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.