(R)-5-((5-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-((morpholin-2-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile | 1137478-52-4

• 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: (R)-5-((5-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-((morpholin-2-ylmethyl)amino)pyridin-2-yl)amino)pyrazine-2-carbonitrile
• 英文别名: (R)-5-(5-(3-hydroxy-3-methylbut-1-ynyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile；5-[[5-(3-hydroxy-3-methylbut-1-ynyl)-4-[[(2R)-morpholin-2-yl]methylamino]pyridin-2-yl]amino]pyrazine-2-carbonitrile
• CAS: 1137478-52-4
• 化学式: C₂₀H₂₃N₇O₂
• 分子量: 393.448
• InChiKey: IDZXROKRAQBADP-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-氯-4-氨基吡啶 在 bis-triphenylphosphine-palladium(II) chloride 、 tris-(dibenzylideneacetone)dipalladium(0) 、 copper(l) iodide 、 potassium acetate 、 一氯化碘 、 sodium hydride 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.41h， 生成 (R)-5-((5-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-((morpholin-2-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

• [EN] PYRAZIN-2-YL-PYRIDIN-2-YL-AMINE AND PYRAZIN-2-YL-PYRIMIDIN-4-YL-AMINE COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS PYRAZIN-2-YL-PYRIDIN-2-YL-AMINE ET PYRAZIN-2-YL-PYRIMIDIN-4-YL-AMINE ET LEURS UTILISATIONS
  申请人：CANCER REC TECH LTD

  公开号：WO2009044162A1

  公开（公告）日：2009-04-09

  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 of formula (I), 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 Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionisiπq radiation. wherein: -X= is independently -CRA5= or -N=; and the rest of the substituents are as specified in the claims.

  本发明一般涉及治疗化合物领域，更具体地涉及某些联苯胺化合物（在此称为BAA化合物），特别是某些式（I）的吡啶-2-基-吡啶-2-基-胺和吡嗪-2-基-吡啶-4-基-胺化合物，该化合物等抑制检查点激酶1（CHK1）激酶功能。本发明还涉及包含这种化合物的药物组合物，以及利用这种化合物和组合物在体外和体内抑制CHK1激酶功能，并治疗由CHK1介导的疾病和症状，通过抑制CHK1激酶功能而得到缓解的疾病和症状，包括增生性疾病如癌症等，可选择与另一药剂结合，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）微管靶向剂；和（e）电离辐射。其中：-X=独立为-CRA5=或-N=；其余取代基如索引中所述。
• [EN] 5-(PYRIDIN-2-YL-AMINO)-PYRAZINE-2-CARBONITRILE COMPOUNDS AND THEIR THERAPEUTIC USE<br/>[FR] COMPOSÉS DE TYPE 5-(PYRIDIN-2-YL-AMINO)-PYRAZINE-2-CARBONITRILE ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：CANCER REC TECH LTD

  公开号：WO2013068755A1

  公开（公告）日：2013-05-16

  The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyridyl-amino-pyrazine carbonitrile compounds that, 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 thymidylate synthase (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，本发明涉及某些吡啶基氨基吡嗪碳腈化合物，该化合物在某种程度上抑制检查点激酶1（CHK1）激酶功能。本发明还涉及包含这些化合物的药物组合物，以及在体外和体内使用这些化合物和组合物来抑制CHK1激酶功能，并用于治疗由CHK1介导的疾病和症状，这些疾病和症状通过抑制CHK1激酶功能得到缓解，包括增生性疾病如癌症等，可选择与另一药剂组合使用，例如：（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或胸苷酸合成酶（TS）抑制剂；（d）微管靶向剂；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：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。
• 5-(Pyridin-2-yl-Amino)-Pyrazine-2-Carbonitrile Compounds and Their Therapeutic Use
  申请人：Cancer Research Technology Limited

  公开号：US20140315925A1

  公开（公告）日：2014-10-23

  The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyridyl-amino-pyrazine carbonitrile compounds that, 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 thymidylate synthase (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，本发明涉及某些吡啶基氨基吡嗪羰基化合物，其抑制检查点激酶1（CHK1）激酶功能等。本发明还涉及包含这些化合物的制药组合物，以及在体内外使用这些化合物和组合物来抑制CHK1激酶功能，以及治疗由CHK1介导、通过抑制CHK1激酶功能改善的疾病和病况，包括增殖性疾病如癌症等，可选择与另一药剂组合使用，例如(a) DNA拓扑异构酶I或II抑制剂;（b）DNA损伤剂;（c）抗代谢物或胸腺嘧啶酸合酶（TS）抑制剂;（d）微管靶向剂;和（e）电离辐射。
• 5-[[4-[[MORPHOLIN-2-YL]METHYLAMINO]-5-(TRIFLUOROMETHYL)-2-PYRIDYL]AMINO]PYRAZINE-2-CARBONITRILE AND THERAPEUTIC USES THEREOF
  申请人：Cancer Research Technology Limited

  公开号：US20150126471A1

  公开（公告）日：2015-05-07

  The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as “TFM 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 a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionising radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

  本发明涉及治疗化合物领域。更具体地，本发明涉及5-[[4-[[吗啡啉-2-基]甲基氨基]-5-(三氟甲基)-2-吡啶基]氨基]吡嗪-2-羧腈化合物（以下简称“TFM化合物”），其抑制检查点激酶1（CHK1）激酶功能等。本发明还涉及包含此类化合物的制药组合物，以及在体内外使用此类化合物和组合物来抑制CHK1激酶功能，以及治疗由CHK1介导的疾病和情况，通过抑制CHK1激酶功能来缓解的疾病和情况等，包括增生性疾病，如癌症等，可选地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）抗代谢物或胸腺嘧啶酸合成酶（TS）抑制剂；（d）微管靶向药物；（e）电离辐射；（f）减数分裂调节因子或有丝分裂检查点调节因子的抑制剂；（g）DNA损伤信号传导体的抑制剂；或（h）DNA损伤修复酶的抑制剂。