The steps to build the core structure of Ensetesvir began with the reaction of semicarbazide 3.8 with tert-butyl isocyanate, followed by the use of N,N′-carbonyldiimidazole (CDI) to ensure the formation of 1,3,5-triazinone 3.10. Next, N-alkylation with bromide 3.11 gave benzyl triazone 3.12. Under acidic conditions, pyrazole was replaced with m-cresol, which facilitated the introduction of indazole 3.7 with a minimum number of by-products in the subsequent steps of the synthesis. TFA-mediated reaction simultaneously removed the N-tert-butyl group to afford compound 3.13 in 91% yield. N-alkylation with chloride 3.4 in the presence of a base gave intermediate 3.14, which was then treated with reactive building block 3.7 in the presence of anhydrous acetic acid. Isolation of Ensetesvir fumarate was achieved by exposure to fumaric acid in water-acetone.
