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-1H-imidazole-5-carboxamide as a
hinge binder. The most potent BTK inhibitor 26 demonstrates
impressive selectivity, favorable pharmacokinetic properties, and
robust antitumor efficacy in vivo, 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-1H-imidazole-5-carboxamide scaffold
used as the hinge binder of kinase inhibitors, which will largely
expand the chemical diversity of kinase inhibitors.