2-(3-(3-hydroxy-5-methylphenyll)-4-(6-((3-hydroxypropyl)amino)-2-(pyridin-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile

• 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-(3-(3-hydroxy-5-methylphenyll)-4-(6-((3-hydroxypropyl)amino)-2-(pyridin-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile
• 英文别名: 2-(3-(3-hydroxy-5-methylphenyl)-4-(6-(isobutylamino)-2-(pyridin-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile；2-[3-(3-Hydroxy-5-methylphenyl)-4-[6-(3-hydroxypropylamino)-2-pyridin-3-ylpyrimidin-4-yl]pyrazol-1-yl]acetonitrile；2-[3-(3-hydroxy-5-methylphenyl)-4-[6-(3-hydroxypropylamino)-2-pyridin-3-ylpyrimidin-4-yl]pyrazol-1-yl]acetonitrile
• 化学式: C₂₄H₂₃N₇O₂
• 分子量: 441.492
• InChiKey: KCGNSZSHWLXFFG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,4-二氯-6-甲基嘧啶 在 三氟二甲基硫醚络合物 、 caesium carbonate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 43.0h， 生成 2-(3-(3-hydroxy-5-methylphenyll)-4-(6-((3-hydroxypropyl)amino)-2-(pyridin-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile
  参考文献：
  名称：

  Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

  摘要：

  With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silica modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.023

文献信息

• ＲＯＳ 카이네이즈 저해활성을 갖는 2,4,6-삼치환된 피리미딘 화합물
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY 한국과학기술연구원(319980077518) BRN ▼209-82-03522

  公开号：KR101556317B1

  公开（公告）日：2015-10-01

  본 발명은 신규 2,4,6-삼치환된 피리미딘 화합물과 약제학적으로 허용 가능한 이의 염, 이 화합물의 제조방법, 그리고 이 화합물을 항암제로 사용하는 의약용도에 관한 것이다. 본 발명에 따른 신규 화합물들은 ROS 카이네이즈 엔자임에 대하여 매우 우수한 활성을 가지고 있으므로 뇌암, CNS 관련 암, 수막종 (meningiomas)과 역형성별 세포종 (astrocytomas), 다형성 교모세포종 (glioblastoma multiforme), 비소세포성 폐암 (NSCLC) 등의 질환을 치료 및 예방하는 항암제로 유용하다.

  This is the Chinese translation of the text you provided: 该发明涉及新型2,4,6-三取代嘧啶化合物及其药学上可接受的盐，该化合物的制备方法，以及将该化合物用作抗癌药物的药用用途。根据本发明，这些新型化合物对ROS激酶酶表现出非常优异的活性，因此对治疗和预防脑癌、与中枢神经系统相关的癌症、脑膜瘤（meningiomas）和星形胶质细胞瘤（astrocytomas）、多形性胶质母细胞瘤（glioblastoma multiforme）、非小细胞肺癌（NSCLC）等疾病具有用处。
• Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors
  作者：Ahmed Z. Abdelazem、Mohammad M. Al-Sanea、Byung Sun Park、Hye Mi Park、Kyung Ho Yoo、Taebo Sim、Jong Bae Park、Seung-Hoon Lee、So Ha Lee

  DOI：10.1016/j.ejmech.2014.11.023

  日期：2015.1

  With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silica modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.