5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid | 1168091-66-4

• 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: 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid
• 英文别名: 5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyrazine-6-carboxylic acid
• CAS: 1168091-66-4
• 化学式: C₁₃H₈FIN₄O₂
• 分子量: 398.135
• InChiKey: SHKMDYSCYHUJJG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  79.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.25h， 生成 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (2-hydroxy-ethoxy)-amide
  参考文献：
  名称：

  Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

  摘要：

  Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi's [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450's 2C9 and 2C19. Lowering the logD by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (azabenzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.08.008
• 作为产物：
  描述：

  5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester 在 三甲基氢氧化锡 、 盐酸 作用下， 以 1,2-二氯乙烷 、 水 、 乙酸乙酯 为溶剂， 反应 1.0h， 以97.7%的产率得到5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid
  参考文献：
  名称：

  [EN] 5-ANILINOIMIDAZOPYRIDINES AND METHODS OF USE
  [FR] 5-ANILINOIMIDAZOPYRIDINES ET PROCÉDÉS D'UTILISATION

  摘要：

  该发明涉及具有抗癌和/或抗炎活性的式I的咪唑吡啶化合物，更具体地涉及抑制MEK激酶活性的咪唑吡啶化合物。该发明提供了用于抑制异常细胞生长或治疗哺乳动物体内的增生性疾病或治疗炎症性疾病的组合物和方法。该发明还涉及使用这些化合物进行哺乳动物细胞的体外、体内和体内诊断或治疗，或相关病理条件的方法。

  公开号：

  WO2009085983A1

文献信息

• 5-ANILINOIMIDAZOPYRIDINES AND METHODS OF USE
  申请人：Price Stephen

  公开号：US20100004269A1

  公开（公告）日：2010-01-07

  The invention relates to imidazopyridines of formula I with anti-cancer and/or anti-inflammatory activity and more specifically to imidazopyridines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

  本发明涉及具有抗癌和/或抗炎活性的式I的咪唑吡啶，更具体地涉及抑制MEK激酶活性的咪唑吡啶。本发明提供了用于抑制异常细胞生长或治疗哺乳动物的增殖性疾病或治疗炎症性疾病的组合物和方法。本发明还涉及使用该化合物进行哺乳动物细胞的体外、原位和体内诊断或治疗，或相关病理条件的方法。
• 5-anilinoimidazopyridines and methods of use
  申请人：Genentech, Inc.

  公开号：US08288408B2

  公开（公告）日：2012-10-16

  The invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of an imidazopyridine of formula I with anti-hyperproliferative activity.

  本发明涉及一种抑制哺乳动物中异常细胞增长或治疗增生性疾病的方法，包括向该哺乳动物注射具有抗增生活性的式I的咪唑吡啶类化合物的治疗有效量。
• 5-anilinoimidazo[1,5-a]-pyridines inhibitors of MEK kinase
  申请人：Genentech, Inc.

  公开号：US07923456B2

  公开（公告）日：2011-04-12

  The invention relates to imidazopyridines of formula I with anti-cancer and/or anti-inflammatory activity and more specifically to imidazopyridines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

  本发明涉及公式I的咪唑吡啶化合物，其具有抗癌和/或抗炎活性，更具体地，涉及抑制MEK激酶活性的咪唑吡啶化合物。本发明提供了用于抑制异常细胞生长或治疗哺乳动物的增生性疾病或治疗炎症性疾病的组合物和方法。本发明还涉及使用该化合物进行哺乳动物细胞的体外、体内诊断或治疗，或相关病理条件的方法。
• 5-Anilinoimidazopyridines and Methods of Use
  申请人：Genentech, Inc.

  公开号：EP2690101A1

  公开（公告）日：2014-01-29

  The invention relates to imidazopyridines of formula 1 with anti-cancer and/or anti-inflammatory activity and more specifically to imidazopyridines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

  本发明涉及具有抗癌和/或抗炎活性的式 1 的咪唑吡啶，更具体地说，涉及抑制 MEK 激酶活性的咪唑吡啶。本发明提供了用于抑制异常细胞生长或治疗过度增殖性疾病或治疗哺乳动物炎症疾病的组合物和方法。本发明还涉及使用这些化合物体外、原位和体内诊断或治疗哺乳动物细胞或相关病理状况的方法。
• Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
  申请人：Genentech, Inc.

  公开号：US10646567B2

  公开（公告）日：2020-05-12

  The present invention describes combination treatment comprising a PD-1 axis binding antagonist and a MEK inhibitor and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer.

  本发明描述了由PD-1轴结合拮抗剂和MEK抑制剂组成的组合治疗及其使用方法，包括治疗需要增强免疫原性的病症的方法，如增加肿瘤免疫原性以治疗癌症。