Indeed, the resulting 66 had a ~3‐fold improved plasma half‐life in mice when compared to the lead 65 (from 18 min to 1 h). The in vitro kinetic plasma solubility has been increased by a factor of ~19 (from 6 µM for the lead to 112 µM for best derivative), and the thermodynamic solubility by a factor of ~13 (from 41 to 530 µM). Compound 66 also showed reduced binding to mouse plasma protein. However, compared to the lead (IC50, 0.18 µM), the structural modifications caused a reduction of activity against SARS‐CoV‐2 Mpro (IC50, 2.39 µM) and enteroviral 3 C proteases. Nevertheless, the introduction of a cyclopropyl group as in 67 instead of P2‐cyclohexyl enhanced the antiviral activity against β‐coronaviruses.