A series of new acrylamide derivatives containing 1,2,3-thiadiazole were synthesized, characterized, and evaluated for their anti-hepatitis B virus (HBV) activities in vitro. The IC50 of compounds 9b (10.4 microg/mL), 9c (3.59 microg/mL) and 17a (9.00 microg/mL) of the inhibition on the replication of HBV DNA were higher than that of the positive control lamivudine (14.8 microg/mL). Compound 9d exhibited significant activity against secretion of HBeAg (IC50=12.26 microg/mL).