Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2–P4 linkers

A series of macrocyclic compounds containing a cyclic constraint in the P2–P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155 K, A156T, A156 V, and D168 V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ∼20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2–P4 linker.