Discovery of a 2′-fluoro-2′-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties

[Display omitted] A series of 2′-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.