Hepatits B virus (HBV) is an infectious disease, which can cause acute and chronic infections. Every year, an over 7.5 million person dies due to HBV. No effective drug exists for the treatment of HBV. Thus, we designed and synthesized 16 new pyridine-pyrazole-sulfonate compounds containing pyridine-SCH2-pyrazole and pyridine-pyrazole derivatives. Their structures were characterized by 1 H-NMR, 13C-NMR, IR, mass spectroscopy, and high performance liquid chromatography. All the compounds were evaluated for their anti-HBV activities and established the structure-activity relationship (SAR) in HepG2 2.2.15 cells. We found the pyridine-pyrazole derivatives could inhibit the HBV gene expression and viral DNA replication. Among these compounds, 2-[3-(2-nitrophenylsulfonyl)oxy-5-pyrazol-yl]pyridine 19d shown the most potent inhibitory activity with IC50 value of 9.19 µM, and high selectivity index, SI (TC50/IC50) 35.46. Hence, we believe our compounds could serve as reservoir for anti-HBV drug development.