Design, synthesis and biological evaluations of a series of Pyrido[1,2-a]pyrimidinone derivatives as novel selective FGFR inhibitors

Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2- a ]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure–activity relationships and preliminary assessment identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro . Candidate 23d suppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile, 23d showed excellent kinase selectivity for the FGFR family. Furthermore, 23d showed higher aqueous solubility than Erdafitinib. Moreover, 23d exhibited potent antitumor activity (tumor growth inhibition = 106.4%) in FGFR2-amplified SNU-16 gastric cancer xenograft model using a daily oral dose of 30 mg/kg. These results suggest that 23d is a promising candidate for further drug development. • A series of pyrido[1,2- a ]pyrimidinone derivatives were identified as novel FGFR inhibitors. • Compound 23d exhibited excellent in vitro activity and good kinase selectivity. • Compound 23d showed a significantly improved solubility compared with Erdafitinib. • Potent in vivo antitumor efficacy encouraged compound 23d to be a promising drug candidate.