L0909 is an orally available inhibitors of Hepatitis C virus with a novel mechanism of action (EC50 = 0.022 μM, SI > 600). L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.