Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants

The
discovery of potent and pan-genotypic HCV NS5A inhibitors faces
many challenges including the significant diversity among genotypes,
substantial potency shift conferred on some key resistance-associated
variants, inconsistent SARs between different genotypes and mutants,
and the lacking of models of inhibitor/protein complexes for rational
inhibitor design. As part of ongoing efforts on HCV NS5A inhibition
at Merck, we now describe the discovery of a novel series of chromane
containing NS5A inhibitors. SAR studies around the “Z”
group of the tetracyclic indole scaffold explored fused bicyclic rings
as alternates to the phenyl group of elbasvir (1, MK-8742)
and identified novel chromane and 2,3-dihydrobenzofuran derivatives
as “Z” group replacements offered good potency across
all genotypes. This effort, incorporating the C-1 fluoro substitution
at the tetracyclic indole core, led to the discovery of a new series
of NS5A inhibitors, such as compounds 14 and 25–28, with significantly improved potency against
resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a
L31V. Compound 14 also showed reasonable PK exposures
in preclinical species (rat and dog).