Early Process Development of CH7057288, a Benzofuran-Containing Selective NTRK Inhibitor

This work describes the development of a scalable manufacturing process for CH7057288, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor that selectively targets NTRK positive cancers. NTRK fusions are extremely attractive and promising therapeutic targets, and in order to deliver CH7057288 as a new treatment option for patients, it is crucial to be able to rapidly supply a large amount of this innovative drug for GLP toxicology studies and first-in-human (FIH) studies. By employing an 11-step process, we have been able to synthesize CH7057288 from methyl 2-(3-aminophenyl)-2-methylpropanoate with high purity and in excellent yield. The distinguishing features of this process include sequential double cyclization, leading to four-membered benzofuran-fused heterocycles. By employing this process, we successfully produced a total of 5.5 kg of CH7057288.