Design and Synthesis of Pyrazoline Inhibitors of SARS-CoV‑2 NSP14

Non-structural protein 14 (NSP14) is a key two-domain protein responsible for maintaining coronavirus replication fidelity, and in its absence reproduction is severely impacted. With the goal of identifying new inhibitors of SARS-CoV-2 NSP14, we selected a previously reported scaffold as an appropriate starting point. Medicinal chemistry exploration provided a series of trisubstituted pyrazolines as inhibitors of NSP14 methyltransferase (MTase) activity, with improved synthetic tractability and in a promising molecular property space. This led to compound 35 as a potent inhibitor of NSP14 MTase with a favorable in vitro ADMET profile, and antiviral activity against SARS-CoV-2 replication. We propose that 35 is a useful chemical probe which is well-positioned to further interrogate in vitro biology and for further optimization toward the treatment of human coronaviruses.