This report details the efforts to identify irreversible and reversible peptidomimetic inhibitors of the SARS CoV-1 3CLpro as potential IV agents for the treatment of SARS and other coronavirus diseases. Two classes, acyloxymethylketones and hydroxymethylketones, were discovered as potent inhibitors of the SARS 3CLpro. The hydroxymethylketone derivative 4 demonstrated potent SARS CoV-1 inhibition in 3CLpro and antiviral assays. Additionally, 4 possesses acceptable solubility, stability in plasma, and low in vitro and in vivo clearances suitable for further development as a coronavirus treatment.49 Importantly, the potent inhibition of SARS CoV-2 3CLpro has prompted further preclinical investigations of 4 as a potential therapeutic treatment for patients with COVID-19.