Starting from compound5(CCF0058981), a structure-based optimization of the P1 subsite was performed against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). Inhibitor5and the compounds disclosed bind to 3CLprousing a non-covalent mode of action that utilize a His163 H-bond interaction in the S1 subpocket. In an effort to examine more structurally diverse P1 groups a number of azoles and heterocycles were designed. Several azole ring systems and replacements, including C-linked azoles, with similar or enhanced potency relative to 5 were discovered (28,29, and30) with demonstrated IC50values less than 100 nM. In addition, pyridyl and isoquinoline P1 groups were successful as P1 replacements leading to 3-methyl pyridyl36(IC50= 85 nM) and isoquinoline27(IC50= 26 nM). High resolution X-ray crystal structures of these inhibitors were utilized to confirm binding orientation and guide optimization. These findings have implications towards antiviral development and preparedness to combat SARS-like zoonotic coronavirus outbreaks.