Modified fluorinated nucleoside analogues

Abstract

The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.

1 - 129 . (canceled) 
   
   
       130 : A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of the formula: 
     
       
         
         
             
             
         
       
       wherein 
       Base is a purine or pyrimidine base; 
       X is O, S, CH 2 , Se, NH, N-alkyl, CHW (R, S, or racemic), C(W) 2 , wherein W is F, Cl, Br, or I; 
       R 1  and R 7  are independently H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, H-phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyallylamino or its peptide derivatives, sulfonate ester, including alkyl or arylallyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid (or racemic mixture), a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  is H or phosphate; 
       R 2  is H or phosphate; R 1  and R 2  or R 7  can also be linked with cyclic phosphate group; 
       R 2  and R 2′  are independently H, C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-4  allyl), C(O)O(C 1-4  alkyl), C(O)O(C 1-4  alkynyl), C(O)O(C 1-4  alkenyl), O(C 1-4  acyl), O(C 1-4  alkyl), O(C 1-4  alkenyl), S(C 1-4  acyl), S(C 1-4  allyl), S(C 1-4  alkynyl), S(C 1-4  alkenyl), SO(C 1-4 acyl), SO(C 1-4  alkynyl), SO(C 1-4  alkynyl), SO(C 1-4  alkenyl), SO 2 (C 1-4  acyl), SO 2 (C 1-4  alkyl), SO 2 (C 1-4  allynyl), SO 2 (C 1-4  alkenyl), O 3 S(C 1-4  acyl), O 3 S(C 1-4  alkyl), O 3 S(C 1-4  alkenyl), NH 2 , NH(C 1-4  alkyl), NH(C 1-4  alkenyl), NH(C 1-4  alkynyl), NH(C 1-4  acyl), N(C 1-4  alkyl) 2 , N(C 1-18  acyl) 2 , wherein allyl, alkynyl, alkenyl and vinyl are optionally substituted by N 3 , CN, one to three halogen (Cl, Br, F, I), NO 2 , C(O)O(C 1-4  alkynyl), C(O)O(C 1-4  alkyl), C(O)O(C 1-4  alkynyl), C(O)O(C 1-4  alkenyl), O(C 1-4  acyl), O(C 1-4  alkyl), O(C 1-4  alkenyl), S(C 1-4  acyl), S(C 1-4  allyl), S(C 1-4  alkynyl), S(C 1-4  alkenyl), SO(C 1-4  acyl), SO(C 1-4  alkyl), SO(C 1-4  allynyl), SO(C 1-4  alkenyl), SO 2 (C 1-4  acyl), SO 2 (C 1-4  alkyl), SO 2 (C 1-4  allynyl), SO 2 (C 1-4  alkenyl), O 3 S(C 1-4  acyl), O 3 S(C 1-4  allyl), O 3 S(C 1-4  alkenyl), NH 2 , NH(C 1-4  alkyl), NH(C 1-4  alkenyl), NH(C 1-4  alkynyl), NH(C 1-4  acyl), N(C 1-4  allyl) 2 , N(C 1-4  acyl) 2 , OR 7 ; R 2  and R 2  can be linked together to form a vinyl optionally substituted by one or two of N 3 , CN, Cl, Br, F, I, NO 2 ; and 
       R 6  is an optionally substituted alkyl (including lower alkyl), cyano (CN), CH 3 , OCH 3 , OCH 2 CH 3 , hydroxy methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N3), CHCN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , alkyne (optionally substituted), or fluoro; 
       or its pharmaceutically acceptable salt or prodrug thereof.