Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2′-cyano, azido or amino nucleosides according to Formula 1001 or 2001: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R 1 and R 2 are as described herein.

1 . A compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein:
 Base is a nucleobase; 
 R 1  is cyano, azido or amino; and 
 R 2  is hydrogen, halo, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 7  cycloalkyl. 
 
       
     
     
         2 . The compound of  claim 1  according to Formula Ia or Ib: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  according to Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3  according to Formula IIa or IIb: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1  according to Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5  according to Formula IIIa or IIIb: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  according to Formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 3  according to Formula IVa or IVb: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein:
 Base is   
       
         
           
           
               
               
           
         
       
       or a tautomer thereof;
 R 4  is hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino or alkoxy; 
 R 5  is hydrogen, halogen or methyl; and 
 R 6  is hydrogen, amino, or halo. 
 
     
     
         10 . The compound of  claim 9  according to any of Formulas (V)-(XVI): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 2  is hydrogen, methyl, or halo. 
     
     
         13 . The compound of  claim 1  according to any of Formulas 1-3: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient, carrier or diluent. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the composition is an oral formulation. 
     
     
         16 . A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the host is a human. 
     
     
         18 . The method of  claim 16 , wherein the administration directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host. 
     
     
         19 . The method of  claim 16 , wherein the compound or composition is administered in combination or alternation with a second anti-viral agent, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof. 
     
     
         20 . The method of  claim 19 , wherein the second anti-viral agent is telaprevir, boceprevir, samatasvir, simeprevir, sofosbuvir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, or a combination thereof. 
     
     
         21 . The method of  claim 19 , wherein the second anti-viral agent is telaprevir, boceprevir, samatasvir, simeprevir, sofosbuvir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, or a combination thereof, and further wherein the administration is not in combination or alternation with ribavirin.