Substituted hydroxamic acids and uses thereof

Abstract

This invention provides compounds of formula (I): wherein R 1 , R 2 , G, n, p and q 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 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         p is 0-2; 
         q is 1-3; 
         provided that the total of p and q is 1-3; 
         G is —R 3 , —V 1 —R 3 , —V 1 -L 1 -R 3 , -L 1 -V 2 —R 3 , -L 1 -R 3 , or -L 1 -V 2 -L 2 -R 3 ; 
         L 1  and L 2  are each independently unsubstituted or substituted C 1-3  alkylene, where one carbon atom may be replaced with —CR A ═CR A —. 
         V 1  is —C(O)—, —C(S)—, —C(O)—N(R 4a )—, —C(O)—O—, or —S(O) 2 —; 
         V 2  is —C(O)—, —C(S)—, —N(R 4a )—, —C(O)—N(R 4a )—, —N(R 4a )—C(O)—, —SO 2 —N(R 4a )—, —N(R 4a )—SO 2 —, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O) 2 —, —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, halo, or unsubstituted or substituted C 1-4  aliphatic; 
         each occurrence of R 4a  is independently hydrogen, or unsubstituted or substituted C 1-4  aliphatic; 
         R 1  is hydrogen, halo, —CN, C 1-3  alkyl, C 1-3 haloalkyl, —O—C 1-3  alkyl, —O—C 1-3  haloalkyl, —NHC(O)C 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or NHS(O) 2 C 1-3  alkyl; 
         ring A is optionally further substituted with n occurrences of R 2 ; 
         each occurrence of R 2  is independently halo, C 1-4  aliphatic, —CN, —OR B , —SR C , —N(R B ) 2 , —NR B C(O)R B , —NR B C(O)N(R B ) 2 , —NR B CO 2 R C , —CO 2 R B , —C(O)R B , —C(O)N(R B ) 2 , —OC(O)N(R B ) 2 , —S(O) 2 R C , —SO 2 N(R B ) 2 , —S(O)R C , —NR B SO 2 N(R B ) 2 , —NR B SO 2 R C , or a C 1-4  aliphatic substituted with R D , halo, —CN, —OR B , —SR C , —N(R B ) 2 , —NR B C(O)R B , —NR B C(O)N(R B ) 2 , —NR B CO 2 R C , —CO 2 R B , —C(O)R B , —C(O)N(R B ) 2 , —OC(O)N(R B ) 2 , —S(O) 2 R C , —SO 2 N(R B ) 2 , —S(O)R B , —NR B SO 2 N(R B ) 2 , or —NR B SO 2 R C ; or two R 2  are taken together to form a 3-6 membered cycloaliphatic ring; 
         each occurrence of R B  is independently H or C 1-4  aliphatic; or two R B  on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O and S; 
         each occurrence of R C  is independently C 1-4  aliphatic; 
         each occurrence of R D  is independently 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         n is 0-4. 
       
     
     
         2 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         p is 0-2; 
         q is 1-3; 
         provided that the total of p and q is 1-3; 
         G is —R 3 , —V 1 —R 3 , —V 1 -L 1 -R 3 , -L 1 -V 1 —R 3 , -L 2 -V 2 —R 3 , —V 1 -L 1 -V 2 —R 3 , or -L 1 -R 3 ; 
         L 1  is unsubstituted or substituted C 1-3  alkylene chain, where one carbon atom may be replaced with —CR A ═CR A —; 
         L 2  is unsubstituted or substituted C 2-3  alkylene chain, where one carbon atom may be replaced with —CR A ═CR A —; 
         V 1  is —C(O)—, —C(S)—, —C(O)—N(R 4a )—, —C(O)—O—, or —S(O) 2 —; 
         V 2  is —C(O)—, —C(S)—, —N(R 4a )—, —C(O)—N(R 4a )—, —N(R 4a )—C(O)—, —SO 2 —N(R 4a )—, —N(R 4a )—SO 2 —, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O) 2 —, —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 1-4 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; 
         each occurrence of R 4a  is independently hydrogen, or an optionally substituted C 1-4  aliphatic group; 
         R 1  is hydrogen, chloro, fluoro, —O—C 1-4  alkyl, cyano, hydroxy, C 1-4  alkyl, or C 1-4  fluoroalkyl; 
         ring A is optionally further substituted with n occurrences of R 2 ; 
         each occurrence of R 2  is independently fluoro, C 1-4  alkyl, C 1-4  haloalkyl, or R D ; or two R 2  are taken together to form a 3-6 membered cycloaliphatic ring; 
         each occurrence of R D  is independently 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 
         n is 0-4. 
       
     
     
         3 . The compound of  claim 2 , wherein:
 R 1  is hydrogen or methyl;   each occurrence of R 2  is independently fluoro, methyl, or trifluoromethyl;   V 1  is —C(O)—, —C(O)—N(R 4a ), or —S(O) 2 —;   V 2  is —N(R 4a )—, —C(O)—NR 4a —N(R 4a )—C(O)—, —SO 2 —N(R 4a )—, —N(R 4a )—SO 2 —, —O—, or —S—; and   n is 0-2.   
     
     
         4 . The compound of  claim 2 , represented by formulas (II-A)-(II-F): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2 , wherein:
 R 3  when substituted is substituted with 1-4 independent occurrences of —R 5 , wherein R 5  is —R 5a , —R 5d , -L 3 -R 5d , or —V 3 -L 3 -R 5d ;   each occurrence of R 5a  is independently halogen, C 1-4  aliphatic, —CN, —NO 2 , —N(R 5 ) 2 , —OR 5b , —SR 5b , —S(O) 2 R 5c , —S(O)R 5c —C(O)R 5b , —C(O)OR 5b , —C(O)N(R 5b ) 2 , —S(O) 2 N(R 5b ) 2 , —OC(O)N(R 5b ) 2 , —N(R 5e )C(O)R 5b , —N(R 5e )SO 2 R 5e , —N(R 5e )C(O)OR 5b , —N(R 5e )C(O)N(R 5b ) 2 , or —N(R 5e )SO 2 N(R 5b ) 2 , or a C 1-4  aliphatic substituted with R 5dd , halogen, —CN, —NO 2 , —N(R 5b ) 2 , —OR 5b , —SR 5c , —S(O) 2 R 5c , —S(O)R 5c —C(O)R 5b , —C(O)OR 5b , —C(O)N(R 5b ) 2 , —S(O) 2 N(R 5b ) 2 , —OC(O)N(R 5b ) 2 , —N(R 5e )C(O)R 5b , —N(R 5e )SO 2 R 5e , —N(R 5e )C(O)OR 5b , —N(R 5e )C(O)N(R 5b ) 2 , or —N(R 5e )SO 2 N(R 5b ) 2 ;   each occurrence of R 5b  is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 5b  on the same nitrogen atom can be taken together with the nitrogen atom to which they are bound to form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;   each occurrence of R 5c  is independently an optionally substituted group selected from C 1-6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;   each occurrence of R 5d  is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;   each occurrence of R 5dd  is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;   each occurrence of R 5e  is independently hydrogen or an optionally substituted C 1-6  aliphatic group;   each occurrence of V 3  is independently —N(R 5e ), —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 5e )—, —S(O) 2 N(R 5e )—, —OC(O)N(R 5e )—, —N(R 5e )C(O)—, —N(R 5e )SO 2 —, —N(R 5e )C(O)O—, —N(R 5e )C(O)N(R 5e )—, —N(R 5e )SO 2 N(R 5e )—, —OC(O)—, or —C(O)N(R 3e )O—; and   L 3  is an optionally substituted C 1-3  alkylene chain, where one carbon atom may be replaced with CR A ═CR A —.   
     
     
         6 . The compound of  claim 5 , wherein:
 G is —R 3 , —C(R 6 )(R 6′ )—R 3 , —C(O)—R 3 , or —S(O) 2 —R 3 ;   R 6  is hydrogen, C 1-4  aliphatic, C 3-6  cycloaliphatic, or 6-10-membered aryl;   R 6′  is hydrogen, C 1-4  aliphatic, C 3-6  cycloaliphatic, or 6-10-membered aryl; or   R 6  and R 6′  are taken together to form a C 3-6  cycloaliphatic group;   R 3  is —R 3a ; and   R 3a  is 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, wherein R 3a  if substituted is substituted with 0-1 occurrences of —R 5a , and one occurrence of —R 5d .   
     
     
         7 . The compound of  claim 6 , represented by formulas (II-A)-(II-C): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; 
         each occurrence of R 2  is independently fluoro, methyl, or trifluoromethyl; 
         n is 0-2; 
         R 5a  is chloro, fluoro, C 1-4  alkyl, C 1-6  fluoroalkyl, —O—C 1-6  alkyl, —O—C 1-6  fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-6  alkyl, —NHC 1-6  alkyl, —N(C 1-6  alkyl) 2 , —C(O)NHC 1-6  alkyl, —C(O)N(C 1-6  alkyl) 2 , —NHC(O)NHC 1-6  alkyl, —NHC(O)N(C 1-6  alkyl) 2 , or —NHS(O) 2 C 1-6  alkyl; 
         R 5d  if substituted is substituted with 0-2 occurrences of —R 7a ; and 
         each occurrence of R 7a  is independently chloro, fluoro, bromo, iodo, C 1-6  alkyl, C 1-6  fluoroalkyl, —O—C 1-6  alkyl, —O—C 1-6  fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-6  alkyl, —NHC 1-6  alkyl, —N(C 1-6  alkyl) 2 , —C(O)NHC 1-6  alkyl, —C(O)N(C 1-6  alkyl) 2 , —NHC(O)NHC 1-6  alkyl, —NHC(O)N(C 1-6  alkyl) 2 , or —NHS(O) 2 C 1-6  alkyl. 
       
     
     
         8 . The compound of  claim 7 , represented by formulas (II-A)-(II-B): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 7 , wherein:
 R 1  is hydrogen or methyl; and   n is 0.   
     
     
         10 . The compound of  claim 7 , wherein:
 R 5d  is thienyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl, pyrimidinyl, or benzothienyl.   
     
     
         11 . The compound of  claim 5 , wherein:
 G is —[C(R 6 )(R 6′ )] z —R 3 , —C(O)—[C(R 6 )(R 6′ )] z —R 3 , —C(O)—NH—[C(R 6 )(R 6′ )] z —R 3 , —S(O) 2 —[C(R 6 )(R 6′ )] z —R 3 , —[C(R 6 )(R 6′ )] z —V 2a —R 3 , —C(O)—[C(R 6 )(R 6′ )] y —V 2a —R 3 , —C(R 6 )(R 6′ )—V 2a′ —R 3 , or —C(O)—C(R 6 )(R 6′ )—V 2a —R 3 ;   R 6  is hydrogen, C 1-4  aliphatic, C 3-6  cycloaliphatic, or 6-10-membered aryl;   R 6′  is hydrogen, C 1-4  aliphatic, C 3-6  cycloaliphatic, or 6-10-membered aryl; or   R 6  and R 6′  are taken together to form a C 3-6  cycloaliphatic group;   V 2a  is —C(O)—, —O—, —S—, —N(R 4a )—, or —C(O)N(R 4a )—;   V 2a′  is —O—, —S—, or —N(R 4a )—;   R 3  is —R 3d ;   R 3d  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, wherein R 3d  if substituted is substituted with 0-2 independent occurrences of —R 5a ;   z is 0-3; and   y is 1-2.   
     
     
         12 . The compound of  claim 11 , represented by formula (II-A)-(II-C): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; 
         each occurrence of R 2  is independently fluoro, methyl, or trifluoromethyl; 
         n is 0-2; 
         R 3d  is unsubstituted or substituted with 0-1 occurrences of —R 5a ; and 
         R 5a  is chloro, fluoro, C 1-4  alkyl, C 1-6  fluoroalkyl, —O—C 1-6  alkyl, —O—C 1-6  fluoroalkyl, cyano, hydroxy, —NHC(O)C 1-6  alkyl, —NHC 1-6  alkyl, —N(C 1-6 alkyl) 2 , —C(O)NHC 1-6  alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)NHC 1-6  alkyl, —NHC(O)N(C 1-6 alkyl) 2 , or —NHS(O) 2 C 1-6  alkyl. 
       
     
     
         13 . The compound of  claim 12 , represented by formulas (II-A)-(II-B): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 12 , wherein:
 R 1  is hydrogen or methyl; and   n is 0.   
     
     
         15 . The compound of  claim 12 , wherein:
 R 5a  is chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.   
     
     
         16 . The compound of  claim 12 , wherein:
 G is —[C(R 6 )(R 6′ )] z —R 3 , —C(O)—[C(R 6 )(R 6′ )] z —R 3 , or —S(O) 2 —[C(R 6 )(R 6′ )] z —R 3 .   
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  or  2 , and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 1  or  2 . 
     
     
         19 . The method of  claim 18 , wherein the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myeloid leukemia, or acute lymphoblastic leukemia. 
     
     
         20 . A method for inhibiting HDAC6 activity in a patient comprising administering a pharmaceutical composition comprising an amount of a compound of  claim 1  or  2  effective to inhibit HDAC6 activity in the patient.