Compounds and pharmaceutical compositions for the treatment of viral infections

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorders, including HCV infections. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, wherein;
 R is a moiety derivable by removal of a hydrogen from a hydroxy group of an antiviral drug; 
 X is O or S; 
 Q is OR 4 , SR 4  or NR 5 R 6 ; 
 each E is independently CR 7 R 8 ; 
 each n is 1 or 2; 
 R 1  and R 2  are selected as follows: 
 i) R 1  and R 2  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl; 
 ii) R 1  and R 2  together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; or 
 iii) R 1  is hydrogen, alkyl or cycloalkyl, and R 2  is (G) m C(O)Q 1 , wherein
 Q 1  is OR 4 , SR 4  or NR 5 R 6 ; 
 each G is independently CR 7 R 8 ; and 
 each m is 1 or 2; 
 
 R 3  and R 4  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl or cycloalkenyl; 
 R 5  and R 6  are selected as follows: 
 i) R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl or cycloalkenyl; or 
 ii) R 5  and R 6  together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and 
 R 7  and R 8  are selected as follows: 
 i) R 7  and R 8  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein alkyl is optionally substituted by alkoxy; or 
 ii) R 7  and R 8  together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring; and 
 
         wherein if R 2  is (G) m C(O)Q 1 , G is CR 7 R 8 ; m is 1, and one of R 7  or R 8  is hydrogen, the other of R 7  and R 8  is C 4 -C 6  alkyl. 
       
     
     
         2 .- 46 . (canceled) 
     
     
         47 . A compound of formula II, 
       
         
           
           
               
               
           
         
         wherein Base is selected from one of formulae (i) to (xv): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R L  is independently hydrogen, alkyl, cycloalkyl, acyl, carbamyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester, alkyl sulfonyl, aryl sulfonyl, arylalkyl sulfonyl, a lipid, a phospholipid, an amino acid or a carbohydrate; and each R M  is independently hydrogen or alkyl; or R L  and R M  together with the N atom to which they are attached from heterocyclyl. 
       
     
     
         48 . The compound of  claim 47 , wherein R L  is hydrogen, alkyl or cycloalkyl. 
     
     
         49 . The compound of  claim 47 , wherein R L  is cyclopropyl or cyclopentyl. 
     
     
         50 . The compound of  claim 47 , wherein R L  is methyl, ethyl, propyl, or isopropyl. 
     
     
         51 . The compound of  claim 47 , wherein R M  is hydrogen. 
     
     
         52 . The compound of  claim 47 , wherein R M  is methyl. 
     
     
         53 . The compound of  claim 47 , wherein R L  and R M  together with the N atom to which they are attached from pyrrolidinyl or morpholinyl. 
     
     
         54 .- 55 . (canceled) 
     
     
         56 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         57 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         58 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         59 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         60 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         61 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         62 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         63 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         64 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         65 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         66 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         67 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         68 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         69 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         70 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         71 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         72 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         73 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         74 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         75 . A compound of  claim 1 , or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         76 .- 82 . (canceled)