Discovery and Development of Lorlatinib: A Macrocyclic Inhibitor of EML4-ALK for the Treatment of NSCLC

This chapter describes the discovery and synthesis of lorlatinib, a selective EML4-ALK inhibitor for the treatment of non-small cell lung cancers. We give a brief overview of the SAR behind the discovery of lorlatinib, and discuss early optimization efforts into the synthesis through macrolactamization of the amide-based macrocycles. In addition, we discuss rationale for developing an alternative synthesis of this class of macrocycles, and herein describe the initiation and optimization of a second-generation approach to access the API based through a Pd-mediated direct-arylation. Accelerated timelines for the project required enabling strategies to be implemented to facilitate the synthesis of preclinical supplies of the lead compound through the macrolactamization-based chemistry, while the expedited development of the commercial synthesis utilizing the direct ring closure is described.