Pyrazolo[1,5-a]pyrimidine derivative (1) is a potent, selective inhibitor (CK2α KD = 10 pM) of the serine/threonine protein kinase CK2, an attractive drug discovery target in oncology. The medicinal chemistry design strategy behind 1 was aimed at understanding the impact of the trans-2-(aminomethyl)cyclopropyl substituent on potency, physical properties and ADME. The initial route, while suitable for the generation of 1 and related analogs for SAR studies, relied on a multi-step synthesis culminating in a late-stage chiral separation. Optimization of this route, by conducting the chiral separation at an earlier stage on a less-advanced intermediate, and by reworking a problematic Pd-catalyzed cross-coupling step, afforded 1 in improved overall yield and enantiomeric purity. Herein we describe the medicinal chemistry design strategy for 1 and the optimization of a synthetic route to enable delivery of the compound on multigram scale.

Synthesis and medicinal chemistry optimization of CK2 kinase inhibitors

251st National Meeting (2016)

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