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: 
         W is N or CR 5 ; X is N or CR 6 ; Y is N or CR 7 ; and Z is N or CR 8 ; provided not more than two of W, X, Y, and Z are N; 
         R 1  is selected from H and C 1 -C 3  alkyl; 
         R 2  is C 2 -C 3  alkylene optionally substituted with C 1 -C 2  haloalkyl or 3 or 4-membered cycloalkyl; 
         R 3  and R 4 , together with the nitrogen atom to which they are attached, form:
 a 4, 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 3  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, carboxy, aryl, cyano, halo, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents each independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, and halo, 
 
         provided that if R 3  and R 4 , together with the nitrogen atom to which they are attached, form a 5 or 6-membered heteromonocyclic group, then:
 i) R 2  is C 2 -C 3  alkylene substituted with C 1 -C 2  haloalkyl or 3 or 4-membered cycloalkyl, or 
 ii) R 8  is halo or C 1 -C 3  alkyl, or 
 iii) the 5 or 6-membered heteromonocyclic group is substituted with one to five substituents each independently selected from: C 1 -C 3  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, carboxy, aryl, cyano, halo, and heteroaryl, wherein aryl and heteroaryl are optionally further substituted with one to five substituents each independently selected from C 1 -C 3 alkyl, C 1 -C 3  haloalkyl, and halo; and 
 
         R 5 , R 6 , R 7  and R 8  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 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 2 -C 3  alkylene optionally substituted with 3 or 4-membered cycloalkyl. 
     
     
         4 . A compound according to  claim 3 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is H. 
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula V: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 2 -C 3  alkylene optionally substituted with 3 or 4-membered cycloalkyl. 
     
     
         8 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula VI: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H. 
     
     
         10 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is H. 
     
     
         11 . A compound according to  claim 1 , or
 a pharmaceutically acceptable salt thereof, wherein R 8  is selected from H, halo, and methyl.   
     
     
         12 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from H and methyl. 
     
     
         13 - 40 . (canceled) 
     
     
         41 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
 (2S)-2-Methyl-1-((R)-2-(3-methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propyl)pyrrolidin-1-ium formate;   N-(2-(3-Azabicyclo[3.2.1]octan-3-yl)ethyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(Isoindolin-2-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-((2R)-1-(3-Azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (S)—N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(3,4-Dihydroisoquinolin-2(1H)-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(3-Phenylazetidin-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   D1: N—((R)-1-((abs)-3-(Difluoromethoxy)piperidin-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   D2: N—((R)-1-((abs)-3-(Difluoromethoxy)piperidin-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(5-Azaspiro[2.5]octan-5-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(6-Azaspiro[2.5]octan-6-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(Azepan-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(1-Azaspiro [3.3]heptan-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (R)—N-(1-(5-Azaspiro[2.4]heptan-5-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N—((R)-1-(3-Azabicyclo[3.2.1]octan-3-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   2-((R)-2-(4-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propyl)octahydrocyclopenta[c]pyrrol-2-ium formate;   (R)—N-(1-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-((2R)-1-(3-Azabicyclo[3.2.0]heptan-3-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   D1: N—((R)-1-((abs-1,5-cis)-6-Azabicyclo[3.2.0]heptan-6-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   D2: N—((R)-1-((abs-1,5-cis)-6-Azabicyclo[3.2.0]heptan-6-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-((2R)-1-(6,6-Dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   (2S)-1-((R)-2-(3-Fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propyl)-2-methylpyrrolidin-1-ium formate;   N—((R)-1-((S)-2-Methylpyrrolidin-1-yl)propan-2-yl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide;   3-methyl-N—((R)-1-((S)-2-methylpyrrolidin-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide;   N-((2R)-1-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide; and   3-fluoro-N—((R)-1-((S)-2-methylpyrrolidin-1-yl)propan-2-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide.   
     
     
         42 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         43 . 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. 
     
     
         44 . 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. 
     
     
         45 . 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. 
     
     
         46 . The method of  claim 44 , wherein said at least one histone deacetylase is HDAC-4. 
     
     
         47 . The method of  claim 44 , wherein said condition or disorder involves a neurodegenerative pathology. 
     
     
         48 . The method of  claim 44 , wherein said condition or disorder is Huntington's disease.