 -C 6 -alkoxy;
R a and R b are H, or R a and R b together form a fused C 6 -aryl;
R 1 is selected from the group consisting of H and C 1 -C 6 -alkyl;
R 2 is selected from the group consisting of H, C 1 -C 6 -alkyl, and C 6 -aryl;
R 3 is selected from the group consisting of H, C 1 -C 6 -alkyl, and C 6 -aryl;
or R 2 and R 3 together form a C 2 -C 6 -heterocyclyl;
R 4 is selected from the group consisting of H, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-OH, and C 1 -C 6 —NH 2 ;
R 5 is C 1 -C 6 -alkyl;
or R 4 and R 5 together form a C 2 -C 6 -heterocyclyl, wherein heterocyclyl is optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, C 1 -C 6 -haloalkyl, hydroxy, or C 1 -C 6 -alkoxy;
R 6 is selected from the group consisting of C 1 -C 6 -alkyl and C 0 -C 6 -alkyl-C 6 -aryl, wherein aryl is optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, or hydroxy; and
R 7 is H;
wherein the disease mediated by HDAC1 and/or HDAC2 is selected from the group consisting of sickle-cell disease, beta-thalassemia, lung cancer, colon cancer, neuroblastoma, leukemia, and lymphoma.
2. The method of claim 1 , having the structure of Formula II:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein Z is selected from the group consisting of C(O)NR 4 R 5 , C(O)OR 6 , C(O)—C 3 -C 6 -cycloalkyl, C(O)—C 2 -C 6 -heterocyclyl, and C(O)C 0-6 -alkyl-heteroaryl, wherein heteroaryl, cycloalkyl, or heterocyclyl are optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, or hydroxy; and
R 6 is C 6 -aryl.
4. The method of claim 1 , wherein Z is selected from the group consisting of H, C 1 -C 6 -alkyl, and C 6 -aryl.
5. The method of claim 1 , wherein R 1 is H.
6. The method of claim 1 , wherein R 2 is H.
7. The method of claim 1 , wherein R 3 is H, methyl, ethyl, isopropyl, or phenyl.
8. The method of claim 1 , wherein the compound of Formula I is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein R 2 is H.
10. The method of claim 8 , wherein R 3 is H, methyl, or isopropyl.
11. The method of claim 8 , wherein R 4 is H and R 5 is C 1 -C 6 -alkyl.
12. The method of claim 8 , wherein R 4 and R 5 together form a heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl are optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, or hydroxy.
13. The method of claim 8 , wherein X 1 and X 2 are N;
R 1 is H;
R 2 is H;
R 3 is H or C 1 -C 4 -alkyl; and
R 4 and R 5 together form a heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl are optionally substituted by 1 or 2 of C 1 -C 6 -alkyl, halo, or hydroxy.
14. The method of claim 8 wherein the compound of Formula III is selected from:
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or pharmaceutically acceptable salts thereof.
15. The method of claim 8 wherein the compound of Formula III is selected from:
001
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or pharmaceutically acceptable salts thereof.
16. The method of claim 1 , wherein the hemoglobinopathy is sickle-cell disease or beta-thalassemia.
17. The method of claim 1 , wherein the disease is lung cancer, colon cancer, neuroblastoma, leukemia, or lymphoma.
18. The method of claim 1 , wherein the disease is neuroblastoma.
19. The method of claim 1 , wherein the subject is a human.