Bruton's tyrosine kinase (BTK) plays a critical role in B cell receptor (BCR)-mediated signaling pathways responsible for the development and function of B cells, which makes it an attractive target for the treatment of many types of B-cell malignancies. Herein, a series of N5-substituted 6,7-dioxo-6,7-dihydropteridine-based, irreversible BTK inhibitors were reported with IC₅₀ values ranging from 1.9 to 236.6 nM in the enzymatic inhibition assay. Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme, as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLCγ2. Overall, this series of compounds could provide a promising starting point for further development of potent BTK inhibitors for B-cell malignancy treatment.

中文翻译：

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N5取代的6,7-二氧-6,7-二氢蝶啶衍生物作为有效的布鲁顿酪氨酸激酶抑制剂的发现和生物学评估

布鲁顿酪氨酸激酶（BTK）在负责B细胞发育和功能的B细胞受体（BCR）介导的信号通路中起关键作用，这使其成为治疗多种B细胞恶性肿瘤的有吸引力的靶标。在本文中，据报道在酶促抑制试验中，一系列基于N5取代的6,7-二氧杂-6,7-二氢蝶啶的不可逆BTK抑制剂的IC ₅₀值为1.9至236.6 nM。化合物6和7显着抑制过表达BTK酶的Ramos细胞的增殖，以及Tyr223处BTK的自磷酸化及其下游信号分子PLCγ2的激活。总体而言，这一系列化合物可为进一步开发用于B细胞恶性肿瘤治疗的有效BTK抑制剂提供有希望的起点。