Starting from compound 5 (CCF0058981), a structure-based optimization of the P1 subsite was performed against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). Inhibitor 5 and the compounds disclosed bind to 3CLpro using 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, and 30) with demonstrated IC50 values <100 nM. In addition, pyridyl and isoquinoline P1 groups were successful as P1 replacements leading to 3-methyl pyridyl 36 (IC50 = 85 nM) and isoquinoline 27 (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 toward antiviral development and preparedness to combat SARS-like zoonotic coronavirus outbreaks.Graphical Abstract