Discovery of imidazo[1,2-b]pyridazine derivatives as potent TRK inhibitors for overcoming multiple resistant mutants.

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently attracted extensive attention as promising cancer therapeutic targets since the approval of Larotrectinib, Entrectinib and Repotrectinib by FDA. Herein, we reported the discovery of a series of novel imidazo[1,2-b]pyridazine derivatives as potent second-generation TRK inhibitors. The representative compound 15m potently inhibited TRKWT, TRKG595R and TRKG667C with IC50 values of 0.08 nM, 2.14 nM and 0.68 nM, respectively. Compound 15m also exhibited good antiproliferative activity against a panel of Ba/F3 cell lines transformed with wild type, xDFG, solvent-front as well as gatekeeper mutant TRK fusion proteins. Furthermore, compound 15m dose-dependently induced apoptosis of Ba/F3-TRKAWT and Ba/F3-TRKAG667C cells. In addition, compound 15m displayed good oral bioavailability (F = 55.26 %). Collectively, compound 15m is a promising lead compound as a TRK inhibitor and deserves further structural optimization to address clinical refractory acquired resistances.