Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2

[Display omitted] •N-substituted 1,6-naphthyridinones was identified as new MET inhibitor.•Lead compound 4r displayed promising selectivity against VEGFR-2.•Excellent PK profiles and antitumor efficacy brought 4r to further optimization. New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors.