For this investigation, we targeted the SARS-CoV-2 main protease, M pro , a non-structural protein that plays a key role viral replication. M pro has been noted by several groups to be a promising target for drug design due to its importance in SARS-CoV-2's lifecycle and lack of related homologues in humans which has resulted in the success of approved SARS-CoV-2 antiviral treatments, nirmatrevir (Paxlovid) and ensitrevir (Xocova). Numerous high throughput assays to quantitatively measure M pro inhibition for rapid fragment screening have been developed. We opted for a previously reported fluorogenic assay which utilizes the synthetic fluorogenic M pro substrate, [5-FAM]-AVLQSGFR-[Lys(Dabcyl)]-K-amide. Prior effort from the COVID Moonshot consortium resulted in the rapid discovery of an orally bioavailable, nanomolar inhibitor of M pro , 1, through the use of crowdsourcing, MLdirected synthetic complexity scores, and computationally guided structure activity relationship (SAR) screening. The authors noted the importance of the isoquinoline motif for M pro P1 pocket activity, but a high tolerance of structural variation of the M pro P2 pocket binding motifs. This allowed for the simplification of the original chromane ring to 1's chloro-tetrahydroisoquinoline, which furnished an N-centered handle for further SAR. Library-based derivatization of this handle with Schotten-Baumann sulfomidation resulted in a promising M pro inhibitor drug candidate with improved enzymatic inhibition, antiviral activity, and improved oral bioavailability, highlighting the importance of this tail. We began a further investigation upon the N-centered handle tailoring through