Although FGFR inhibitors hold promise in treating various cancers, resistance to the FGFR inhibitors caused by acquired secondary mutations has emerged. To discover novel FGFR inhibitors capable of inhibiting FGFR mutations, including gatekeeper mutations, we designed and synthesized several new pyridinyltriazine derivatives. A structure-activity relationship (SAR) study led to the identification of 17a as a highly potent panFGFR inhibitor against wild-type and mutant FGFRs. Notably, 17a is superior to infigratinib in terms of kinase-inhibitory and cellular activities, especially against V555M-FGFR3. Molecular dynamics simulations provide a clear understanding of why pyridinyltraizine derivative 17a possesses activity against V555M-FGFR3. Moreover, 17a significantly suppresses proliferation of cancer cells harboring FGFR mutations via FGFR signaling blockade, cell cycle arrest, and apoptosis. Furthermore, 17a and 17b exhibited remarkable efficacies in TEL-V555M-FGFR3 Ba/F3 xenograft mouse model and 17a is more efficacious than infigratinib. This study provides new insight into the design of novel FGFR inhibitors that are active against FGFR mutants.