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 =l O(C═O)OC   l-4  alkyl, NHCHMeCO 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 1  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;  
         R d  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 H4;    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]upyrimidine, 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]lpyrimidine, 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-ethyl-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.