Taking 63 as a lead, aided by its X‐ray structure in complex with SARS‐CoV‐1, HCoV‐NL63, and coxsackievirus Mpros, systematic structural modifications were investigated, focusing on the P2‐moiety. As a result, the replacement of P2‐phenyl with P2‐cyclohexyl (64) was found to be the best substitution, while P2‐cyclopentyl (65) showed similar potency against the enzyme SARS‐CoV‐1 Mpro. In Huh7 cells, 64 also showed strong antiviral activity with an EC50 of 400 pM, but in Vero cells the antiviral activity of 64 was drastically reduced to 5 µM. This compound also exhibited antiviral activity against a range of enteroviruses in various cell lines.