Alphaviruses, a group of widespread, enveloped, single-stranded positive sense RNA viruses, are transmitted by Aedes aegypti and Aedes albopictus mosquitoes, posing a significant threat to public health . These viruses are divided into two categories based on their geographical emergence: Old World alphaviruses, including chikungunya virus (CHIKV), Ross River virus (RRV), and O'nyong-nyong virus (ONNV) that typically present with rash, fever, and prolonged arthralgia that can persist for months post-infection ; and New World alphaviruses, including Venezuelan (VEEV), Western (WEEV) and Eastern (EEEV) Equine Encephalitis viruses and Mayaro virus (MAYV) that often result in encephalitis-like neurological symptoms, accompanied by fever, headache, and nausea, which can be fatal with 30-50% of EEEV cases resulting in mortality . Despite the severity of these diseases, there are currently no FDAapproved drugs for any alphavirus-caused disease, highlighting the urgent need for the development of alphavirus therapeutics. The largest non-structural protein in the alphavirus genome, nsP2, is essential for viral replication . nsP2 contains a C-terminal cysteine protease that uses a catalytic dyad of cysteine and histidine residues to catalyze substrate cleavage. Two covalent inhibitors of alphavirus nsP2 protease that contain a common b-amidomethyl-vinyl sulfone warhead have been recently disclosed (Figure ). Compound #11 was reported as a micromolar inhibitor of VEEV nsP2 protease activity with antiviral activity . Likewise, we reported the discovery of RA-0002034 as potent covalent inhibitor CHIKV nsP2 protease with IC50 = 60 nM . Vinyl sulfone 1 inhibited VEEV and CHIKV replication with EC50 = 0.3 and 0.01 µM, respectively, and decreased viral titer across a wide range of New and Old World alphaviruses . Notably, the 5arylpyrazole in 1 conferred an increase in potency for nsP2 protease inhibition compared to the 1,2-dihydroquinoline in Compound #11 demonstrating the importance of the heterocyclic amide substituent in molecular recognition by the viral protease.