Substituted hydroxamic acids and uses thereof

Abstract

This invention provides compounds of formula (I): wherein ring A, X 1 , X 2 , X 3 , R 2 , R 4b , R 10 , 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.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         ring A is an aromatic 6-membered ring connected through one of positions (a) or (b);
 X 1  is CR 1  or N; 
 (i) when ring A is connected through position (a), X 2  is C; and X 3  is CR 1  or N; or 
 (ii) when ring A is connected through position (b), X 3  is C; and X 2  is CR 1  or N; 
 
         each occurrence of R 1  is independently hydrogen, 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, —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or —NHS(O) 2 C 1-3  alkyl. 
         each occurrence of R 10  is independently hydrogen, halogen, hydroxy, —O—C 1-3  alkyl, or —O—C 1-3  fluoroalkyl; 
         R 2  is C 1-6  aliphatic, C 1-6  fluoroaliphatic, or unsubstituted or substituted 6-10-membered aryl; 
         R 4b  is hydrogen, or C 1-4  aliphatic; 
         G is —R 3 , —V 1 —R 3 , -L 2 -V 1 —R 3 , -L 2 -V 2 —R 3 , or -L 1 -R 3 ; 
         L, 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(O)—CR A ═CR A —, —C(O)—N(R 4a )—, —C(O)—O—, or —S(O) 2 —; 
         V 2  is —C(S)—, —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 1-5 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 aliphatic. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 X 1  is CR 1 ; and   (i) when ring A is connected through position (a), X 2  is C; and X 3  is CR 1 ; or   (ii) when ring A is connected through position (b), X 3  is C; and X 2  is CR 1 .   
     
     
         3 . The compound of  claim 1 , wherein:
 R 4b  is H; and   R 2  is methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or phenyl.   
     
     
         4 . The compound of  claim 1 , wherein:
 G is —V 1 —R 3 ; and   V 1  is —C(O)—, —C(O)—N(R 4a )—, or —S(O) 2 —.   
     
     
         5 . The compound of  claim 1 , wherein:
 R 1  is hydrogen, chloro, fluoro, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; and   R 10  is hydrogen.   
     
     
         6 . The compound of  claim 1 , represented by formula (II-a): 
       
         
           
           
               
               
           
         
         wherein 
         ring A is an aromatic 6-membered ring connected through one of positions (a) or (b);
 X 1  is CR 1  or N; 
 (i) when ring A is connected through position (a), X 2  is C; and X 3  is CR 1  or N; or 
 (ii) when ring A is connected through position (b), X 3  is C; and X 2  is CR 1  or N; 
 
         each occurrence of R 1  is independently hydrogen, 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, —C(O)NHC 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, or —NHS(O) 2 C 1-3 alkyl. 
         each occurrence of R 10  is independently hydrogen, halogen, hydroxy, —O—C 1-3 alkyl, or —O—C 1-3 -fluoroalkyl; 
         R 2  is C 1-6  aliphatic, C 1-6  fluoroaliphatic, or unsubstituted or substituted 6-10-membered aryl; 
         R 4b  is hydrogen, or C 1-4  aliphatic; 
         G is —R 3 , —V 1 —R 3 , -L 2 -V 1 —R 3 , -L 2 -V 2 —R 3 , or -L 1 -R 3 ; 
         L, is an unsubstituted or substituted C 1-3  alkylene chain; 
         L 2  is an unsubstituted or substituted C 2-3  alkylene chain; 
         V, is —C(O)—, —C(O)—CR A ═CR A —, —C(O)—N(R 4a )—, —C(O)—O—, or —S(O) 2 —; 
         V 2  is —C(S)—, —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(e)-, 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 1-5 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. 
       
     
     
         7 . The compound of  claim 6 , wherein:
 X 1  is CR 1 ; and   (i) when ring A is connected through position (a), X 2  is C; and X 3  is CR 1 ; or   (ii) when ring A is connected through position (b), X 3  is C; and X 2  is CR 1 .   
     
     
         8 . The compound of  claim 6 , wherein:
 R 4b  is H; and   R 2  is methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or phenyl.   
     
     
         9 . The compound of  claim 6 , wherein:
 G is —V 1 —R 3 ; and   V 1  is —C(O)—, —C(O)—N(R 4a )—, or —S(O) 2 —.   
     
     
         10 . The compound of  claim 6 , wherein:
 R 1  is hydrogen, chloro, fluoro, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl; and   R 10  is hydrogen.   
     
     
         11 . The compound of  claim 6 , 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(R 5 )═C(R 5 )(R 10 ), —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)—C(O)R 5 , —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 1-5 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 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); 
 each R 4  is independently hydrogen, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-5 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 1-5 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 7  is independently unsubstituted or substituted 4-10-membered heterocyclyl having 1-5 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 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 ; 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). 
   
     
     
         12 . The compound of  claim 11 , 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, —CN, —OH, C 1-4  alkyl, C 1-3  fluoroalkyl, —O—C 1-3  alkyl, 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 1-5 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 1-3  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, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         13 . The compound of  claim 11 , represented by formula (III-a-i): 
       
         
           
           
               
               
           
         
         wherein: 
         each occurrence of R 1  is independently hydrogen, chloro, fluoro, hydroxy, trifluoromethyl, or methyl; 
         R 10  is hydrogen; 
         G is —V 1 —R 3 ; and 
         V 1  is —C(O)—, —C(O)—N(R 4a )— or —S(O) 2 —. 
       
     
     
         14 . The compound of  claim 13 , wherein R 1  is hydrogen. 
     
     
         15 . The compound of  claim 13 , wherein R 2  is methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or phenyl. 
     
     
         16 . The compound of  claim 13 , wherein R 2  is methyl, ethyl, isopropyl, or n-propyl. 
     
     
         17 . The compound of  claim 13 , 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, —CN, —OH, 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, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-5 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 1-3  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, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         18 . The compound of  claim 11 , represented by formula (III-a-v): 
       
         
           
           
               
               
           
         
         wherein: 
         each occurrence of R 1  is independently hydrogen, chloro, fluoro, hydroxy, trifluoromethyl, or methyl; 
         R 10  is hydrogen; 
         G is —V 1 —R 3 ; and 
         V 1  is —C(O)—, —C(O)—N(R 4a )— or —S(O) 2 —. 
       
     
     
         19 . The compound of  claim 18 , wherein R 1  is hydrogen. 
     
     
         20 . The compound of  claim 18 , wherein R 2  is methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or phenyl. 
     
     
         21 . The compound of  claim 18 , wherein R 2  is methyl, ethyl, isopropyl, or n-propyl. 
     
     
         22 . The compound of  claim 18 , wherein:
 each substitutable saturated ring carbon atom in R 3  is unsubstituted or substituted with —R 5a ;   the total number of Rya substituents is p;
 p is 1-2; 
 each R 5a  is independently halogen, —CN, —OH, 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, 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-5 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 1-3  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, or —NHS(O) 2 C 1-3  alkyl. 
   
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         24 . 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 . 
     
     
         25 . The method of  claim 24 , wherein the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myelogenous leukemia, or acute lymphoblastic leukemia. 
     
     
         26 . A method for inhibiting HDAC6 activity in a patient comprising administering a pharmaceutical composition comprising an amount of a compound of  claim 1  effective to inhibit HDAC6 activity in the patient.