2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-methylpyrimidin-4-amine | 1043436-09-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-methylpyrimidin-4-amine
• 英文别名: 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-methylpyrimidin-4-amine
• CAS: 1043436-09-4
• 化学式: C₁₁H₁₂ClN₅
• 分子量: 249.703
• InChiKey: QBNNUQXHMSCSPN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 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-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-methylpyrimidin-4-amine 、 (S)-(-)-1-(4-氟苯基)乙胺 在 N,N-二异丙基乙胺 作用下， 以 正丁醇 为溶剂， 生成 N'-(5-cyclopropyl-2H-pyrazol-3-yl)-N-[(1S)-1-(4-fluorophenyl)ethyl]-5-methylpyrimidine-2,4-diamine
  参考文献：
  名称：

  Identification of 4-Aminopyrazolylpyrimidines as Potent Inhibitors of Trk Kinases

  摘要：

  The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of IN (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.

  DOI：

  10.1021/jm800343j
• 作为产物：
  描述：

  2,4-二氯-5-甲基嘧啶 、 3-氨基-5-环丙基-1H-吡唑 在 N,N-二异丙基乙胺 作用下， 以 异丙醇 为溶剂， 反应 5.0h， 生成 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-methylpyrimidin-4-amine
  参考文献：
  名称：

  鉴定TRD-35作为有效的选择性DRAK2抑制剂

  摘要：

  在DRAK2中建议的TRD-35（厚青色棒）的绑定模式。

  DOI：

  10.1002/bkcs.12005

文献信息

• [EN] SERINE/THREONINE PAK1 INHIBITORS<br/>[FR] INHIBITEURS DE SÉRINE/THRÉONINE PAK1
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013026914A1

  公开（公告）日：2013-02-28

  Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有以下式I的化合物，其中A、Z、R1a、R1b、R2、R3、R4、R5、R6、R7、R9、R10、Ra、Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了用于治疗癌症和高增殖性疾病的组合物和方法。
• [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。
• 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。
• SERINE/THREONINE KINASE INHIBITORS
  申请人：Aliagas-Martin Ignacio

  公开号：US20130225620A1

  公开（公告）日：2013-08-29

  Compounds having the formula I wherein A, Z, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R a , R b and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.

  具有公式I的化合物，其中A，Z，R1a，R1b，R2，R3，R4，R5，R6，R7，R9，R10，Ra，Rb和n的定义如本文所述，是PAK1的抑制剂。还公开了治疗癌症和高增殖性疾病的组合物和方法。
• Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family
  作者：Jennifer Alisa Amrhein、Lena Marie Berger、Amelie Tjaden、Andreas Krämer、Lewis Elson、Tuomas Tolvanen、Daniel Martinez-Molina、Astrid Kaiser、Manfred Schubert-Zsilavecz、Susanne Müller、Stefan Knapp、Thomas Hanke

  DOI：10.3390/ijms232314834

  日期：——

  The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N-myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d, which exhibited high cellular potency for CDK16 (EC50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20–120 nM and 50–180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2/M phase cell cycle arrest at all tested concentrations for 43d, caused by inhibition of CDK16.

  PCTAIRE 亚家族属于 CDK（依赖细胞周期蛋白的激酶）家族，是一类未被充分研究的黑暗激酶。它们表现出高度保守的结合口袋，并通过与细胞周期蛋白 Y 结合而激活。CDK16 与 N-肉豆蔻酰化的细胞周期蛋白 Y 结合后会靶向质膜，并在脑和睾丸等有丝分裂后组织中高度表达。细胞周期蛋白 16 的失调与多种疾病有关，包括乳腺癌、前列腺癌和宫颈癌。在这里，我们通过改变不同的残基，利用杂合抑制剂 1 中的 N-（1H-吡唑-3-基）嘧啶-4-胺分子来靶向 CDK16。进一步的优化步骤产生了 43d，它对 CDK16（EC50 = 33 nM）以及 PCTAIRE 和 PFTAIRE 家族的其他成员具有很高的细胞效力，分别为 20-120 nM 和 50-180 nM。针对大约 100 种具有代表性的激酶进行的 DSF 筛选显示，43d 对其他激酶具有选择性抑制作用。在活力评估中，43d 以剂量依赖的方式减少了细胞数量。FUCCI 细胞周期测定显示，在所有测试浓度下，43d 都会抑制 CDK16，导致细胞周期停滞在 G2/M 期。