2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors

Abstract

A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher's; or Fabry's disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

1 - 89 . (canceled) 
     
     
         90 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       R 1  is a phenyl group substituted with one or more —OR 30 ;
 each R 30  is independently 
 i) hydrogen; 
 ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or 
 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; 
 —N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino; and 
 R 4  is an aliphatic or aryl group, wherein aryl is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —NCS, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —NR 51 C(O)OR 52 , —N(R 51 )C(O)N(R 51 ) 2 , —C(O)R 50 , —C(S)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —S(O) 2 R 50 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 50 , —NR 51 SO 2 N(R 51 ) 2 , —NR 51 SO 2 R 52 , —V 4 —Ar 3 , —V—OR 51 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —NR 51 CO 2 R 52 , —V 4 —N(R 51 )C(O)N(R 51 ) 2 , —V 4 —C(O)R 50 , —V 4 —C(S)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —V 4 —S(O) 2 R 50 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 50 , —V 4 —NR 51 SO 2 N(R 51 ) 2 , —V 4 —NR 51 SO 2 R 52 , —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(S)—V 4 —N(R 51 ) 2 , —C(S)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —S(O) 2 —V 4 —N(R 51 ) 2 , —S(O) 2 —V 4 —Ar 3 , —SO 2 N(R 51 )—V 5 —N(R 51 ) 2 , —SO 2 N(R 51 )—V 4 —Ar 3 , —S(O)—V 4 —N(R 51 ) 2 , —S(O)—V 4 —Ar 3 , —S(O) 2 —O—V 5 —N(R 51 ) 2 , —S(O) 2 —O—V 4 —Ar 3 , —NR 51 SO 2 —V 4 —N(R 51 ) 2 , —NR 51 SO 2 —V 4 —Ar 3 , —O—[CH 2 ] p′ —O—, —S—[CH 2 ] p′ —S—, and —[CH 2 ] q′ —;
 each V 4  is independently a C1-C10 alkylene group; 
 each V 5  is independently a C2-C10 alkylene group; 
 each Ar 3  is independently a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each Ar 3  being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and 
 each R 50  is independently 
 i) hydrogen; 
 ii) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each R 51  is independently R 50 , —CO 2 R 50 , —SO 2 R 50  or —C(O)R 50 ; or 
 
 —N(R 51 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group; and each R 52  is independently:
 i) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each p′ is 1, 2, 3 or 4; and 
 each q′ is 3, 4, 5 or 6. 
 
 
     
     
         91 . The compound of  claim 90 , wherein R 4  is an optionally substituted aryl or arylalkyl group, wherein aryl, used alone or as in arylalkyl, is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom and arylalkyl includes straight and branched saturated chains. 
     
     
         92 . The compound of  claim 90 , wherein the compound is a (1R,2R) stereoisomer. 
     
     
         93 . The compound of  claim 90 , wherein R 4  is an aryl or lower arylalkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 5 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —C(O)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— and —[CH 2 ] q′ —, wherein lower arylalkyl includes straight and branched saturated chains containing one to six carbon atoms. 
     
     
         94 . The compound of  claim 90 , represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 8  is —H, or an aryl or C1-C6 alkyl group each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 5 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —C(O)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— and —[CH 2 ] q′ —; and k is 0, 1, 2, 3, 4, 5 or 6. 
       
     
     
         95 . The compound of  claim 94 , wherein R 8  is selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 each of rings A-Z5 is optionally substituted. 
 
     
     
         96 . The compound of  claim 95 , wherein —N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group. 
     
     
         97 . The compound of  claim 96 , wherein each of rings A-Z5 is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH 2 ] p —O— or —[CH 2 ] q —. 
     
     
         98 . The compound of  claim 97 , wherein:
 —N(R 2 R 3 ) is pyrrolidinyl; and   the phenyl group represented by R 1  is optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH 3 , —OC 2 H 5  and —O—[CH 2 ] p —O—.   
     
     
         99 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 90 , or a pharmaceutically acceptable salt thereof. 
     
     
         100 . A method of treating a subject having type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; or Tay-Sachs, Gaucher's or Fabry's disease, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       R 1  is a phenyl group substituted with one or more —OR 30 ;
 each R 30  is independently 
 i) hydrogen; 
 ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or 
 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; 
 —N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino; and 
 R 4  is an aliphatic or aryl group, wherein aryl is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —NCS, —N(R 51 ) 2 , —NR 51 C(O)R 5 , —NR 51 C(O)OR 52 , —N(R 51 )C(O)N(R 51 ) 2 , —C(O)R 50 , —C(S)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —S(O) 2 R 50 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 50 , —NR 51 SO 2 N(R 51 ) 2 , —NR 51 SO 2 R 52 , —V 4 —Ar 3 , —V—OR 50 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —NR 51 CO 2 R 52 , —V 4 —N(R 51 )C(O)N(R 51 ) 2 , —V 4 —C(O)R 50 , —V 4 —C(S)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —V 4 —S(O) 2 R 50 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 50 , —V 4 —NR 51 SO 2 N(R 51 ) 2 , —V 4 —NR 51 SO 2 R 52 , —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 5  1) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 5  1) 2 , —C(O)—V 4 —Ar 3 , —C(S)—V 4 —N(R 51 ) 2 , —C(S)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —S(O) 2 —V 4 —N(R 51 ) 2 , —S(O) 2 —V 4 —Ar 3 , —SO 2 N(R 51 )—V 5 —N(R 51 ) 2 , —SO 2 N(R 51 )—V 4 —Ar 3 , —S(O)—V 4 —N(R 51 ) 2 , —S(O)—V 4 —Ar 3 , —S(O) 2 —O—V 5 —N(R 51 ) 2 , —S(O) 2 —O—V 4 —Ar 3 , —NR 51 SO 2 —V 4 —N(R 51 ) 2 , —NR 51 SO 2 —V 4 —Ar 3 , —O—[CH 2 ] p′ —O—, —S—[CH 2 ] p′ —S—, and —[CH 2 ] q′ —;
 each V 4  is independently a C1-C10 alkylene group; 
 each V 5  is independently a C2-C10 alkylene group; 
 each Ar 3  is independently a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each Ar 3  being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and 
 each R 50  is independently 
 i) hydrogen; 
 ii) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each R 51  is independently R 50 , —CO 2 R 50 , —SO 2 R 50  or —C(O)R 50 ; or 
 
 —N(R 51 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group; and each R 52  is independently:
 i) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each p′ is 1, 2, 3 or 4; and 
 each q′ is 3, 4, 5 or 6. 
 
 
     
     
         101 . A method of decreasing plasma TNF-α; lowering blood glucose levels; decreasing glycated hemoglobin levels; or inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       R 1  is a phenyl group substituted with one or more —OR 30 ;
 each R 30  is independently 
 i) hydrogen; 
 ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or 
 iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; 
 —N(R 2 R 3 ) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino; and 
 R 4  is an aliphatic or aryl group, wherein aryl is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar 3 , Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —NCS, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —NR 51 C(O)OR 52 , —N(R 51 )C(O)N(R 51 ) 2 , —C(O)R 50 , —C(S)R 50 , —C(O)OR 50 , —OC(O)R 50 , —C(O)N(R 51 ) 2 , —S(O) 2 R 50 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 50 , —NR 51 SO 2 N(R 51 ) 2 , —NR 51 SO 2 R 52 , —V 4 —Ar 3 , —V—OR 51 , —V 4 —O(haloalkyl), —V 4 —SR 50 , —V 4 —NO 2 , —V 4 —CN, —V 4 —N(R 51 ) 2 , —V 4 —NR 51 C(O)R 50 , —V 4 —NR 51 CO 2 R 52 , —V 4 —N(R 51 )C(O)N(R 51 ) 2 , —V 4 —C(O)R 50 , —V 4 —C(S)R 50 , —V 4 —CO 2 R 50 , —V 4 —OC(O)R 50 , —V 4 —C(O)N(R 51 ) 2 —, —V 4 —S(O) 2 R 50 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 50 , —V 4 —NR 51 SO 2 N(R 51 ) 2 , —V 4 —NR 51 SO 2 R 52 , —O—V 4 —Ar 3 , —O—V 5 —N(R 51 ) 2 , —S—V 4 —Ar 3 , —S—V 5 —N(R 51 ) 2 , —N(R 51 )—V 4 —Ar 3 , —N(R 51 )—V 5 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —N(R 51 ) 2 , —NR 51 C(O)—V 4 —Ar 3 , —C(O)—V 4 —N(R 51 ) 2 , —C(O)—V 4 —Ar 3 , —C(S)—V 4 —N(R 51 ) 2 , —C(S)—V 4 —Ar 3 , —C(O)O—V 5 —N(R 51 ) 2 , —C(O)O—V 4 —Ar 3 , —O—C(O)—V 5 —N(R 51 ) 2 , —O—C(O)—V 4 —Ar 3 , —C(O)N(R 51 )—V 5 —N(R 51 ) 2 , —C(O)N(R 51 )—V 4 —Ar 3 , —S(O) 2 —V 4 —N(R 51 ) 2 , —S(O) 2 —V 4 —Ar 3 , —SO 2 N(R 51 )—V 5 —N(R 51 ) 2 , —SO 2 N(R 51 )—V 4 —Ar 3 , —S(O)—V 4 —N(R 51 ) 2 , —S(O)—V 4 —Ar 3 , —S(O) 2 —O—V 5 —N(R 51 ) 2 , —S(O) 2 —O—V 4 —Ar 3 , —NR 51 SO 2 —V 4 —N(R 51 ) 2 , —NR 51 SO 2 —V 4 —Ar 3 , —O—[CH 2 ] p′ —O—, —S—[CH 2 ] p′ —S—, and —[CH 2 ] q′ —;
 each V 4  is independently a C1-C10 alkylene group; 
 each V 5  is independently a C2-C10 alkylene group; 
 each Ar 3  is independently a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, each Ar 3  being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and 
 each R 50  is independently 
 i) hydrogen; 
 ii) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each R 51  is independently R 50 , —CO 2 R 50 , —SO 2 R 50  or —C(O)R 50 ; or 
 
 —N(R 51 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group; and each R 52  is independently:
 i) a group which is a carbocyclic aromatic ring having 6 to 14 carbon atoms or an aromatic ring having 5 to 14 ring atoms selected from carbon and at least one heteroatom, the group being optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or 
 ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; and 
 each p′ is 1, 2, 3 or 4; and 
 each q′ is 3, 4, 5 or 6.