Inhibition of coronavirus (CoV) -encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens . Herein we report on structure-activity relationships (SAR) of the non-covalent active-site directed inhibitor (R) -5-amino-2-methyl-N- (1- (naphthalen-1-yl) ethyl) benzamide (2b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro . Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors . The studies also provide a deeper understanding of the binding modes of this inhibitor class . Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.