Design, Synthesis, and Biological Evaluation of 2‑Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound 9ka exhibited an IC 50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome selectivity. Compound 9ka also exhibited good oral pharmacokinetic properties with an AUC (0‑t) value of 38 950.06 h·ng/mL, a T 1/2 value of 3.06 h, and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon 30 mg/kg oral administration. Compound 9ka may serve as a promising lead compound for further anticancer drug development.