4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile | 1096471-87-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile
• 英文别名: 4-Hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile；4-oxo-3,9-dihydropyrimido[4,5-b]indole-7-carbonitrile
• CAS: 1096471-87-2
• 化学式: C₁₁H₆N₄O
• 分子量: 210.195
• InChiKey: QQEFEUDSLNRJJP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  81
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile 在 盐酸 、 三乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 二氯甲烷 、 水 为溶剂， 反应 19.25h， 生成 4-(2-(aminomethyl)morpholino)-9H-pyrimido[4,5-b]indole-7-carbonitrile
  参考文献：
  名称：

  Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

  摘要：

  Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

  DOI：

  10.1021/jm2007326
• 作为产物：
  描述：

  4-氯-3-硝基苯甲腈 在 甲酸铵 、 sodium hydride 、 溶剂黄146 、 锌 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 20.0h， 生成 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile
  参考文献：
  名称：

  Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

  摘要：

  Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

  DOI：

  10.1021/jm2007326

文献信息

• [EN] 9H-PYRIMIDO[4,5-B]INDOLES, 9H-PYRIDO[4',3':4,5]PYRROLO[2,3-D]PYRIDINES, AND 9H-1,3,6,9-TETRAAZA-FLUORENES AS CHK1 KINASE FUNCTION INHIBITORS<br/>[FR] 9H-PYRIMIDO[4,5-B]INDOLES, 9H-PYRIDO[4',3':4,5]PYRROLO[2,3-D]PYRIDINES, ET 9H-1,3,6,9-TÉTRAAZA-FLUORÈNES EN TANT QU'INHIBITEURS DE LA FONCTION KINASE CHK1
  申请人：CANCER REC TECH LTD

  公开号：WO2009004329A1

  公开（公告）日：2009-01-08

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain tricyclic compounds (referred to herein as TC compounds), and especially certain 9H-pyrimido[4,5-b]indole, 9H-pyrido[4',3':4,5]pyrrolo[2,3-d)pyridine, and 9H-1,3,6,9-tetraaza-fluorene 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 Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明一般涉及治疗化合物领域，更具体地涉及某些三环化合物（在此称为TC化合物），特别是某些9H-嘧啶并[4,5-b]吲哚，9H-吡啶并[4'，3'：4,5]吡咯[2,3-d]吡啶和9H-1,3,6,9-四氮杂芴化合物，这些化合物等等，能够抑制检查点激酶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，以及在体内外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，通过抑制CHK1激酶功能改善的疾病和症状等，包括癌症等增殖性疾病，可选地与另一药剂结合，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。
• 9H-PYRIMIDO[4,5-B]INDOLES, 9H-PYRIDO[4',3':4,5]PYRROLO[2,3-D]PYRIDINES, AND 9H 1,3,6,9 TETRAAZA-FLUORENES AS CHK1 KINASE FUNCTION INHIBITORS
  申请人：Collins Ian

  公开号：US20100210639A1

  公开（公告）日：2010-08-19

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain tricyclic compounds (referred to herein as TC compounds), and especially certain 9H-pyrimido[4,5-b]indole, 9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyridine, and 9H-1,3,6,9-tetraaza-fluorene 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，更具体地涉及某些三环化合物（在此称为TC化合物），特别是某些9H-嘧啶并[4,5-b]吲哚，9H-吡啶[4′，3′：4,5]吡咯[2,3-d]吡啶和9H-1,3,6,9-四氮杂芴化合物，它们可以抑制检查点激酶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激酶功能得到改善等疾病和病况，包括增生性疾病如癌症等，可选地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TS抑制剂;（d）微管靶向剂;和（e）电离辐射。
• 9H-pyrimido[4,5-B]indoles, 9H-pyrido[4',3':4,5]pyrrolo[2,3-D]pyridines, and 9H 1,3,6,9 tetraaza-fluorenes as CHK1 kinase function inhibitors
  申请人：Collins Ian

  公开号：US08618121B2

  公开（公告）日：2013-12-31

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain tricyclic compounds (referred to herein as TC compounds), and especially certain 9H-pyrimido[4,5-b]indole, 9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyridine, and 9H-1,3,6,9-tetraaza-fluorene 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，更具体地涉及某些三环化合物（在此称为TC化合物），特别是某些9H-嘧啶并[4,5-b]吲哚，9H-吡啶[4'，3'：4,5]吡咯[2,3-d]吡啶和9H-1,3,6,9-四氮杂芴化合物，它们可以抑制检查点激酶1（CHK1）的激酶功能。本发明还涉及包含这种化合物的药物组合物，以及使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介导的疾病和病症，通过抑制CHK1激酶功能而得到改善，等等，包括增殖性疾病如癌症等，可选择与另一种药物一起使用，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。
• 9H-PYRIMIDO[4,5-B]INDOLES, 9H-PYRIDO[4',3':4,5]PYRROLO[2,3-D]PYRIDINES, AND 9H-1,3,6,9-TETRAAZA-FLUORENES AS CHK1 KINASE FUNCTION INHIBITORS
  申请人：Cancer Research Technology Limited

  公开号：EP2170886A1

  公开（公告）日：2010-04-07
• US8618121B2
  申请人：——

  公开号：US8618121B2

  公开（公告）日：2013-12-31