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 IIa:
or a pharmaceutically acceptable salt thereof
wherein,
Y is selected from the group consisting of:
Z is selected from the group consisting of 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 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; and
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 hydroxyl;
wherein the disease mediated by HDAC1 and/or HDAC2 is selected from the group consisting of sickle-cell anemia, beta-thalassemia, lung cancer, colon cancer, prostate cancer, breast cancer, glioma, glioblastoma, neuroblastoma, leukemia, lymphomas, and multiple myeloma.
2. The method of claim 1 , wherein Y is:
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 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 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.
9. The method of claim 1 , wherein the compound of Formula IIa has the structure of Formula IIIa:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the disease is sickle-cell disease or beta-thalassemia.
11. The method of claim 1 , wherein the disease is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, or lymphoma.
12. The method of claim 1 , wherein the leukemia is acute myelogenous leukemia or acute megakaryocytic leukemia.
13. A method for treating a disease mediated by HDAC1 and/or HDAC2 in a subject comprising administering to the subject a compound selected from:
ID
Structure
004
005
006
013
015
016
017
019
020
021
022
023
024
025
028
030
031
032
and pharmaceutically acceptable salts thereof;
wherein the disease mediated by HDAC1 and/or HDAC2 is selected from the group consisting of sickle-cell anemia, beta-thalassemia, lung cancer, colon cancer, prostate cancer breast cancer, glioma, glioblastoma, neuroblastoma, leukemia, lymphomas, and multiple myeloma.
14. The method of claim 13 , wherein the disease is sickle-cell disease or beta-thalassemia.
15. The method of claim 13 , wherein the disease is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, or lymphoma.
16. The method of claim 13 , wherein the leukemia is acute myelogenous leukemia or acute megakaryocytic leukemia.
17. The method of claim 1 , wherein the compound of Formula IIa is:
or a pharmaceutically acceptable salt thereof,
and the disease mediated by HDAC1 and/or HDAC2 is beta-thalassemia.