Histone deacetylase inhibitors and compositions and methods of use thereof

Abstract

Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, compositions thereof, and methods of their use.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 R 1  is selected from: H and C 1 -C 3  alkyl; 
 p is 0; and R 2  and R 3 , together with the carbon to which they are attached, form a 3 to 6-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2  alkyl, C 1 -C 2  haloalkyl or halo; or 
 p is 1; R 2  is H; and R 3  and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group, wherein said cyclopropyl group is optionally substituted with one or two halo groups; 
 R 5  is C 0 -C 3  alkylene; 
 R 6  is selected from: H, C 1 -C 3  alkyl, and C 1 -C 3  haloalkyl; and 
 R 7  is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted on the aromatic moiety with one to five substituents each independently selected from: C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 4 alkoxy, amino, cyano, halo, and hydroxyl; or 
 R 6  and R 7 , together with the nitrogen atom to which they are both attached, form a 5, 6, or 7-membered heteromonocyclic group, or a 6, 7, 8, 9, or 10-membered heterobicyclic group, each of which is optionally substituted with one to five substituents each independently selected from: C 1 -C 4  alkoxy, C 1 -C 3  alkyl, C 1 -C 3  haloalkoxy, C 1 -C 3  haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein aryl, 3 or 4-membered cycloalkyl, and heteroaryl are optionally further substituted with one to five substituents each independently selected from: C 1 -C 3  alkoxy, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, cyano, and halo; 
 W is N or CR 8 ; X is N or CR 9 ; Y is N or CR 10 ; and Z is N or CR 11 ; provided not more than two of W, X, Y, and Z are N; and 
 R 8 , R 9 , R 10 and R 11  are each independently selected from: H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and halo. 
 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2  is H; and R 3  and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group, wherein said cyclopropyl group is optionally substituted with one or two halo groups. 
     
     
         4 . A compound according to  claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4 , together with the carbon atoms to which they are each attached, form a cyclopropyl group. 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 3 , together with the carbon to which they are attached, form a 3 to 6-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2  alkyl, C 1 -C 2  haloalkyl or halo. 
     
     
         7 . A compound according to  claim 6 , wherein R 2  and R 3 , together with the carbon to which they are attached, form a 3 or 4-membered cycloalkyl group, optionally substituted with one or two C 1 -C 2  alkyl, C 1 -C 2  haloalkyl or halo. 
     
     
         8 . A compound according to  claim 7 , wherein R 2  and R 3 , together with the carbon to which they are attached, form a 3 or 4-membered cycloalkyl group. 
     
     
         9 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 6  is selected from: H, C 1 -C 3  alkyl, and C 1 -C 3  haloalkyl; and   R 7  is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted on the aromatic moiety with one to five substituents each independently selected from: C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 4 alkoxy, amino, cyano, halo, and hydroxyl.   
     
     
         10 . A compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6  is selected from: H and C 1 -C 3  alkyl. 
     
     
         11 . A compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 7  is selected from: aryl, aryl-C 1 -C 4 -alkyl, heteroaryl, and heteroaryl-C 1 -C 4 -alkyl. 
     
     
         12 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  and R 7 , together with the nitrogen atom to which they are both attached, form a 5, 6, or 7-membered heteromonocyclic group, optionally substituted with one to five substituents each independently selected from: C 1 -C 4  alkoxy, C 1 -C 3  alkyl, C 1 -C 3  haloalkoxy, C 1 -C 3  haloalkyl, 3 or 4-membered cycloalkoxy, 3 or 4-membered cycloalkyl, 3 or 4-membered heterocycloalkyl, aryl, cyano, halo, and heteroaryl, wherein aryl, 3 or 4-membered cycloalkyl, and heteroaryl are optionally further substituted with one to five substituents each independently selected from: C 1 -C 3  alkoxy, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, cyano, and halo. 
     
     
         13 .- 25 . (canceled) 
     
     
         26 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
 N-(1-(5-Azaspiro[2.5]octan-5-ylmethyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-(2-Oxa-7-azaspiro[3.5]nonan-7-ylmethyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-(2-Oxa-5-azaspiro[3.4]octan-5-ylmethyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-(3-Azabicyclo[3.2.1]octan-3-ylmethyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-(6-Azaspiro[2.5]octan-6-ylmethyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   E1-(abs)-N-(1-((2-Cyclopropylpyrrolidin-1-yl)methyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   E2-(abs)-N-(1-((2-Cyclopropylpyrrolidin-1-yl)methyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-((3,3-Dimethylpiperidin-1-yl)methyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide formate;   N-(1-(5-Azaspiro[2.4]heptan-5-ylmethyl)cyclobutyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-(2-Oxa-5-azaspiro[3.4]octan-5-ylmethyl)cyclobutyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (2S)-2-Methyl-1-(((abs-1,2-trans)-2-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)cyclopropyl)methyl)pyrrolidin-1-ium formate; and   N-(1-((3,3-Dimethylpiperidin-1-yl)methyl)cyclopropyl)-3-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(1-((3,3-dimethylpiperidin-1-yl)methyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide; and   or a pharmaceutically acceptable salt thereof.   
     
     
         27 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         28 . A process for preparing a pharmaceutical composition comprising admixing a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         29 . A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A method for treating a condition or disorder responsive to inhibition of at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 29 , wherein said at least one histone deacetylase is HDAC-4. 
     
     
         32 . The method of  claim 29 , wherein said condition or disorder involves a neurodegenerative pathology. 
     
     
         33 . The method of  claim 29 , wherein said condition or disorder is Huntington's disease.