The SARS-CoV-encoded papain-like cysteine protease (PLpro) plays crucial roles in viral replication and maturation processes. It is required to cleave the precursor polyproteins into functional proteins. Thus, it is considered to be a promising target for developing specific drugs. For rational optimization of hit compounds, information about the structure-activity relationship (SAR) is fundamental. Herein, we characterize isoindolines as a new class of PLpro inhibitors.