Substituted piperazines as selective 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 - 21 . (canceled) 
     
     
         22 . A method for treating sickle cell disease, beta thalassemia, myelodysplastic syndrome, acute myelogenous leukemia, neuroblastoma, or acute megakaryocytic leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         (a) X is C(H), Y is C(H), and Z is N; 
         R 5  is H or phenyl; and 
         R 6  is H; or 
         (b) X is C(H), Y is C(H), and Z is N; 
         R 5  is 1-furanyl; and 
         R 6  is C 1-4  alkyl, wherein the C 1-4  alkyl group is optionally, independently substituted one or more times with halo, —CN, —NO 2 , —C 1 -C 6  alkoxy, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, and C(O)—C 1 -C 6  alkyl; or 
         (c) X is C(H), Y is N, and Z is C(H); 
         R 5  is H, 1-furanyl, 2-furanyl, pyridinyl, or thiophenyl; and 
         R 6  is H; or 
         (d) X is N, Y is C(H), and Z is C(H); 
         R 5  is H, 1-furanyl, 2-furanyl, pyridinyl, or phenyl, wherein phenyl is optionally substituted with halogen; and 
         R 6  is H. 
       
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 22 , wherein X is C(H), Y is C(H), and Z is N; R 5  is 1-furanyl; and R 6  is CH 3 . 
     
     
         24 . The method of  claim 22 , wherein X is C(H), Y is C(H), and Z is N; R 5  is H; and R 6  is H. 
     
     
         25 . The method of  claim 22 , wherein the compound of Formula III is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of claim  12 , wherein the method treats sickle cell disease. 
     
     
         27 . A method for treating sickle cell disease, beta thalassemia, myelodysplastic syndrome, acute myelogenous leukemia, neuroblastoma, or acute megakaryocytic leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of compound of Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein 
 R 7  is furanyl, pyridinyl, or thiophenyl. 
 
     
     
         28 . The method of  claim 27 , wherein the compound of Formula IV is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 27 , wherein the method treats sickle cell disease. 
     
     
         30 . A method for treating lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, lymphoma, or neuroblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         (a) X is C(H), Y is C(H), and Z is N; 
         R 5  is H or phenyl; and 
         R 6  is H; or 
         (b) X is C(H), Y is C(H), and Z is N; 
         R 5  is 1-furanyl; and 
         R 6  is 01-4 alkyl, wherein the C 1-4  alkyl group is optionally, independently substituted one or more times with halo, —CN, —NO 2 , —C 1 -C 6  alkoxy, —C 1 -C 6  alkyl, —C 1 -C 6  haloalkyl, and C(O)—C 1 -C 6  alkyl; or 
         (c) X is C(H), Y is N, and Z is C(H); 
         R 5  is H, 1-furanyl, 2-furanyl, pyridinyl, or thiophenyl; and 
         R 6  is H; or 
         (d) X is N, Y is C(H), and Z is C(H); 
         R 5  is H, 1-furanyl, 2-furanyl, pyridinyl, or phenyl, wherein phenyl is optionally substituted with halogen; and 
         R 6  is H. 
       
     
     
         31 . The method of  claim 30 , wherein X is C(H), Y is C(H), and Z is N; R 5  is 1-furanyl; and R 6  is CH 3 . 
     
     
         32 . The method of  claim 30 , wherein X is C(H), Y is C(H), and Z is N; R 5  is H; and R 6  is H. 
     
     
         33 . The method of  claim 30 , wherein the compound of Formula III is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 30 , wherein the cancer is neuroblastoma. 
     
     
         35 . The method of  claim 30 , wherein the leukemia is acute myelogenous leukemia or acute megakaryocytic leukemia. 
     
     
         36 . A method for treating lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, lymphoma, or neuroblastoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of compound of Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         R 7  is furanyl, pyridinyl, or thiophenyl. 
       
     
     
         37 . The new of  claim 36 , wherein the compound of Formula IV is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method of  claim 36 , wherein the cancer is neuroblastoma. 
     
     
         39 . The method of  claim 36 , wherein the leukemia is acute myelogenous leukemia or acute megakaryocytic leukemia.