Design, synthesis and biological evaluation of a series of 5-chloropyridine ester-derived severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors is described. Position of the carboxylate functionality is critical to potency. Inhibitor 10 with a 5-chloropyridinyl ester at position 4 of the indole ring is the most potent inhibitor with a SARS 3Clpro IC 50 value of 30 nM and antiviral EC 50 value of 6.9 μM. Molecular Docking studies have provided possible binding modes of these inhibitors.