While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC50 value of 2.8 nM, and was much less active against BaF3-FGFR1 and parental BaF3 cells with IC50 values of >1000 nM. Kinase selectivity profiling revealed that BW710 completely abolished FGFR2 enzymatic activity and was selective against other 75 tyrosine kinases including FGFR1, FGFR3, and FGFR4 at 1 μM. The covalent binding mode between BW710 and FGFR2 was confirmed by MS spectrometry. Further evaluation showed that BW710 potently suppressed the FGFR2 signaling and selectively inhibited FGFR2-driven cancer cell proliferation. Additionally, BW710 also displayed reasonable pharmacokinetic properties with an oral bioavailability of 29 % in mice. Taken together, this study provides a potent, selective and orally bioavailable FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.