Abstract: In this study, a series of novel biaryl amide derivatives featuring an acrylamide covalent warhead were designed and synthesized. The antiviral efficacy of these synthesized compounds against the human β-coronavirus HCoV-OC43 were evaluated using the CCK-8 assay. Among them, compound 6b, containing a 2-fluoroacrylamide covalent warhead, exhibited significant antiviral activity with an EC₅₀ value of 2.52 μmol·L^-1 and a selectivity index (SI) of 29, suggesting a reasonable therapeutic window. Molecular docking studies revealed that compound 6bcould inhibit the activities of host transmembrane serine protease 2 (TMPRSS2) and viral 3-chymotrypsin like protease (3CL^pro) through covalent bond formation, thereby exerting its antiviral effects. These findings not only expand the structural diversity of this class of compounds but also highlight their potential applications in antiviral therapy. Compound 6brepresents an ideal lead compound for the development of a new class of covalent antiviral drugs against coronaviruses.