Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate

The identification of a novel class of potent pan-genotypic
NS5A
inhibitors with good pharmacokinetic profile suitable for potential
use in treating HCV infections is disclosed here. The present series
of compounds are with less complex tricyclic central core, identified
through a systematic SAR study carried out on biphenyl moiety. The
SAR outcome has confirmed the requirement of near planar and linear
conformation of the molecule to achieve the best pan-genotypic activity.
In addition, SAR with substituted imidazoles on improvement of antiviral
activity is disclosed. The newly identified compounds 12, 16, 19–21 have shown
desirable pharmacokinetic profiles with a favorable uptake of compounds
in liver and maintained a significant concentration for up to 8 h
in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to
ledipasvir and daclatasvir. Additional characterization and preliminary
safety assessment resulted in the identification of compound 20 as a potential clinical candidate.