MK-8831

A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC₅₀ values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.