Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase.

Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl) piperazine-2- carboxamideinhibitors of the hepatitis Cviral polymerase are described herein. These compounds bind to the hepatitis C virusnon-structural protein 5B ( NS5B), and co- crystal structuresof select examples from this series with NS5Bare reported. Comparison of co- crystal structuresof a potent analog with both NS5Bgenotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.