Discovery of 1-Amino-1<i>H</i>-imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitors

Abstract

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1<i>H</i>-imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor <b>26</b> demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy <i>in vivo</i>, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1<i>H</i>-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.