The pandemic of the Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused hundreds of millions of infections worldwide [1]. Although the major pandemic was over, SARS-CoV-2 is spreading sporadically, which is a long-term threat to humans. Antivirals against SARS-CoV-2 is an effective strategy to deal with this threat. The SARS-CoV-2 genome encodes four structural proteins and two overlapping polyproteins, pp1a and pp1ab. These long polyproteins are processed into 16 functional non-structural proteins (NSPs) by two self-encoded cysteine proteases, papain-like protease (PLpro) and the main protease (Mpro or 3CLpro) [2], [3]. Some of them are considered as potential drug targets for the treatment of COVID-19, including Mpro, PLpro, spike protein and others [4]. Among these targets, Mpro is an ideal target for the development of antiviral drugs due to its key role in the viral life cycle, its significant difference with human proteases, and its high conserved nature in its variants and other coronaviruses [5].

Up to now, a number of Mpro inhibitors have been reported, such as N3 [6], [7], 13b [8], 11a [9], MI-09 [10], SY110 [11], Nirmatrelvir [12], Simnotrelvir [13] and Ensitrelvir [14] (Fig. 1). Ensitrelvir [14], a non-covalent inhibitor, has been approved by Japan Pharmaceuticals and Medical Devices Agency (PMDA) for the treatment of mild to moderate infection by SARS-CoV-2 in adults. Nirmatrelvir [12], a covalent inhibitor developed by Pfizer Inc., has been officially approved by the US Food and Drug Administration (FDA). As analogue to Nirmatrelvir, Simnotrelvir [13] has been commercialized in combination with ritonavir in China. SY110 [11] developed by our group is a new generation antiviral drug candidate against Omicron and other variants of SARS-CoV-2, which has been approved for clinical study. However, according reports [15], [16], α-ketoamides, with chiral tertiary carbon next to ketoamide, such as the launched drug Telaprevir [17], [18] and Boceprevir [19], [20], are epimerizable under physiological conditions and convert into inactive configuration. SY110 has considerable possibility for epimerization. Here we report an attempt to overcome the potential epimerization of SY110 by deriving from quaternized P1 groups.