VEGFR-2 plays a critical role in vasculogenesis and VEGFR-2 inhibitors have been broadly used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we identified a potent lead compound (HMQ-16) bearing biphenyl scaffold. Rearragement and replacement of arylcarbamoyl in HMQ-16 with urea moiety generated a series of novel VEGFR-2 inhibitors. In order to enhance the affinity with VEGFR-2, 4'-acetyl group was converted to oxime group. Fourteen biphenyl urea derivatives were designed and synthesized as potent VEGFR-2 inhibitors. Six of them (T2, T5, T7, T9, T11, T14) exhibited potent VEGFR-2 inhibitory activity comparable to that of Sorafinib. Compound T7 was the most potent with an IC50 value of 1.08 nM. The enzymatic and cellular assays suggested that T7 has potential as a valuable lead compound for further optimization.