Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC<sub>50</sub> = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC<sub>50</sub> = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC<sub>50</sub> = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.