Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase

Abstract

The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.

1 . A compound of the structural formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically aceptable salt thereof; 
 wherein R a  and R h  are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C 1-4  alkoxy, C 2-4  alkenyl, C 2-4  alkynyl, and C 1-4  alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4  alkoxy, C 1-4  alkylthio, or one to three fluorine atoms;  
 R b  is C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4  alkoxy, C 1-4  alkylthio, or one to three fluorine atoms;  
 R c  is hydrogen, fluorine, hydroxy, marcapto, C 1-4  alkoxy, or C 1-4  alkyl; or R b  and R c  together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC 0-4  alkyl;  
 R d  is hydrogen, cyano, nitro, C 1-3  alkyl, NHCONH 2 , CONR j R j , CSNR j R j , COOR j , C(═NH)NH 2 , hydroxy, C 1-3  alkoxy, amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl), or (imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3  alkoxy;  
 R e  and R f  are each independently hydrogen, hydroxy, halogen, C 1-4  alkoxy, amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, C 3-6  cycloalkylamino, di(C 3-6  cycloalkyl)amino, or C 4-6  cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C 1-4  alkyl, and C 1-4  alkoxy;  
 R g  is hydrogen, C 1-4  alkyl, C 2-4  alkynyl, halogen, cyano, carboxy, C 1-4  alkyloxycarbonyl, azido, amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, hydroxy, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, (C 1-4  alkyl) 0-2  aminomethyl, or C 4-6  cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C 1-4  alkyl, and C 1-4  alkoxy;  
 R i  is hydrogen, C 1-10  alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R m R n ;  
 each R j  is independently hydrogen or C 1-6  alkyl; 
 R k  and R l  are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and  
 R m  and R n  are each independently hydroxy, OCH 2 CH 2 SC(═O)C 1-4  alkyl, OCH 2 O(C═O)OC 1-4  alkyl, NRCHMeCO 2 Me, OCH(C 1-4  alkyl)O(C═O)C 1-4  alkyl,  
                     
 with the proviso that when R a  and R c  are α-hydroxy, R e  is amino, R b  is β-methyl and R h  is hydrogen or R h  is β-methyl and R b  is hydrogen, and R f , R g , R i , R k , and R l  are hydrogen, then R d  is not cyano or CONH 2 .  
 
 
   
   
       2 . The compound of  claim 1  of the structural formula:  
     
       
         
         
             
             
         
       
       wherein R a  is hydrogen, halogen, hydroxy, amino, or C 1-4  alkoxy;  
       R b  is C 1-3  alkyl, wherein alkyl is optionally substituted with hydroxy, amino, C 1-3  alkoxy, C 1-3  alkylthio, or one to three fluorine atoms;  
       R c  is hydroxy, fluoro, or C 1-3  alkoxy;  
       Rd is hydrogen, cyano, methyl, halogen, or CONH 2 ;  
       R g  is hydrogen, amino, or C 1-4  alkylamino;  
       R i  is hydrogen, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ; and  
       R e  and R f  are each independently hydrogen, halogen, hydroxy, amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, or C 3-6  cycloalkylamino;  
       with the proviso that when R a  and R c  are α-hydroxy, R e  is amino, R b  is β-methyl, and R f , R g , and R i  are hydrogen, then R d  is not cyano or CONH 2 .  
     
   
   
       3 . The compound of  claim 2  wherein 
 R b  is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;    R c  is hydroxy, fluoro, or methoxy;    R a  is hydrogen, fluoro, hydroxy, amino, or methoxy;    R i  is hydrogen or P 3 O 9 H 4 ;    R g  is hydrogen or amino;    R d  is hydrogen, cyano, methyl, halogen, or CONH 2 ; and    R e  and R f  are each independently hydrogen, fluoro, hydroxy, or amino;    with the proviso that when R b  is β-methyl, R a  and R c  are α-hydroxy, R e  is amino, and R f , R g , and R i  are hydrogen, then R d  is not cyano or CONH 2 .    
   
   
       4 . The compound of  claim 1  selected from the group consisting of: 
 4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-methylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-dimethylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-vinyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-hydroxymethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-methyl-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,    4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    2,4-diamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    2-amino-4-cyclopropylamino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    2-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,    4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,    2-amino-5-methyl-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,    4-amino-7-(3-deoxy-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(3-deoxy-2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine,    4-amino-2-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(3-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(3-C-methyl-β-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2,4-di-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and    4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    and the corresponding 5′-triphosphates;    or a pharmaceutically acceptable salt thereof.    
   
   
       5 . The compound of  claim 4  selected from the group consisting of: 
 4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-methyl-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and    4-amino-7-(2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,    and the corresponding 5′-triphosphates;    or a pharmaceutically acceptable salt thereof.    
   
   
       6 . The compound of  claim 5  which is 
 4-amino-7-(2-C-methyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       7 . The compound of  claim 5  which is 
 4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       8 . The compound of  claim 5  which is 
 4-amino-7-(2-C-fluoromethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       9 . The compound of  claim 5  which is 
 4-amino-5-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       10 . The compound of  claim 5  which is 
 4-amino-5-bromo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       11 . The compound of  claim 5  which is 
 4-amino-5-fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;    or a pharmaceutically acceptable salt thereof.    
   
   
       12 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       13 . The pharmaceutical composition of  claim 12  useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA replication, and/or treating RNA-dependent RNA viral infection.  
   
   
       14 . The pharmaceutical composition of  claim 13  wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase, said RNA-dependent RNA viral replication is HCV replication, and said RNA-dependent RNA viral infection is HCV infection.  
   
   
       15 . A method of inhibiting RNA-dependent RNA viral polymerase and/or inhibiting RNA-dependent RNA viral replication comprising administering to a mammal in need of such inhibition an effective amount of a compound according to  claim 1 .  
   
   
       16 . The method of  claim 15  wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase and said RNA-dependent RNA viral replication is HCV viral replication.  
   
   
       17 . A method of treating RNA-dependent RNA viral infection comprising administering to a mammal in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       18 . The method of  claim 17  wherein said RNA-dependent RNA viral infection is HCV infection.  
   
   
       19 . The method of  claim 18  in combination with a therapeutically effective amount of another agent active against HCV.  
   
   
       20 . The method of  claim 19  wherein said agent active against HCV is ribavirin; levovirin; thymosin alpha-1; an inhibitor of NS3 serine protease; an inhibitor of inosine monophosphate dehydrogenase; interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.  
   
   
       21 . The method of  claim 20  wherein said agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.