The NS5A target of hepatitis C virus (HCV) is a non-structural protein and be essential for viral replication and infectivity, and it has been intensively studied in the discovery of new HCV-NS5A inhibitors since 2002. This presentation discloses our SAR based discovery of highly potent HCV NS5A inhibitors with pan-genotypic picomolar potency and structure-dependent stability. To overcome the structure-based stability problem of some marketed HCV-NS5A inhibitors, different kinds of SAR related compounds have been prepared and evaluated for screening of the potency and stability issues, and several stable structure of new HCV-NS5A inhibitors had not only outstanding pan-genotypic picomolar potency (EC50: picomolar potency, 5-50pM for all GT-1 to GT-6, resp.), but also excellent safety and PK in rats and dogs. Moreover, some preclin. studies have been studied with several potent and stable inhibitors, and there were no any side effect determined with different kinds of potential targets such as hERG, Y93N, Cytochrome P 450, etc, resp. Its metabolic stability is very good, and could be formulated as once-daily dosing tablet. Regarding the safety issue, there was no any death, no any serious drug-related toxicity and adverse events observed during toxicity study in rats (100-2000mg/kg/day, resp.). In conclusion, several of discovered HCV-NS5A inhibitors had all pan-genotypic picomolar potency, excellent safety and stability, which appeared much better than other reported NS5A inhibitors. Our goal is to develop a leading anti-HCV DAA combination therapy with one of our optimized NS5A inhibitors ZN6188 and another best-in-class NS3 inhibitor ZN2007 in clin. studies.