3-[(1R)-2-(二甲基氨基)-1-甲基乙氧基]-5-[[4-甲氧基-5-(1-甲基-1H-吡唑-4-基)-2-吡啶基]氨基]-2-吡嗪甲腈 | 1404095-34-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 3-[(1R)-2-(二甲基氨基)-1-甲基乙氧基]-5-[[4-甲氧基-5-(1-甲基-1H-吡唑-4-基)-2-吡啶基]氨基]-2-吡嗪甲腈
• 英文名称: (R)-3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile
• 英文别名: CCT-244747；3-[(2R)-1-(dimethylamino)propan-2-yl]oxy-5-[[4-methoxy-5-(1-methylpyrazol-4-yl)pyridin-2-yl]amino]pyrazine-2-carbonitrile
• CAS: 1404095-34-6
• 化学式: C₂₀H₂₄N₈O₂
• 分子量: 408.463
• InChiKey: IENLGMOXAQMNEH-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  R-(-)-1-二甲氨基-2-丙醇 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium hydride 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 mineral oil 为溶剂， 反应 31.5h， 生成 3-[(1R)-2-(二甲基氨基)-1-甲基乙氧基]-5-[[4-甲氧基-5-(1-甲基-1H-吡唑-4-基)-2-吡啶基]氨基]-2-吡嗪甲腈
  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] 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。
• 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。
• PROGNOSTIC BIOMARKER FOR CANCER
  申请人：Universitat Autònoma de Barcelona

  公开号：EP3231875A1

  公开（公告）日：2017-10-18

  The invention relates to an in vitro method for determining the prognosis of a patient suffering from cancer, wherein the cancer is not hepatocarcinoma, based on CDK5RAP3 gene expression levels. The invention also relates to in vitro methods for predicting the clinical response of a patient suffering from cancer to a treatment with a DNA damaging agent, or for selecting a patient suffering from cancer for a therapy with a DNA damaging agent or for selecting a therapy for a patient suffering from cancer.

  本发明涉及一种根据CDK5RAP3基因表达水平确定癌症患者预后的体外方法，其中癌症不是肝癌。本发明还涉及一种体外方法，用于预测癌症患者对 DNA 损伤剂治疗的临床反应，或用于选择癌症患者接受 DNA 损伤剂治疗，或用于选择癌症患者的治疗方法。
• 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：US10259806B2

  公开（公告）日：2019-04-16

  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) ionizing 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.

  本发明一般涉及治疗化合物领域。更具体地说，本发明涉及5-[[4-[[吗啉-2-基]甲基氨基]-5-(三氟甲基)-2-吡啶基]氨基]吡嗪-2-甲腈化合物（本文称为 "TFM化合物"），该化合物除其他外能抑制检查点激酶1（CHK1）激酶的功能。本发明还涉及包含此类化合物的药物组合物，以及此类化合物和组合物在体外和体内抑制 CHK1 激酶功能的用途，以及在治疗由 CHK1 介导的、通过抑制 CHK1 激酶功能而得到改善的疾病和病症等方面的用途，包括癌症等增殖性病症、可选择与另一种制剂联合使用，例如：(a) DNA拓扑异构酶 I 或 II 抑制剂；(b) DNA 损伤剂；(c) 抗代谢物或胸苷酸合成酶（TS）抑制剂；(d) 微管靶向制剂；(e) 电离辐射；(f) 有丝分裂调节剂或有丝分裂检查点调节剂的抑制剂；(g) DNA 损伤信号转导物的抑制剂；或 (h) DNA 损伤修复酶的抑制剂。