Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-<i>d</i>]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent

Abstract

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-<i>d</i>]pyrimidinone analogue <b>I</b> showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound <b>3d</b>, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of <b>3d</b>, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound <b>11b</b> (<b>TAK-931</b>) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.