A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.

中文翻译：

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鉴定新型噻唑并 [5,4-b] 吡啶衍生物作为有效的磷酸肌醇 3-激酶抑制剂

本文设计并合成了一系列新型2-吡啶基、4-吗啉基取代的噻唑并[5,4-b]吡啶类似物。这些噻唑并 [5,4-b] 吡啶通过七个步骤从市售物质以中等至良好的产率有效制备。所有这些 N-杂环化合物均通过核磁共振 (NMR) 和高分辨率质谱 (HRMS) 分析进行表征，并进行了磷酸肌醇 3-激酶 (PI3K) 酶促测定。结果表明这些N-杂环化合物显示出有效的PI3K抑制活性，代表性化合物(19a)的IC50可达到3.6nm。构效关系 (SAR) 研究表明，磺酰胺功能对 PI3Kα 抑制活性很重要，2-氯-4-氟苯磺酰胺 (19b)、或 5-氯噻吩-2-磺酰胺 (19c) 显示出有效的抑制活性，IC50 值为纳摩尔。连接到噻唑并 [5,4-b] 吡啶的吡啶基是 PI3Kα 抑制效力的另一个关键结构单元，被苯基取代会导致活性显着降低。酶促抑制结果显示化合物19a以纳摩尔IC50值抑制PI3Kα、PI3Kγ或PI3Kδ，但其对PI3Kβ的抑制活性降低约10倍。进一步的对接分析表明，化合物19a的N-杂环核心通过关键的氢键相互作用直接参与了与激酶的结合。苯基取代导致活性显着降低。酶促抑制结果显示化合物19a以纳摩尔IC50值抑制PI3Kα、PI3Kγ或PI3Kδ，但其对PI3Kβ的抑制活性降低约10倍。进一步的对接分析表明，化合物19a的N-杂环核心通过关键的氢键相互作用直接参与了与激酶的结合。苯基取代导致活性显着降低。酶促抑制结果显示化合物19a以纳摩尔IC50值抑制PI3Kα、PI3Kγ或PI3Kδ，但其对PI3Kβ的抑制活性降低约10倍。进一步的对接分析表明，化合物19a的N-杂环核心通过关键的氢键相互作用直接参与了与激酶的结合。