Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors

FGFR has been considered a crucial oncogenic driver and promising target for cancer therapy. Herein, we reported the design and synthesis of 3-amino-<i>N</i>-(3,5-dihydroxyphenyl)-6-methylpyrazine-2-carboxamide derivatives as novel FGFR inhibitors. SAR exploration led to the identification of <b>18i</b> as a pan-FGFR inhibitor with favorable <i>in vitro</i> activity against FGFR1-4. Moreover, <b>18i</b> blocked the activation of FGFR and downstream signaling pathways at the submicromolar level and exhibited potent antitumor activity in multiple cancer cell lines with FGFR abnormalities. Molecular docking was performed to investigate the possible binding modes of <b>18i</b> within the binding site of FGFR2. These results suggest that compound <b>18i</b> is a promising candidate for further drug discovery.