tert-butyl 4-((4-((5-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate | 909863-42-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: tert-butyl 4-((4-((5-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate
• CAS: 909863-42-9
• 化学式: C₂₅H₂₈ClFN₄O₄
• 分子量: 502.973
• InChiKey: MYEYXJOJEWOLNP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.95
• 重原子数：
  35.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  85.81
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-((4-((5-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以85%的产率得到4-(5-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline
  参考文献：
  名称：

  Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

  摘要：

  Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

  DOI：

  10.1021/ml400146c
• 作为产物：
  描述：

  6-乙酰氧基-4-氯-7-甲氧基喹唑啉 在 盐酸 、 偶氮二甲酸二叔丁酯 、 氨 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 异丙醇 为溶剂， 反应 17.0h， 生成 tert-butyl 4-((4-((5-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

  摘要：

  Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

  DOI：

  10.1021/ml400146c

文献信息

• Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics
  作者：Peter Ballard、Robert H. Bradbury、Craig S. Harris、Laurent F.A. Hennequin、Mark Hickinson、Jason G. Kettle、Jane Kendrew、Teresa Klinowska、Donald J. Ogilvie、Stuart E. Pearson、Emma J. Williams、Ingrid Wilson

  DOI：10.1016/j.bmcl.2006.06.054

  日期：2006.9

  The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pK(a) modulation are discussed. (c) 2006 Elsevier Ltd. All rights reserved.