Further studies on hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors toward improved replicon cell activities: benzimidazole and structurally related compounds bearing the 2-morpholinophenyl moiety

Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).