Process Development and Scale-Up for the Preparation of the 1‑Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461

A practical and scalable route to the Wnt inhibitor SEN461 <b>1</b> is described herein. The optimized route consists of nine chemical steps. The intermediates are solids and were isolated by filtrations. Critical reactions steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, we developed a synthetic procedure for the preparation of multihundred gram quantities of the final product. A further process development for the phase 1 clinical batch campaign is reported

<i>N</i>‑[5-(5-Fluoropyridin-3-yl)‑1<i>H</i>‑pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): A Medicinal Chemistry Effort toward an α7 Nicotinic Acetylcholine Receptor Agonist Preclinical Candidate

α7 nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer’s disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound <b>1</b> (SEN15924, WAY-361789) led to the identification of <b>12</b> (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models