Piperidine derivatives as hdac1/2 inhibitors

Abstract

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 compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein,
 X 1  is CR 7  or N; 
 X 2  is CH or N; 
 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 -C 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 selected from the group consisting of H, C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl. 
         
       
     
     
         2 . The compound of  claim 1 , having the structure of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein X 1  and X 2  are each N, or X 1  and X 2  are each CH. 
     
     
         4 . The compound of  claim 1 , wherein Y is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound 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 -C 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. 
 
     
     
         6 . The compound of  claim 1 , wherein Z is selected from the group consisting of H, C 1 -C 6 -alkyl, and C 6 -aryl. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         8 . The compound of  claim 1 , wherein R 2  is H. 
     
     
         9 . The compound of  claim 1 , wherein R 3  is H, methyl, ethyl, isopropyl, or phenyl. 
     
     
         10 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A method for inhibiting the activity of HDAC1 and/or HDAC2 in a subject, comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         21 - 29 . (canceled) 
     
     
         30 . A method for treating a disease or disorder associated with GATA binding protein 2 (Gata2) deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically salt thereof. 
     
     
         31 . A method for increasing GATA binding protein 2 (Gata2) expression in a cell comprising contacting the cell with a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 31 , wherein Gata2 overexpression induces HbG (gamma globin). 
     
     
         33 . A method for inducing HbG (gamma globin) expression in a subject, comprising administering to the subject a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of  claim 33 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in a dosage resulting in about a 2-fold to about a 20-fold increase in HbG in the subject.