Synthesis and SAR of geminal substitutions at the C5′ carbosugar position of pyrimidine-derived HCV inhibitors

The installation of geminal substitution at the C5′ position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5′ position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.