Discovery and Early Development of the Next-Generation ALK Inhibitor, Lorlatinib (18)

Although crizotinib ( 1 ) demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) patients, progression during treatment eventually develops with resistant patient samples revealing a variety of point mutations in the ALK kinase domain. In addition, some patients progress due to cancer metastasis in the brain. Herein, the discovery and development of the next-generation ALK-inhibitor lorlatinib ( 18 ) is described with the goal to address these challenges. The strategies for optimizing efficacy, selectivity, and achieving CNS penetration are disclosed, while the challenges associated with the large-scale synthesis of a macrocyclic compound are also addressed.