(R)-tert-butyl 3-((6-amino-3-cyanopyrazin-2-yl)oxy)pyrrolidine-1-carboxylate | 1184843-10-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (R)-tert-butyl 3-((6-amino-3-cyanopyrazin-2-yl)oxy)pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (3R)-3-(6-amino-3-cyanopyrazin-2-yl)oxypyrrolidine-1-carboxylate
• CAS: 1184843-10-4
• 化学式: C₁₄H₁₉N₅O₃
• 分子量: 305.337
• InChiKey: FDXRHVCTBKVBMK-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl 3-((6-amino-3-cyanopyrazin-2-yl)oxy)pyrrolidine-1-carboxylate 、 6-氯-4-甲氧基烟酸甲酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 (R)-methyl 6-((5-cyano-6-(pyrrolidin-3-yloxy)pyrazin-2-yl)amino)-4-(methoxy)nicotinate
  参考文献：
  名称：

  Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

  摘要：

  Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment based drug design and optimized for CHK1 potency and high selectivity using a cell based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent

  DOI：

  10.1021/jm3012933
• 作为产物：
  描述：

  (R)-1-Boc-3-羟基吡咯烷 、 5-氨基-3-氯-吡嗪-2-甲腈 在 sodium hydride 作用下， 以 1,4-二氧六环 、 mineral oil 为溶剂， 反应 14.5h， 以43%的产率得到(R)-tert-butyl 3-((6-amino-3-cyanopyrazin-2-yl)oxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

  摘要：

  Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment based drug design and optimized for CHK1 potency and high selectivity using a cell based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent

  DOI：

  10.1021/jm3012933

文献信息

• [EN] BICYCLYLARYL-ARYL-AMINE COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS DE TYPE BICYCLYLARYL-ARYL-AMINE ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009103966A1

  公开（公告）日：2009-08-27

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicyclylaryl-aryl-amines compounds of the following formula (referred to herein as BCAA 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: (I).

  本发明一般涉及治疗化合物领域，更具体地涉及以下式（以下简称BCAA化合物）的某些双环芳基芳基胺化合物，该化合物在某些情况下抑制检查点激酶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内外抑制CHK1激酶功能，并用于治疗由CHK1介导的疾病和症状，通过抑制CHK1激酶功能得到缓解等，包括增殖性疾病如癌症等，可选地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TS抑制剂；（d）微管靶向药物；和（e）电离辐射。
• [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。
• 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。
• BICYCLYLARYL-ARYL-AMINE COMPOUNDS AND THEIR USE
  申请人：Collins Ian

  公开号：US20100331328A1

  公开（公告）日：2010-12-30

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicyclylaryl-aryl-amines compounds of the following formula (referred to herein as BCAA 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，更具体地涉及以下公式（在此称为BCAA化合物）的某些双环芳基-芳基胺化合物，该化合物等可抑制检查点激酶1（CHK1）激酶功能。本发明还涉及包含这种化合物的制药组合物，以及使用这种化合物和组合物在体内外抑制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情况，包括增生性疾病如癌症等，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）微管靶向剂；和（e）电离辐射。
• US8530468B2
  申请人：——

  公开号：US8530468B2

  公开（公告）日：2013-09-10