VEGFR-2, Tie-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we developed a series of pyridines incorporated with 1,2,3-triazole as multi-target inhibitors based on the crystal structure alignment of the kinase domain of angiogenic RTKs. Biological results indicated that these multi-target inhibitors displayed considerable potential as novel anti-angiogenic agents. Among them, compound BD7 exhibited the most potent inhibition against the three RTKs simultaneously, and good activity on inhibiting viability of human umbilical endothelial cells. Therefore, 1,2,3-triazole could serve as a promising DFG binding group for multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 bearing pyridine as hinge binding group.