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.

中文翻译：

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发现 1-氨基-1H-咪唑-5-甲酰胺衍生物作为高选择性共价布鲁顿酪氨酸激酶 (BTK) 抑制剂

布鲁顿的酪氨酸激酶 (BTK) 抑制剂抑制 BTK 的异常激活导致 B 细胞恶性肿瘤治疗的范式转变。然而，由于批准的抑制剂依鲁替尼的脱靶副作用，迫切需要发现更具选择性的共价 BTK 抑制剂。在此，我们公开了携带 1-氨基-1 H-咪唑-5-甲酰胺作为铰链粘合剂的新型 BTK 抑制剂的发现和初步活性研究。最有效的 BTK 抑制剂26在体内表现出令人印象深刻的选择性、良好的药代动力学特性和强大的抗肿瘤功效，这表明其作为 B 细胞淋巴瘤的新治疗选择的潜力。重要的是，据我们所知，这是用作激酶抑制剂铰链粘合剂的1-氨基-1 H-咪唑-5-甲酰胺支架的第一个例子，这将在很大程度上扩大激酶抑制剂的化学多样性。