The warhead reactivity and binding affinity to P1′ are both important design considerations to ensure specificity of irreversible inhibitors. Krantz has demonstrated that the inherent chemical reactivity of acyloxymethylketones can be tuned to inhibit cysteine proteases through the modulation of substituent effects on the carboxylate leaving group.37 The importance of leaving group “strength” was confirmed by the strong dependence between the pKa of the leaving carboxylate and cathepsin B enzyme inhibition. These otherwise weak electrophiles are elegant “quiescent” inhibitors that harness the very same interactions with catalytic residues that lead to proteolysis rate acceleration. Molecular modeling of a 2,6-dichlorobenzoate design with SARS CoV-1 3CLpro indicated that a low strain conformation of the ketone carbonyl was aligned in the oxyanion hole and the substituted benzoate is accommodated within the P1′ site. A series of acyloxymethylketone derivatives were prepared, as depicted in Table 1.