Abstract There is an urgent need for a safe, highly effective orally bioavailable drug that can be used in the outpatient setting. Ideally, such drugs would have broad-spectrum potential and would be activity against SARS-CoV-2 and other existing and potentially future emergent coronaviruses. A viable strategy to accelerate drug development is repositioning of approved drug and/or existing clinical candidates as chemical scaffolds to create new chemically optimized clinical development candidates. Working in partnership with a team of drug hunters at Merck, focused compound libraries derived from existing antiviral classes discovered/developed against other conserved viral targets and new Lead series to both host and viral targets were screened. The most promising candidates were found to target the main (3CL or MPro) protease. The 3CLpro inhibitors being optimized are peptidyl mimetics of the active site amino acid substrates that were derived from an initial hit boceprevir. Boceprevir is an HCV NS3 protease inhibitor developed by Merck as the first direct acting antiviral used to treat HCV-infection. Initial structure-based optimization of 3CLpro was used to increase analog potency >170-fold relative to the parent compound. Program protease inhibitors now under optimization represent multiple distinct sub-series of new chemical entities. To aid in this process, a robust cell-based SARS-CoV-2 replicon system was established to rapidly evaluate compounds for potency. Lead compounds with inhibitory activity of <10 nM were identified following detailed dose response in EC50,90/CC50 studies yielding therapeutic index ratios >1000. The compounds have suitable pharmacologic development properties and are candidates for animal efficacy studies. The objective of this program is to establish Optimized Leads suitable as oral drug candidates to enter IND enabling studies by 1) finalizing Leads for in vitro potency (IC90 <10 nM; EC50 <10 nM) and safety (CC50 >10 µM) with high therapeutic index >1000; and in vivo lung efficacy against SARS-CoV-2 (TCID50 >5 logs) and other coronaviruses; 2) define PK/PD Relationships, tolerability, resistance, and pre-IND considerations, and 3) perform IND-enabling and de-risking studies. This Program takes advantage of the Merck’s team expertise in developing antiviral drugs and the MAVDA in providing high-end Core support for animal models, resistance assessment, and access to viral models beyond SARS-CoV-2.