Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole () and 4-cyanopyrazole () analogs exhibited / ratios >9000 M s. 3-Arylisoxazole () was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like . A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.