Pan-NS3 protease inhibitors of hepatitis C virus based on an R-elongated pyrazinone scaffold

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated Rurea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (K = 30 nM) and R155K (K = 2 nM), and genotype 3a (K = 5 nM).