Discovery of Pyrrolopyrazine Carboxamide Derivatives as Potent and Selective FGFR2/3 Inhibitors that Overcome Mutant Resistance.

Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated with FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker and electrophile moieties based on the pyrrolopyrazine carboxamide core and identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound potently inhibited FGFR2 and FGFR3, even in the context of common inhibitor-resistance mutations, including in the gatekeeper, molecular brake, and activation loop regions. Compound spared FGFR1/4 and other kinases without causing diarrhea and serum phosphate elevation . Oral administration of compound induced tumor stasis or regression in the SNU-16 gastric cancer model with favorable pharmacokinetics and robust pharmacodynamic suppression.