3CPLro-IN-2 (compound C1) is a potent and orally active inhibitor of SARS-CoV-2 3CLpro with an IC 50 and K i of 1.55 and 6.09 μM, respectively. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive agent target for fighting COVID-19.