(E)-5-((5-(4-hydroxybut-1-en-1-yl)-4-((piperidin-4-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile | 1137478-22-8

• 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: (E)-5-((5-(4-hydroxybut-1-en-1-yl)-4-((piperidin-4-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile
• 英文别名: (E)-5-(5-(4-hydroxybut-1-enyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile；5-[[5-[(E)-4-hydroxybut-1-enyl]-4-(piperidin-4-ylmethylamino)pyridin-2-yl]amino]pyrazine-2-carbonitrile
• CAS: 1137478-22-8
• 化学式: C₂₀H₂₅N₇O
• 分子量: 379.465
• InChiKey: HWJXFVLYPYGUCO-HNQUOIGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  119
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-氯-4-氨基吡啶 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 potassium acetate 、 一氯化碘 、 sodium hydride 、 sodium carbonate 、 caesium carbonate 、 溶剂黄146 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 8.5h， 生成 (E)-5-((5-(4-hydroxybut-1-en-1-yl)-4-((piperidin-4-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile
  参考文献：
  名称：

  Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

  摘要：

  Multiparameter optimization of a series of 5((4-aminopyridin-2-yl)amino)pyrazine-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.5b01938

文献信息

• Pyrazin-2-yl-pyridin-2-yl-amine and pyrazin-2-yl-pyrimidin-4-yl-amine Compounds and Their Use
  申请人：Collins Ian

  公开号：US20120040967A1

  公开（公告）日：2012-02-16

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain biarylamine compounds (referred to herein as BAA compounds), and especially certain pyrazin-2-yl-pyridin-2-yl-amine and pyrazine-2-yl-pyrimidin-4-yl-amine compounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明涉及治疗化合物领域，更具体地涉及某些双芳基胺化合物（以下称为BAA化合物），尤其是某些吡嗪-2-基吡啶-2-基胺和吡嗪-2-基嘧啶-4-基胺化合物，它们可以抑制检查点激酶1（CHK1）激酶的功能。本发明还涉及包含这些化合物的药物组合物，以及在体内外使用这些化合物和组合物来抑制CHK1激酶的功能，并在治疗由CHK1介导的疾病和病况，通过抑制CHK1激酶的功能得到改善的疾病和病况，包括增殖性疾病如癌症等，可选择与另一种药物联合使用，例如（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）微管靶向药物；和（e）电离辐射。
• PYRAZIN-2-YL-PYRIDIN-2-YL-AMINE AND PYRAZIN-2-YL-PYRIMIDIN-4-YL-AMINE COMPOUNDS AND THEIR USE
  申请人：Cancer Research Technology Limited

  公开号：EP2197874B1

  公开（公告）日：2016-08-31
• US8058045B2
  申请人：——

  公开号：US8058045B2

  公开（公告）日：2011-11-15
• US8367658B2
  申请人：——

  公开号：US8367658B2

  公开（公告）日：2013-02-05
• Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (<i>R</i>)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)
  作者：James D. Osborne、Thomas P. Matthews、Tatiana McHardy、Nicolas Proisy、Kwai-Ming J. Cheung、Michael Lainchbury、Nathan Brown、Michael I. Walton、Paul D. Eve、Katherine J. Boxall、Angela Hayes、Alan T. Henley、Melanie R. Valenti、Alexis K. De Haven Brandon、Gary Box、Yann Jamin、Simon P. Robinson、Isaac M. Westwood、Rob L. M. van Montfort、Philip M. Leonard、Marieke B. A. C. Lamers、John C. Reader、G. Wynne Aherne、Florence I. Raynaud、Suzanne A. Eccles、Michelle D. Garrett、Ian Collins

  DOI：10.1021/acs.jmedchem.5b01938

  日期：2016.6.9

  Multiparameter optimization of a series of 5((4-aminopyridin-2-yl)amino)pyrazine-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.