Des-A-ring benzothiadiazines: Inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase

Described herein is a set of non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase based on a benzothiadiazine screening hit. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, a minimum core required for activity was explored. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies. In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure–activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.