The Synthesis and evaluation of a novel class of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid Hepatitis C virus polymerase NS5B inhibitors

Herein we report the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4′-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested.

Graphical abstractPresented is the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4′-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested.Figure optionsDownload full-size imageDownload as PowerPoint slide