Substituted hydroxamic acids and uses thereof

Abstract

This invention provides compounds of formula (I): wherein X 1 , X 2 , R 1a , R 1b , R 1c , R 1d , n, and G have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.

What is claimed is: 
     
         1 - 32 . (canceled) 
     
     
         33 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         X 1  is CH or N; 
         X 2  is CH or N; 
         n is 2; 
         R 1a  is hydrogen, fluoro, C 1-4  alkyl, or C 1-3  fluoroalkyl; 
         R 1b  is hydrogen, fluoro, C 1-4  alkyl, or C 1-3  fluoroalkyl; or R 1a  and R 1b  are taken together to form an oxo group; 
         each occurrence of R 1c  is independently hydrogen, fluoro, C 1-4  alkyl, or C 1-3  fluoroalkyl; 
         each occurrence of R 1d  is independently hydrogen, fluoro, C 1-4  alkyl, or C 1-3  fluoroalkyl; 
         G is —R 3 , —V 1 —R 3 , —V 1 -L 1 -R 3 , -L 2 -V 1 —R 3 , -L 2 -V 2 —R 3 , or -L 1 -R 3 ; or when R 1a  and R 1b  are taken together to form an oxo group, G is —R 3 , or -L 1 -R 3 ; 
         L 1  is an unsubstituted or substituted C 1-3  alkylene chain; 
         L 2  is an unsubstituted or substituted C 2-3  alkylene chain; 
         V 1  is —C(O)—, —C(S)—, —C(O)—CR A ═CR A —, —C(O)—N(R 4a )—, —C(O)—O—, or —S(O) 2 —; 
         V 2  is —N(R 4a )—, —N(R 4a )—C(O)—, —SO 2 —N(R 4a )—, —N(R 4a )—SO 2 —, —O—, —S—, —S(O)—, 
         N(R 4a )—C(O)—N(R 4a )—, —N(R 4a )—C(O)—O—, —O—C(O)—N(R 4a )—, or —N(R 4a )—SO 2 —N(R 4a )—; 
         R 3  is unsubstituted or substituted C 1-6  aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each occurrence of R A  is independently hydrogen, fluoro, or unsubstituted or substituted C 1-4  aliphatic; and 
         each occurrence of R 4a  is independently hydrogen, or unsubstituted or substituted C 1-4  aliphatic. 
       
     
     
         34 . The compound of  claim 33 , wherein:
 X 1  is CH and X 2  is N; or X 1  is N and X 2  is CH.   
     
     
         35 . The compound of  claim 33 , wherein:
 G is —V 1 —R 3 , or —V 1 -L 1 -R 3 ; and   V 1  is —C(O)—.   
     
     
         36 . The compound of  claim 33 , wherein:
 R 1a  is hydrogen, fluoro, or methyl;   R 1b  is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R 1a  and R 1b  are taken together to form an oxo group;   each occurrence of R 1c  is independently hydrogen, fluoro, or methyl; and   each occurrence of R 1d  is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.   
     
     
         37 . The compound of  claim 33 , wherein:
 each substitutable carbon chain atom in R 3  is unsubstituted or substituted with 1-2 occurrences of —R 5dd ;   each substitutable saturated ring carbon atom in R 3  is unsubstituted or substituted with ═O, ═S, ═C(R 5 ) 2 , ═N—N(R 4 ) 2 , ═N—OR 5 , ═N—NHC(O)R 5 , ═N—NHCO 2 R 6 , ═N—NHSO 2 R 6 , ═N—R 5  or —R 5a ;   each substitutable unsaturated ring carbon atom in R 3  is unsubstituted or is substituted with —R 5a ;   each substitutable ring nitrogen atom in R 3  is unsubstituted or substituted with —R 9b ;
 each R 5a  is independently halogen, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —P(O)(R 5 ) 2 , —P(O)(OR 5 ) 2 , unsubstituted or substituted C 1-6  aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two adjacent R 5a , taken together with the intervening ring atoms, form an unsubstituted or substituted fused aromatic ring or an unsubstituted or substituted non-aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 5dd  is independently fluoro, hydroxy, —O(C 1-3  alkyl), cyano, —N(R 4 ) 2 , —C(O)(C 1-3  alkyl), —CO 2 H, —C(O)NH 2 , —N—C(O)—(C 1-3  alkyl), —N—C(O)—O—(C 1-3  alkyl), or —C(O)NH(C 1-3  alkyl). 
 each R 4  is independently hydrogen, unsubstituted or substituted C 1-6  aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form an unsubstituted or substituted 5- to 6-membered heteroaryl or an unsubstituted or substituted 4- to 8-membered heterocyclyl having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur; 
 each R 5  is independently hydrogen, unsubstituted or substituted C 1-6  aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
 each R 6  is independently unsubstituted or substituted C 1-6  aliphatic, or unsubstituted or substituted 6-10-membered aryl; 
 each R 9b  is independently —C(O)R 5 , —C(O)N(R 4 ) 2 , —CO 2 R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , unsubstituted C 1-4  aliphatic, or C 1-4  aliphatic substituted with 1-2 occurrences of R 7  or R 8 ; 
 each R 7  is independently unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 
 each R 8  is independently halogen, —OH, —O(C 1-3  alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3  alkyl), —CO 2 H, —CO 2 (C 1-3  alkyl), —C(O)NH 2 , or —C(O)NH(C 1-3  alkyl). 
   
     
     
         38 . The compound of  claim 37 , wherein:
 each substitutable saturated ring carbon atom in R 3  is unsubstituted or substituted with —R 5a ;   the total number of R 5a  substituents is p;
 p is 1-2; 
 each R 5a  is independently halogen, cyano, hydroxy, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, —O—C 1-3  fluoroalkyl, —NHC(O)C 1-3  alkyl, —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3 alkyl, 
   —NHS(O) 2 C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ,   6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and
 each occurrence of R 7a  is independently halogen, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, —O—C 1-3  fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         39 . The compound of  claim 37 , represented by formula (I-e): 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound of  claim 39 , wherein:
 R 1a  is hydrogen, fluoro, or methyl;   R 1b  is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R 1a  and R 1b  are taken together to form an oxo group;   each occurrence of R 1c  independently hydrogen, fluoro, or methyl; and   each occurrence of R 1d  is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.   
     
     
         41 . The compound of  claim 40 , wherein
 R 1a  and R 1b  are not taken together to form an oxo group;   G is —V 1 —R 3 , or —V 1 -L 1 -R 3 ;   V 1  is —C(O)—; and   L 1  is —CH 2 —.   
     
     
         42 . The compound of  claim 41 , wherein:
 R 1a  is hydrogen;   R 1b  K is hydrogen, fluoro, or methyl;   R 1c  is hydrogen; and   each occurrence of R 1d  is independently hydrogen, fluoro, or methyl.   
     
     
         43 . The compound of  claim 40 , wherein:
 each substitutable saturated ring carbon atom in R 3  is unsubstituted or substituted with —R 5a ;   the total number of R 5a  substituents is p;
 p is 1-2; 
 each R 5a  is independently halogen, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, —O—C 1-3  fluoroalkyl, —NHC(O)C 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, —NHS(O) 2 C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and 
 each occurrence of R 7a  is independently halogen, C 1-4  alkyl, C 1-3 -fluoroalkyl, —O—C 1-3  alkyl, —O—C 1-3 -fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         44 . The compound of  claim 37 , represented by formula (I-f): 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 44 , wherein:
 R 1a  is hydrogen, fluoro, or methyl;   R 1b  is hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; or R 1a  and R 1b  are taken together to form an oxo group;   each occurrence of R 1c  is independently hydrogen, fluoro, or methyl; and   each occurrence of R 1d  is independently hydrogen, fluoro, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl.   
     
     
         46 . The compound of  claim 45 , wherein
 R 1a  and R 1b  are not taken together to form an oxo group;   G is —V 1 —R 3 , or —V 1 -L 1 -R 3 ;   V 1  is —C(O)—; and   L 1  is —CH 2 —.   
     
     
         47 . The compound of  claim 46 , wherein
 R 1a  is hydrogen;   R 1b  is hydrogen, fluoro, or methyl;   R 1c  is hydrogen; and   each occurrence of R 1d  is independently hydrogen, fluoro, or methyl.   
     
     
         48 . The compound of  claim 45 , wherein:
 each substitutable saturated ring carbon atom in R 3  is unsubstituted or substituted with —R 5a ;   the total number of R 1a  substituents is p;
 p is 1-2; 
 each R 5a  is independently halogen, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, —O—C 1-3  fluoroalkyl, —NHC(O)C 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, —NHS(O) 2 C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and 
 each occurrence of R 7a  is independently halogen, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-3  alkyl, —NHC 1-3  alkyl, —N(C 1-3 alkyl) 2 , —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         49 . A pharmaceutical composition comprising a compound of  claim 33  and a pharmaceutically acceptable carrier.