This study reports the design and synthesis of two lead compounds, 11a and 11b, targeting the SARS-CoV-2 main protease (Mpro). Both compounds exhibit excellent inhibitory activity against Mpro and potent anti-SARS-CoV-2 infection activity. X-ray crystal structures of Mpro in complex with 11a and 11b at 1.5 Å resolution reveal that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of Mpro. Both compounds show good pharmacokinetic (PK) properties in vivo, with 11a demonstrating low toxicity, suggesting their potential as promising drug candidates. The SARS-CoV-2 main protease is a key enzyme in the viral life cycle, playing a critical role in viral replication and transcription. The design of inhibitors targeting Mpro is based on the structure of the enzyme and its active site, which is highly conserved among coronaviruses. The inhibitors were designed to form covalent bonds with the enzyme, with the aldehyde group in the P1 position of the inhibitor forming a covalent bond with Cys145. The (S)-γ-lactam ring in the P1 position of the inhibitor fits well into the S1 site of Mpro, and the cyclohexyl group in the P2 position inserts into the S2 site, while the indole group in the P3 position interacts with the S4 site. The compounds 11a and 11b were synthesized through a two-step route, with the ester derivatives first reduced to primary alcohols and then oxidized to aldehydes. The compounds were tested for their inhibitory activity against SARS-CoV-2, showing high inhibition activity with IC50 values of 0.053 ± 0.005 μM and 0.040 ± 0.002 μM for 11a and 11b, respectively. The compounds also exhibited good anti-SARS-CoV-2-infection activity in cell culture, with EC50 values of 0.53 ± 0.01 μM and 0.72 ± 0.09 μM, and high selectivity indices. The crystal structures of Mpro in complex with 11a and 11b reveal that both compounds occupy the substrate-binding pocket and block the enzyme activity of Mpro. The compounds interact with the enzyme through various hydrogen bonds and hydrophobic interactions, with the aldehyde group forming a covalent bond with Cys145. The (S)-γ-lactam ring in the P1 position of the inhibitor fits well into the S1 site of Mpro, and the cyclohexyl group in the P2 position inserts into the SThis study reports the design and synthesis of two lead compounds, 11a and 11b, targeting the SARS-CoV-2 main protease (Mpro). Both compounds exhibit excellent inhibitory activity against Mpro and potent anti-SARS-CoV-2 infection activity. X-ray crystal structures of Mpro in complex with 11a and 11b at 1.5 Å resolution reveal that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of Mpro. Both compounds show good pharmacokinetic (PK) properties in vivo, with 11a demonstrating low toxicity, suggesting their potential as promising drug candidates. The SARS-CoV-2 main protease is a key enzyme in the viral life cycle, playing a critical role in viral replication and transcription. The design of inhibitors targeting Mpro is based on the structure of the enzyme and its active site, which is highly conserved among coronaviruses. The inhibitors were designed to form covalent bonds with the enzyme, with the aldehyde group in the P1 position of the inhibitor forming a covalent bond with Cys145. The (S)-γ-lactam ring in the P1 position of the inhibitor fits well into the S1 site of Mpro, and the cyclohexyl group in the P2 position inserts into the S2 site, while the indole group in the P3 position interacts with the S4 site. The compounds 11a and 11b were synthesized through a two-step route, with the ester derivatives first reduced to primary alcohols and then oxidized to aldehydes. The compounds were tested for their inhibitory activity against SARS-CoV-2, showing high inhibition activity with IC50 values of 0.053 ± 0.005 μM and 0.040 ± 0.002 μM for 11a and 11b, respectively. The compounds also exhibited good anti-SARS-CoV-2-infection activity in cell culture, with EC50 values of 0.53 ± 0.01 μM and 0.72 ± 0.09 μM, and high selectivity indices. The crystal structures of Mpro in complex with 11a and 11b reveal that both compounds occupy the substrate-binding pocket and block the enzyme activity of Mpro. The compounds interact with the enzyme through various hydrogen bonds and hydrophobic interactions, with the aldehyde group forming a covalent bond with Cys145. The (S)-γ-lactam ring in the P1 position of the inhibitor fits well into the S1 site of Mpro, and the cyclohexyl group in the P2 position inserts into the S