Accelerated Development of a Scalable Synthesis of CY6463, a CNS-Penetrant sGC Stimulator for the Treatment of Neurodegenerative Diseases

Soluble guanylate cyclase (sGC) stimulators are small molecules that increase nitric oxide (NO) signaling by binding to sGC, leading to an increase in cyclic guanosine monophosphate production. Such compounds have previously been studied clinically for noncentral nervous system (CNS) disorders. CY6463 is the first CNS-penetrant sGC stimulator to enter clinical trials and has the potential to positively impact a range of neurodegenerative diseases. In this paper, we present the development of an efficient, robust, and scalable synthesis of this compound that allowed for rapid generation of larger quantities of material, thereby accelerating advancement into early clinical studies, while minimizing the use of resources. The synthesis features a palladium-catalyzed one-pot Negishi coupling/cyanation sequence and a novel triazole formation from a Boc-protected amidrazone. Optimization of the reactions, safety considerations, and control of impurities, as well as a mechanistic study of the triazole formation reaction, are discussed.