Method of treating polycystic kidney diseases with ceramide derivatives

Abstract

A method of treating polycystic kidney disease in a subject comprises administering to the subject an effective amount of a compound represented by Structural Formula (1): or a pharmaceutically acceptable salt thereof.

1 . A method of treating polycystic kidney disease in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; 
 Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group; 
 R 2  and R 3  are each independently —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 2  and R 3  taken together with the nitrogen atom of N(R 2 R 3 ) form a substituted or unsubstituted non-aromatic heterocyclic ring; 
 X is a covalent bond; —(CR 5 R 6 ) m —; —(CR 5 R 6 ) n -Q-; —O—; —S—; or —NR 7 —; 
 Q 
 
         is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR 8 —, —NR 8 —, —NR 8 C(O)—, —NR 8 C(O)NR 8 —, —OC(O)—, —SO 3 —, —SO—, —S(O) 2 —, —SO 2 NR 8 —, or —NR 8 SO 2 —;
 When X is —(CR 5 R 6 ) m , R 4  is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, —CN, —NCS, —NO 2  or a halogen; or 
 When X is other than —(CR 5 R 6 ) m , R 4  is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group; and 
 R 5  and R 6  are each independently —H, —OH, —SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group; 
 each R 7  is independently —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 7  and R 4  taken together with the nitrogen atom of NR 7 R 4  form a substituted or unsubstituted non-aromatic heterocyclic group; 
 each R 8  is independently —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; 
 n is 1, 2, 3, 4 or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; and 
 m is 1, 2, 3, 4 or 5. 
 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is an aryl group or a heteroaryl group, each of which optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl,
 Ar 1 , —OR 30 , —O(haloalkyl), —SR 30 , —NO 2 , —CN, —NCS, —N(R 31 ) 2 , —NR 31 C(O)R 30 , —NR 31 C(O)OR 32 , —N(R 31 )C(O)N(R 31 ) 2 , —C(O)R 30 , —C(S)R 30 , —C(O)OR 30 , —OC(O)R 30 , —C(O)N(R 31 ) 2 , —S(O) 2 R 30 , —SO 2 N(R 31 ) 2 , —S(O)R 32 , —SO 3 R 32 , —NR 31 SO 2 N(R 31 ) 2 , —NR 31 SO 2 R 32 ,   —V o —Ar 1 , —V o —OR 30 , —V o —O(haloalkyl), —V o —SR 30 , —V o —NO 2 , —V o —CN, —V o —N(R 31 ) 2 , —V o —NR 31 C(O)R 30 , —V o —NR 31 CO 2 R 32 , —V o —N(R 31 )C(O)N(R 31 ) 2 , —V o —C(O)R 30 , —V o —C(S)R 30 , —V o —CO 2 R 30 , —V o —OC(O)R 30 , —V o —C(O)N(R 31 ) 2 —, —V o —S(O) 2 R 32 , —V o —SO 2 N(R 31 ) 2 , —V o —S(O)R 32 , —V o —SO 3 R 32 , —V o —NR 31 SO 2 N(R 31 ) 2 , —V o —NR 31 SO 2 R 32 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —NR 31 C(O)—   V o —N(R 31 ) 2 , —NR 31 C(O)—V o —Ar 1 , —C(O)—V o —N(R 31 ) 2 , —C(O)—V o —Ar 1 , —C(S)—V o —N(R 31 ) 2 , —C(S)—V o —Ar 1 , —C(O)O—V 1 —N(R 31 ) 2 , —C(O)O—V o —Ar 1 , —O—C(O)—V 1 —N(R 31 ) 2 , —O—C(O)—V o —Ar 1 , —C(O)N(R 31 )—V 1 —N(R 31 ) 2 , —C(O)N(R 31 )—V o —Ar 1 , —S(O) 2 —V o —N(R 31 ) 2 , —S(O) 2 —V o —Ar 1 , —SO 2 N(R 31 )—V 1 —N(R 31 ) 2 , —SO 2 N(R 31 )—V o —Ar 1 , —S(O)—V o —N(R 31 ) 2 , —S(O)—V o —Ar 1 , —S(O) 2 —O—V 1 —N(R 31 ) 2 , —S(O) 2 —O—V o —Ar 1 , —NR 31 SO 2 —V o —N(R 31 ) 2 , —NR 31 SO 2 —V o —Ar 1 , —O—[CH 2 ] p —O—, —S—[CH 2 ] p —S— and —[CH 2 ] q —;
 each V o  is independently a C1-C10 alkylene group; 
 each V 1  is independently a C2-C10 alkylene group; 
 Ar 1  is an aryl group or a heteroaryl group, each of which independently is 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; and 
 each R 30  is independently 
 i) hydrogen; 
 ii) an aryl group or a heteroaryl group, each of which independently is 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 31  is independently R 30 , —CO 2 R 30 , —SO 2 R 30  or —C(O)R 30 ; or 
   —N(R 31 ) 2  taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino; and
 each R 32  is independently: 
 i) an aryl group or a heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy 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, alkylcarbonyl and haloalkoxy and haloalkyl; and
 each p is independently 1, 2, 3 or 4; and 
 each q is independently 3, 4, 5 or 6. 
 
   
     
     
         3 . The method of  claim 2 , wherein:
 Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′; and   R and R′ are each independently —H; a C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; or an aryl group or a heteroaryl group, each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , C1-C6 alkoxy, lower haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group; or   R and R′ taken together with the nitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; —OH; —CN; —NCS; —NO 2 ; —NH 2 ; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of   
       halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, aryl and heteroaryl; and an aryl group or a heteroaryl group, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO 2 , —NH 2 , C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aliphatic group and C1-C6 haloaliphatic group. 
     
     
         4 . The method of  claim 3 , wherein:
 —N(R 2 R 3 ) is a 5- or 6-membered non-aromatic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl,   
       haloalkyl, —OR 40 , —O(haloalkyl), —SR 40 , —NO 2 , —CN, —N(R 41 ) 2 , —NR 41 C(O)R 40 , —NR 41 C(O)OR 42 , —N(R 41 )C(O)N(R 41 ) 2 , —C(O)R 40 , —C(S)R 40 , —C(O)OR 40 , —OC(O)R 40 , —C(O)N(R 41 ) 2 , —S(O) 2 R 42 , —SO 2 N(R 41 ) 2 , —S(O)R 42 , —SO 3 R 42 , Ar 2 , 
       V 2 —Ar 2 , —V 2 —OR 40 , —V 2 —O(haloalkyl), —V 2 —SR 40 , —V 2 —NO 2 , —V 2 —CN, —V 2 —N(R 41 ) 2 , —V 2 —NR 41 C(O)R 40 , —V 2 —NR 41 CO 2 R 42 , —V 2 —N(R 41 )C(O)N(R 41 ) 2 , —V 2 —C(O)R 40 , —V 2 —C(S)R 40 , —V 2 —CO 2 R 40 , —V 2 —OC(O)R 40 , —V 2 —C(O)N(R 41 ) 2 —, —V 2 —S(O) 2 R 42 , —V 2 —SO 2 N(R 41 ) 2 , —V 2 —S(O)R 42 , —V 2 —SO 3 R 42 , —O—V 2 —Ar 2  and —S—V 2 —Ar 2 ;
 each V 2  is independently a C1-C4 alkylene group; 
 Ar 2  is an aryl group or a heteroaryl group, each of which independently is 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; and 
 each R 40  is independently 
 i) hydrogen; 
 ii) an aryl group or a heteroaryl group, each of which independently is 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; and 
 each R 41  is independently R 40 , —CO 2 R 40 , —SO 2 R 40  or —C(O)R 40 ; or 
 
       —N(R 41 ) 2  taken together is an optionally substituted non-aromatic heterocyclic group with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; and
 each R 42  is independently: 
 i) an aryl group or a heteroaryl group, each of which independently is 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 
 ii) 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. 
 
     
     
         5 . The method of  claim 4 , wherein R 5  and R 6  are each independently —H; —OH; a halogen; or a C1-C6 alkoxy or C1-C6 alkyl group. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 5 , wherein each of the aliphatic, the aryl and the heteroaryl groups represented by each of R 4 , R 7  and R 8  independently is 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 52 , —SO 2 N(R 51 ) 2 , —S(O)R 52 , —SO 3 R 52 , —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 52 , —V 4 —SO 2 N(R 51 ) 2 , —V 4 —S(O)R 52 , —V 4 —SO 3 R 52 , —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 an aryl group or a heteroaryl group, each of which independently is 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) an aryl group or a heteroaryl group, each of which independently is 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 a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; and
 each R 52  is independently: 
 i) an aryl group or a heteroaryl group, each of which independently is 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 
 the non-aromatic heterocyclic group represented by —N(R 4 R 7 ) is optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino; 
 each p′ is 1, 2, 3 or 4; and 
 each q′ is 3, 4, 5 or 6. 
   
     
     
         8 . The method of  claim 7 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 4  is an optionally substituted aliphatic group. 
       
     
     
         9 . The method of  claim 8 , wherein:
 R 1  is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl,   
       haloalkyl, —OR 30 , —SR 30 , —N(R 31 ) 2 , 
       Ar 1 , —V o —OR 30 , —V o —N(R 31 ) 2 , —V o —Ar 1 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —O—[CH 2 ] p —O—, —S—[CH 2 ] p —S—, and —[CH 2 ] q —;
 Ar 1  is a phenyl group each 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; and 
 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; and 
 each R 31  is independently R 30 , or —N(R 31 ) 2  is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. 
 
     
     
         10 . The method of  claim 9 , wherein —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. 
     
     
         11 . The method of  claim 10 , wherein the aliphatic group represented by R 4  is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 ,
 Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 50 , —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′ —.   
     
     
         12 . The method of  claim 11 , wherein Y is —H. 
     
     
         13 . The method of  claim 12 , wherein —N(R 2 R 3 ) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group. 
     
     
         14 . The method of  claim 13 , wherein:
 the phenyl group represented by R 1  is optionally substituted with one or more substituents selected from the group consisting of —OR 30 , alkyl, and —O—[CH 2 ] p —O—.   
     
     
         15 . The method of  claim 14 , wherein the aliphatic group represented by R 4  is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, haloalkyl, amino, alkylamino,
 dialkylamino, —OR 50 , —Ar 3 , —V 4 —Ar 3 , —V—OR 50 , —O(haloalkyl), —V 4 —O(haloalkyl), —O—V 4 —Ar 3 , —O—[CH 2 ] p′ —O— and —[CH 2 ] q′ —.   
     
     
         16 . The method of  claim 15 , wherein:
 Ar 3  is 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; and   each R 50  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. 
     
     
         17 .- 21 . (canceled) 
     
     
         22 . The method of  claim 7 , wherein:
 X is —(CR 5 R 6 ) n -Q-; Q   
       is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR 8 —, —NR 8 —, —NR 8 C(O)—, —NR 8 C(O)NR 8 —, —OC(O)—, —SO 3 —, —SO—, —S(O) 2 —, —SO 2 NR 8 —, or —NR 8 SO 2 —; and R 4  is —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; or
 X is —O—, —S— or —NR 7 —; and R 4  is a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; or 
 X is —(CR 5 R 6 ) m —; and R 4  is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, —CN, —NCS, —NO 2  or a halogen; or 
 X is a covalent bond; and R 4  is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and 
 n is 1, 2, 3, 4, 5 or 6. 
 
     
     
         23 . The method of  claim 22 , wherein the compound is represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 7  is —H or C1-C6 alkyl. 
       
     
     
         24 . The method of  claim 23 , wherein:
 R 1  is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, alkyl,   
       haloalkyl, —OR 30 , —SR 30 , —N(R 31 ) 2 , 
       Ar 1 , —V o —OR 30 , —V o —N(R 31 ) 2 , —V o —Ar 1 , —O—V o —Ar 1 , —O—V 1 —N(R 31 ) 2 , —S—V o —Ar 1 , —S—V 1 —N(R 31 ) 2 , —N(R 31 )—V o —Ar 1 , —N(R 31 )—V 1 —N(R 31 ) 2 , —O—[CH 2 ] p —O—, —S—[CH 2 ] p —S—, and —[CH 2 ] q —;
 Ar 1  is a phenyl group each 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; and 
 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; and 
 each R 31  is independently R 30 , or —N(R 31 ) 2  is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. 
 
     
     
         25 . The method of  claim 24 , wherein —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. 
     
     
         26 . The method of  claim 25 , wherein each of the aliphatic group, the aryl group and the heteroaryl group, represented by each of R 4 , R 7  and R 8  independently is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar 3 ,
 Ar 3 —Ar 3 , —OR 50 , —O(haloalkyl), —SR 50 , —NO 2 , —CN, —N(R 51 ) 2 , —NR 51 C(O)R 50 , —C(O)R 50 , —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′ —.   
     
     
         27 .- 64 . (canceled)