4-chloro-6-(2-methyl-4-nitrophenoxy)pyrimidine

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-chloro-6-(2-methyl-4-nitrophenoxy)pyrimidine
• 英文别名: 4-Chloro-6-(2-methyl-4-nitrophenoxy)pyrimidine
• 化学式: C₁₁H₈ClN₃O₃
• mdl: MFCD26339788
• 分子量: 265.656
• InChiKey: PQSKTKBROYAWEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  80.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-chloro-6-(2-methyl-4-nitrophenoxy)pyrimidine 在 sodium tetrahydroborate 、 nickel(II) chloride hexahydrate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以51%的产率得到4-((6-chloropyrimidin-4-yl)oxy)-3-methylaniline
  参考文献：
  名称：

  通过设计对 VEGFR2、p38α 和 B-Raf 的选择性来鉴定心脏特异性激酶 TNNI3K 的二芳基脲抑制剂

  摘要：

  开发了一系列心脏特异性激酶 TNNI3K 的二芳基脲抑制剂，以阐明 TNNI3K 的生物学功能并评估 TNNI3K 作为治疗心血管疾病的治疗靶点。利用基于结构的设计，激酶选择性的增强被设计到系列中，利用已建立的 TNNI3K、VEGFR2、p38α 和 B-Raf 的 X 射线晶体结构。我们的努力最终发现了一种体内工具化合物47（GSK329），该化合物表现出理想的 TNNI3K 效力和大鼠药代动力学特性，以及对 VEGFR2（40 倍）、p38α（80 倍）和 B-的有希望的激酶选择性Raf（>200 倍）。化合物47在缺血/再灌注心脏损伤小鼠模型中显示出积极的心脏保护结果，表明该系列的优化样本，例如47，是发现治疗心脏病的新药的有利线索。

  DOI：

  10.1021/acs.jmedchem.1c00700
• 作为产物：
  描述：

  4,6-二氯嘧啶 、 2-甲基-4-硝基苯酚 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以69%的产率得到4-chloro-6-(2-methyl-4-nitrophenoxy)pyrimidine
  参考文献：
  名称：

  发现 SPH5030，一种用于 HER2 扩增和 HER2 突变癌症治疗的选择性、有效和不可逆的酪氨酸激酶抑制剂

  摘要：

  小分子不可逆酪氨酸激酶抑制剂作为强效药物已导致 HER2 扩增癌症患者的无病生存和总生存期得到改善。获批的不可逆 HER2 抑制剂来那替尼和吡咯替尼均缺乏 HER2 选择性，导致患者发生脱靶不良事件。治疗期间HER2突变的发展也阻碍了治疗的进展。我们使用分子杂交策略进行结构优化，结合体外和体内药物样特性筛选，获得临床候选SPH5030。总体而言，SPH5030与来那替尼和吡咯替尼相比，对四种常见的 HER2 突变体表现出优异的活性和较高的相对 HER2 选择性，良好的药代动力学特征和理想的生物利用度，在异种移植小鼠模型中具有显着的体内抗肿瘤功效，尤其是在 HER2 突变 A775_G776insYVMA 异种移植小鼠模型中效力远高于来那替尼和吡咯替尼。

  DOI：

  10.1021/acs.jmedchem.1c00710

文献信息

• NITROGENOUS HETEROCYCLIC COMPOUND, PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND USE
  申请人：Shanghai Pharmaceuticals Holding Co., Ltd.

  公开号：EP3424928A1

  公开（公告）日：2019-01-09

  Disclosed are a nitrogenous heterocyclic compound, intermediates, a preparation method, a composition and use thereof. The nitrogenous heterocyclic compound in the present invention is as shown in formula I. The compound has a high inhibitory activity towards ErbB2 tyrosine kinase and a relatively good inhibitory activity towards human breast cancer BT-474 and human gastric cancer cell NCI-N87 which express ErbB2 at a high level, and at the same time has a relatively weak inhibitory activity towards EGFR kinase. Namely, the compound is a highly selective small-molecule inhibitor targeted at ErbB2, and hence it has a high degree of safety, and can effectively enlarge the safety window in the process of taking the drug.

  本公开揭示了一种含氮杂环化合物、中间体、制备方法、组合物及其用途。本发明中的含氮杂环化合物如公式I所示。该化合物对ErbB2酪氨酸激酶具有较高的抑制活性，并且对人类乳腺癌BT-474和人类胃癌细胞NCI-N87表达ErbB2的抑制活性相对较好，同时对EGFR激酶具有相对较弱的抑制活性。换句话说，该化合物是一种高度选择性的针对ErbB2的小分子抑制剂，因此具有很高的安全度，并且可以有效地扩大服药过程中的安全窗口。
• NITROGENOUS HETEROCYCLIC COMPOUND, PREPARATION METHOD, INTERMEDIATE, COMPOSITION, AND APPLICATION
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.

  公开号：US20200190091A1

  公开（公告）日：2020-06-18

  A nitrogenous heterocyclic compound, a preparation method, an intermediate, a composition, and an application. The present invention provides a nitrogenous heterocyclic compound as represented by formula I, pharmaceutically acceptable salts thereof, enantiomers thereof, diastereoisomers thereof, tautomers thereof, solvates thereof, metabolites thereof, or prodrugs thereof. The compound has high inhibitory activity against ErbB2 tyrosine kinase, has good inhibitory activity against human breast cancer cells BT-474, human gastric cancer cells NCI-N87 and the like with high expression of ErbB2, and in addition has relatively weak inhibitory activity against EGFR kinase, that is, the compound is an EGFR/ErbB2 double target inhibitor that attenuates EGFR kinase inhibitory activity or a small-molecule inhibitor having selectivity for an ErbB2 target. (I)

  一种含氮杂环化合物，一种制备方法，一种中间体，一种组合物和一种应用。本发明提供一种由式I表示的含氮杂环化合物，其药学上可接受的盐，其对映体，其非对映异构体，其互变异构体，其溶剂合物，其代谢物或其前药。该化合物对ErbB2酪氨酸激酶具有高抑制活性，对表达ErbB2高的人类乳腺癌细胞BT-474，人类胃癌细胞NCI-N87等具有良好的抑制活性，并且对EGFR激酶具有相对较弱的抑制活性，即该化合物是一种减弱EGFR激酶抑制活性的EGFR/ErbB2双靶点抑制剂或具有选择性作用于ErbB2靶点的小分子抑制剂。 (I)
• Nitrogenous heterocyclic compound, preparation method, intermediate, composition and use
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO., LTD.

  公开号：US10828305B2

  公开（公告）日：2020-11-10

  Disclosed are a nitrogenous heterocyclic compound, intermediates, a preparation method, a composition and use thereof. The nitrogenous heterocyclic compound in the present invention is as shown in formula I. The compound has a high inhibitory activity towards ErbB2 tyrosine kinase and a relatively good inhibitory activity towards human breast cancer BT-474 and human gastric cancer cell NCI-N87 which express ErbB2 at a high level, and at the same time has a relatively weak inhibitory activity towards EGFR kinase. Namely, the compound is a highly selective small-molecule inhibitor targeted at ErbB2, and hence it has a high degree of safety, and can effectively enlarge the safety window in the process of taking the drug.

  本发明公开了一种含氮杂环化合物、中间体、制备方法、组合物及其用途。本发明中的含氮杂环化合物如式 I 所示。该化合物对 ErbB2 酪氨酸激酶有较高的抑制活性，对高水平表达 ErbB2 的人乳腺癌 BT-474 和人胃癌细胞 NCI-N87 有较好的抑制活性，同时对表皮生长因子受体激酶的抑制活性相对较弱。也就是说，该化合物是一种针对 ErbB2 的高选择性小分子抑制剂，因此具有很高的安全性，可以有效地扩大用药过程中的安全窗口期。
• Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular-signal regulated kinase (ERK) dual inhibitors against breast cancer cells
  作者：Yin Chen、Yaxin Zheng、Qinglin Jiang、Feifei Qin、Yonghui Zhang、Leilei Fu、Gu He

  DOI：10.1016/j.ejmech.2016.11.009

  日期：2017.2

  Beginning with our previously reported ERK inhibitor BL-EI001, we found Raf1 to be an important regulator in the ERK interactive network, and then we designed and synthesized a novel series of Raf1/ERIC dual inhibitors against human breast cancers through integrative computational, synthetic and biological screening methods. Moreover, we found that compound 9d suppressed the proliferation of breast cancer cell lines and induced cellular apoptosis via a mitochondrial pathway with only partial dependence on Raf1 and ERK. Our results suggest that an integrative method including in silico design, chemical synthesis, biological screening and bioinformatics analysis could be an attractive strategy for the discovery of multi-target inhibitors against breast cancer. (C) 2016 Elsevier Masson SAS. All rights reserved.
• Discovery of SPH5030, a Selective, Potent, and Irreversible Tyrosine Kinase Inhibitor for HER2-Amplified and HER2-Mutant Cancer Treatment
  作者：Di Li、Yuanxiang Tu、Kaijun Jin、Lingjun Duan、Yuan Hong、Jia Xu、Na Chen、Zhihui Zhang、Hongjian Zuo、Wanchun Gong、Jing Zhang、Qian Wang、Hai Qian、Xuenan Wang、Ying Ke、Guangxin Xia

  DOI：10.1021/acs.jmedchem.1c00710

  日期：2022.4.14

  Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib, both lack HER2 selectivity, leading to off-target adverse events in patients. The development of HER2 mutation during treatment also hampers the progress

  小分子不可逆酪氨酸激酶抑制剂作为强效药物已导致 HER2 扩增癌症患者的无病生存和总生存期得到改善。获批的不可逆 HER2 抑制剂来那替尼和吡咯替尼均缺乏 HER2 选择性，导致患者发生脱靶不良事件。治疗期间HER2突变的发展也阻碍了治疗的进展。我们使用分子杂交策略进行结构优化，结合体外和体内药物样特性筛选，获得临床候选SPH5030。总体而言，SPH5030与来那替尼和吡咯替尼相比，对四种常见的 HER2 突变体表现出优异的活性和较高的相对 HER2 选择性，良好的药代动力学特征和理想的生物利用度，在异种移植小鼠模型中具有显着的体内抗肿瘤功效，尤其是在 HER2 突变 A775_G776insYVMA 异种移植小鼠模型中效力远高于来那替尼和吡咯替尼。