M ^pro , the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M ^pro inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M ^pro and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M ^pro and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M ^pro . The most active compound from this chemotype inhibited M ^pro in vitro with an IC ₅₀ value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M ^pro was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.