Discovery of Benzoheterocyclic-Substituted Amide Derivatives As Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors.

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, IC50 = 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 (IC50 > 10 mu M).