2,6-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine | 1266480-90-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2,6-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine
• CAS: 1266480-90-3
• 化学式: C₁₄H₁₁Cl₂N₅
• 分子量: 320.181
• InChiKey: YANBZCJQHLYMRY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,6-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine 在 potassium carbonate 作用下， 以 四氢呋喃 、 水 、 正丁醇 为溶剂， 反应 17.0h， 生成 1-(4-(6-chloro-4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-1,4-diazepan-1-yl)ethanone
  参考文献：
  名称：

  Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions

  摘要：

  Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (K-i approximate to 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 mu M (1-2 mu g/mL) against the H37Ra isolate of M. tuberculosis.

  DOI：

  10.1021/acsmedchemlett.7b00239
• 作为产物：
  描述：

  2-氨基-5-氯苯甲酸 在 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 N,N-二甲基苯胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 2,6-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine
  参考文献：
  名称：

  基于结构的6-氯-4-氨基喹唑啉-2-羧酰胺衍生物作为有效和选择性p21活化激酶4（PAK4）抑制剂的设计。

  摘要：

  在本文中，我们报告了喹唑啉支架新型PAK4抑制剂的发现和表征。根据PAKs ATP结合袋的形状和化学组成，我们选择了2,4-二氨基喹唑啉系列抑制剂作为起始点。在X射线晶体学和基于结构的药物设计（SBDD）方法的指导下，设计和合成了一系列新型的4-氨基喹唑啉-2-羧酰胺PAK4抑制剂。优化了抑制剂的选择性，治疗效果和药物特性。最好的化合物之一31（CZh226），表现出显着的PAK4选择性（是PAK1的346倍）和有利的激酶选择性谱。此外，该化合物通过在体外调节PAK4定向的下游信号通路有效抑制A549肿瘤细胞的迁移和侵袭。综上所述，这些数据支持31作为PAK4靶向抗癌药物发现的先导化合物和II类PAK进一步生物学研究的有价值的研究探针的进一步开发。

  DOI：

  10.1021/acs.jmedchem.7b01342

文献信息

• [EN] PYRIMIDINE COMPOUNDS AS TUBERCULOSIS INHIBITORS<br/>[FR] COMPOSÉS PYRIMIDINE EN TANT QU'INHIBITEURS DE LA TUBERCULOSE
  申请人：VERTEX PHARMA

  公开号：WO2011019405A1

  公开（公告）日：2011-02-17

  The present invention relates to compounds II useful as inhibitors of treating tuberculosis. The invention also provides processes for preparing compounds of the invention.

  本发明涉及化合物II，用作治疗结核病的抑制剂。该发明还提供了制备本发明化合物的方法。
• Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity
  作者：Tianxiao Wu、Yu Pang、Jing Guo、Wenbo Yin、Mingyue Zhu、Chenzhou Hao、Kai Wang、Jian Wang、Dongmei Zhao、Maosheng Cheng

  DOI：10.3390/molecules23020417

  日期：——

  A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.

  设计、合成并评价了一系列新型2,4-二氨基喹唑啉衍生物作为p21激活激酶4（PAK4）抑制剂。所有化合物均显示出对PAK4的显著抑制活性（半最大抑制浓度IC50 < 1 μM）。其中，化合物8d和9c对PAK4的抑制活性最强（IC50分别为0.060 μM和0.068 μM）。此外，我们观察到化合物8d和9c对A549细胞系显示出强大的抗增殖活性，并抑制了该细胞系的细胞周期分布、迁移和侵袭。此外，进行了分子对接分析，以预测化合物8d的可能结合模式。这一系列化合物有望进一步开发为用于抗癌活性的PAK4抑制剂。
• PYRIMIDINE COMPOUNDS AS TUBERCULOSIS INHIBITORS
  申请人：Wang Tiansheng

  公开号：US20110053916A1

  公开（公告）日：2011-03-03

  The present invention relates to compounds useful as inhibitors of treating tuberculosis. The invention also provides processes for preparing compounds of the inventions and

  本发明涉及用于治疗结核病的抑制剂化合物。该发明还提供了制备该发明化合物的方法。
• Discovery of quinazoline derivatives CZw-124 as a pan-TRK inhibitor with potent anticancer effects in vitro and in vivo
  作者：Tianxiao Wu、Qiaohua Qin、Ruicheng Lv、Nian Liu、Wenbo Yin、Chenzhou Hao、Yin Sun、Chu Zhang、Yixiang Sun、Dongmei Zhao、Maosheng Cheng

  DOI：10.1016/j.ejmech.2022.114451

  日期：2022.8
• EP1686999B1
  申请人：——

  公开号：EP1686999B1

  公开（公告）日：2009-07-01