Fig. 1

nsP2pro inhibitor RA-0002034 (1) undergoes slow intramolecular cyclization to the inactive (2) Isoxazole SGC-NSP2PRO-1 (3) is chemically stable and a potent nsP2pro inhibitor. SGC-NSP2PRO-1N (4) is an inactive analog that retains the vinyl sulfone covalent warhead.