Protein tyrosine phosphatase 1B (PTP1B) is a key factor in negative regulation of the insulin pathway, and is a promising target for the treatment of type-II diabetes, obesity and cancer. Herein, compound ($mathbf{4}$) was first observed to have moderate inhibitory activity against PTP1B with an $IC_{50}$ value of $13.72{pm}1.53{mu}M$. To obtain more potent PTP1B inhibitors, we synthesized a series of chalcone derivatives using compound ($mathbf{4}$) as the lead compound. Compound $mathbf{4l}$ ($IC_{50}=3.12{pm}0.18{mu}M$) was 4.4-fold more potent than the lead compound $mathbf{4}$ ($IC_{50}=13.72{pm}1.53{mu}M$), and more potent than the positive control, ursolic acid ($IC_{50}=3.40{pm}0.21{mu}M$). These results may help to provide suitable drug-like lead compounds for the design of inhibitors of PTP1B as well as other PTPs.