5‐Halopyridinyl esters are troublesome drug candidates because of their potential for rapid hydrolysis by various esterases and other enzymes in mammalian cells. They can potentially also react nonspecifically with other thiols and nucleophiles, a recipe for cytotoxicity. To bypass this problem by developing stable noncovalent inhibitors, Zhang et al. 174  reported a group of methylene ketones and analogous mono‐ and di‐fluorinated methylene ketones based on pyridinyl esters (102 and 103; Figure 28) as SARS‐CoV‐1 Mpro inhibitors. Enzymatic investigations and ESI‐MS experiments illustrate that those inhibitors bind to their target in a noncovalent, reversible manner.