Novel synthetic methodologies utilized in the discovery of small molecule inhibitors of PCSK9 are discussed. Despite the modular architecture of HTS hit <b>1</b>, lead diversification proved a considerable synthetic challenge. As a result, multiple new reactions were developed to advance this chemical series. These include: 1) a new synthesis of aminopyridines from pyridine-N-oxides and amines with the activator PyBroP, 2) a facile synthesis of 2-aminopyridyl amides via coupling of 2-aminopyridine-N-oxides and amines and, 3) a mild reduction of azine-N-oxides with tetrahydroxydiboron. The effectiveness of these methodologies pertaining to the discovery of compound <b>2 </b>as well as their general utility will be discussed.

New synthetic methods used in the discovery of small molecule PCSK9 inhibitors

255th National Meeting (2018)

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