This study focuses on the structure-based design and synthesis of antiviral drug candidates targeting the SARS-CoV-2 main protease (Mpro). Two lead compounds, 11a and 11b, were designed and synthesized, both exhibiting excellent inhibitory activity against Mpro with IC50 values of 0.053 ± 0.005 μM and 0.040 ± 0.002 μM, respectively. High-resolution X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, revealing that the aldehyde groups of both compounds covalently bind to Cys145 of Mpro. In vitro studies showed that both compounds effectively inhibited SARS-CoV-2 infection with EC50 values of 0.53 ± 0.01 μM and 0.72 ± 0.09 μM, respectively, without causing significant cytotoxicity. Pharmacokinetic (PK) properties of 11a were favorable, with a half-life of 4.27 hours and a high bioavailability of 87.8%. In vivo toxicity studies in SD rats and Beagle dogs indicated that 11a was safe and worth further clinical investigation. These findings suggest that 11a and 11b are promising drug candidates for the treatment of COVID-19.This study focuses on the structure-based design and synthesis of antiviral drug candidates targeting the SARS-CoV-2 main protease (Mpro). Two lead compounds, 11a and 11b, were designed and synthesized, both exhibiting excellent inhibitory activity against Mpro with IC50 values of 0.053 ± 0.005 μM and 0.040 ± 0.002 μM, respectively. High-resolution X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, revealing that the aldehyde groups of both compounds covalently bind to Cys145 of Mpro. In vitro studies showed that both compounds effectively inhibited SARS-CoV-2 infection with EC50 values of 0.53 ± 0.01 μM and 0.72 ± 0.09 μM, respectively, without causing significant cytotoxicity. Pharmacokinetic (PK) properties of 11a were favorable, with a half-life of 4.27 hours and a high bioavailability of 87.8%. In vivo toxicity studies in SD rats and Beagle dogs indicated that 11a was safe and worth further clinical investigation. These findings suggest that 11a and 11b are promising drug candidates for the treatment of COVID-19.