3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methylpyrazine-2-carboxamide | 1349151-94-5

• 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: 3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methylpyrazine-2-carboxamide
• 英文别名: 3-Amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methyl-pyrazine-2-carboxamide；3-amino-N-methoxy-N-methyl-6-(4-propan-2-ylsulfonylphenyl)pyrazine-2-carboxamide
• CAS: 1349151-94-5
• 化学式: C₁₆H₂₀N₄O₄S
• 分子量: 364.425
• InChiKey: RLVBRWQRQUMLRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methylpyrazine-2-carboxamide 在 盐酸羟胺 、 sodium acetate 、 溶剂黄146 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 5-(4-(isopropylsulfonyl)phenyl)-3-(5-phenylisoxazol-3-yl)pyrazin-2-amine
  参考文献：
  名称：

  Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor

  摘要：

  The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier et al. (J. Med. Chem. 2011, 54, 2320-2330, DOI: ).

  DOI：

  10.1021/acs.jmedchem.9b00426
• 作为产物：
  描述：

  3-氨基吡嗪-2-羧酸甲酯 在 bis-triphenylphosphine-palladium(II) chloride N-溴代丁二酰亚胺(NBS) 、 水 、 sodium carbonate 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙腈 为溶剂， 反应 53.33h， 生成 3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methylpyrazine-2-carboxamide
  参考文献：
  名称：

  [EN] COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
  [FR] COMPOSÉS UTILISABLES EN TANT QU'INHIBITEURS DE LA KINASE ATR

  摘要：

  公开号：

  WO2011143423A3

文献信息

• COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
  申请人：Charrier Jean-Damien

  公开号：US20120035408A1

  公开（公告）日：2012-02-09

  The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula V: wherein the variables are as defined herein.

  本发明涉及用作ATR蛋白激酶抑制剂的吡嗪和吡啶化合物。本发明还涉及包含该发明化合物的药学上可接受的组合物；使用该发明化合物治疗各种疾病、障碍和病症的方法；制备该发明化合物的过程；制备该发明化合物的中间体；以及在体外应用中使用该化合物的方法，例如研究生物和病理现象中的激酶、通过此类激酶介导的细胞内信号转导途径的研究以及新的激酶抑制剂的比较评估。本发明化合物的化学式为V，其中变量的定义如本文所述。
• Compounds useful as inhibitors of ATR kinase
  申请人：Charrier Jean-Damien

  公开号：US09062008B2

  公开（公告）日：2015-06-23

  The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula V: wherein the variables are as defined herein.

  本发明涉及用作ATR蛋白激酶抑制剂的吡嗪和吡啶化合物。本发明还涉及包含本发明化合物的药学上可接受的组合物；使用本发明化合物治疗各种疾病、疾病和病况的方法；制备本发明化合物的过程；制备本发明化合物的中间体；以及在体外应用中使用化合物的方法，如研究生物和病理现象中的激酶、介导这些激酶的细胞内信号转导途径的研究，以及新的激酶抑制剂的比较评估。本发明化合物具有公式V：其中变量如本文所定义。
• US9062008B2
  申请人：——

  公开号：US9062008B2

  公开（公告）日：2015-06-23
• [EN] COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE<br/>[FR] COMPOSÉS UTILISABLES EN TANT QU'INHIBITEURS DE LA KINASE ATR
  申请人：VERTEX PHARMA

  公开号：WO2011143423A3

  公开（公告）日：2012-03-01
• Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor
  作者：Ronald Knegtel、Jean-Damien Charrier、Steven Durrant、Chris Davis、Michael O’Donnell、Pierre Storck、Somhairle MacCormick、David Kay、Joanne Pinder、Anisa Virani、Heather Twin、Matthew Griffiths、Philip Reaper、Peter Littlewood、Steve Young、Julian Golec、John Pollard

  DOI：10.1021/acs.jmedchem.9b00426

  日期：2019.6.13

  The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier et al. (J. Med. Chem. 2011, 54, 2320-2330, DOI: ).