Three series of benzoheterocyclic-substituted amide derivatives were designed and synthesized as potent ASK1 inhibitors in this work. After undergoing continuous structural optimization, compound 17a was discovered to be a novel inhibitor of ASK1 with good potency (kinase, IC 50 = 26 nM), noteworthy liver microsomal stability (human, T 1/2 = 340.4 min), good pharmacokinetic parameters (rat, T 1/2 p.o. = 2.11 h, AUC last p.o. = 10 900 h ng mL -1 ) and high oral bioavailability (rat, F = 97.9%), while also being inactive towards hERG (IC 50 > 10 μM).