Design of fibroblast growth factor receptor (FGFR) inhibitors containing a 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one motif.

The fibroblast growth factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and various other physiological processes. In this study, we have designed and synthesized a series of FGFR inhibitors featuring the 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one scaffold as a core structural motif. Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR inhibitor. In preclinical evaluations, 1a exhibited remarkable pharmacokinetic properties (oral bioavailability = 66.9%). In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR inhibitor for cancer treatment, supporting its further development in clinical settings.