In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a–J and 16a–d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.

中文翻译：

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新型 2H-苯并[e]-[1,2,4]噻二嗪 1,1-二氧化物衍生物作为 PI3Kδ 抑制剂的合成和评价

在之前的工作中，我们应用旋转限制策略并在吡唑并[3,4-d]嘧啶-4-胺的3-位引入取代基作为亲和元素与更深的疏水口袋相互作用，发现了一系列新型喹唑啉酮作为有效的 PI3Kδ 抑制剂。其中，吲哚衍生物 3 是选择性最强的 PI3Kδ 抑制剂之一，而 3,4-二甲氧基苯基衍生物 4 是一种有效且选择性的双重 PI3Kδ/γ 抑制剂。在这项研究中，我们用磺酰基取代了喹唑啉酮核心中的羰基，设计了一系列新型 2H-苯并[e][1,2,4]噻二嗪 1,1-二氧化物衍生物作为 PI3Kδ 抑制剂。N-(2,6-二甲基苯基)-2-硝基苯磺酰胺5和N-(2,6-二甲基苯基)-2-硝基-5-氟苯磺酰胺6中硝基还原后，所得2-氨基苯磺酰胺与原乙酸三甲酯反应，得到3-甲基-2H-苯并[e][1,2,4]噻二嗪1,1-二氧化物衍生物。3-甲基溴化后，与 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 的亲核取代得到相应的碘化物衍生物，其进一步与一系列芳基硼酸反应Suzuki 偶联以提供 2H-苯并[e][1,2,4]噻二嗪 1,1-二氧化物衍生物 15a-J 和 16a-d。与喹唑啉酮衍生物一致，在亲和口袋处引入 5-吲哚基或 3,4-二甲氧基苯基产生最有效的类似物 15a 和 15b，IC50 值分别为 217 至 266 nM。与喹唑啉酮先导化合物 3 和 4 相比，这些 2H-苯并[e][1,2,4]噻二嗪 1、1-二氧化物衍生物表现出大大降低的 PI3Kδ 抑制效力，但与其他 PI3K 同种型相比保持高选择性。与作为双重 PI3Kδ/γ 抑制剂的喹唑啉酮先导化合物 4 不同，具有相同 3,4-二甲氧基苯基部分的苯并噻二嗪 1,1-二氧化物 15b 的选择性是 PI3Kγ 的 21 倍以上。此外，在 2H-苯并[e][1,2,4]噻二嗪 1,1-二氧化物核的 7-位引入氟原子通常不利于 PI3Kδ 抑制活性。与其高 PI3Kδ 选择性一致，15a 和 15b 显着抑制 SU-DHL-6 细胞增殖。4-二甲氧基苯基部分的选择性是 PI3Kγ 的 21 倍以上。此外，在 2H-苯并[e][1,2,4]噻二嗪 1,1-二氧化物核的 7-位引入氟原子通常不利于 PI3Kδ 抑制活性。与其高 PI3Kδ 选择性一致，15a 和 15b 显着抑制 SU-DHL-6 细胞增殖。4-二甲氧基苯基部分的选择性是 PI3Kγ 的 21 倍以上。此外，在 2H-苯并[e][1,2,4]噻二嗪 1,1-二氧化物核的 7-位引入氟原子通常不利于 PI3Kδ 抑制活性。与其高 PI3Kδ 选择性一致，15a 和 15b 显着抑制 SU-DHL-6 细胞增殖。