Inhibitors of HCV NS5B polymerase

Abstract

The present invention provides compounds of Formula I, compositions and methods that are useful for treating viral infections and associated diseases, particularly HCV infections and associated diseases.

1 . A compound of formula 1:  
     
       
         
         
             
             
         
       
     
     wherein: 
 a) X represents a covalent bond or is selected from the group NR2, S, O, C═O, C(R2)(R′2), CF 2 , CCl 2 , CR2OR′2, CR2NR′2, SO, and SO 2 ;  
 b) Y is selected from the group substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroalkyl;  
 c) Z is selected from the group substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
 d) any two adjacent substituents of Y or Z may be taken together to form a fused carbocyclic or heterocyclic ring of 5 to 7 members;  
 e) R1 is selected from the group H, alkyl, hetero-C 1- C 8 -alkyl, halogen, CN, halo C 1- C 8- alkyl, aryl, heteroaryl, cyclo-C 1- C 8- alkyl and ara-C 1 -C 8 -alkyl;  
 f) R2 is H, C 1- C 8 -alkyl, C 1- C 8  -alkenyl, hetero C 1- C 8  alkyl, C 1- C 8  cycloalkyl, heterocyclo C 1- C 8 alkyl, aryl, ara C 1 C 8  alkyl, heteroaryl or heteroaralkyl;  
 g) R3 is selected from the group H, OH, OR2, N(R2)(R′2) and N(R2)-T-W where T represents a substituted or unsubstituted alkyl or cycloalkyl group of 1-8 carbons;  
 h) W is selected from the group OH, N(R2)(R′2), CON(R2)(R′2), OCO N(R2)(R′2), NCON(R2)(R′2) and CO 2 R2;  
 i) A represents a substituted or unsubstituted aromatic ring;  
 j) the substituents X and R1-double bond (R1C═) are connected to A in a 1,2 1,3 or 1,4 spatial relationship; and  
 k) the substituents A and COR3 have an E (trans) configuration with respect to the double bond to which they are attached.  
 
   
   
       2 . A compound of formula 1:  
     
       
         
         
             
             
         
       
       a) wherein: X represents a covalent bond or is selected from the group NR2, S, O, C═O, C(R2)(R′2), CF 2 , CCl 2 , CR2OR′2, CR2NR′2, SO, and SO 2 ;  
       b) Y is selected from the group substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroalkyl;  
       c) Z is selected from the group substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
       d) any two adjacent substituents of Y or Z may be taken together to form a fused carbocyclic or heterocyclic ring of 5 to 7 members;  
       e) R1 is selected from the group H, alkyl, hetero-C 1- C 8 -alkyl, halogen, CN, halo C 1- C 8 -alkyl, aryl, heteroaryl, cyclo-C 1- C 8 -alkyl and ara-C 1- C 8 -alkyl;  
       f) R2 is H, C 1- C 8 -alkyl, C 1- C 8  -alkenyl, hetero C 1- C 8  alkyl, C 1- C 8  cycloalkyl, heterocyclo C 1- C 8  alkyl, aryl, ara C 1- C 8  alkyl, heteroaryl or heteroaralkyl;  
       g) R3 is selected from the group H, OH, OR2, N(R2)(R′2) and N(R2)-T-W where T represents a substituted or unsubstituted alkyl or cycloalkyl group of 1-8 carbons;  
       h) W is selected from the group OH, N(R2)(R′2), CON(R2)(R′2), OCO N(R2)(R′2), NCON(R2)(R′2) and CO 2 R2;  
       i) A represents a substituted or unsubstituted heteroaromatic ring of 5 or 6 members;  
       j) the substituents X and R1-double bond (R1C═) are connected to A in a 1,2 1,3 or 1,4 spatial relationship; and  
       k) the substituents A and COR3 have an E (trans) configuration with respect to the double bond to which they are attached.