Macrocycles contain various structural features that make them attractive drug targets. They possess a lower number of rotatable bonds making them more conformationally restricted than their acyclic analogs. This can potentially impart higher target binding and selectivity and improved oral bioavailability. Historically, macrocyclic drug candidates originated from natural products and peptides. Advances in modern synthetic methodology have greatly expanded their chemical diversity and synthetic accessibility. This talk will focus on the synthesis of amino pyridine macrocyclic inhibitors for the EML4-ALK project. Various approaches for the macrocyclization will be presented as well as the synthesis of the key intermediates. Finally, the development of efficient and robust chemistries that allowed for the synthesis of multi-gram quantities of compound will be discussed.

Route development and scale-up of macrocyclic inhibitors for the EML4-ALK project

247th National Meeting (2014)

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