6-(azetidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline | 1441146-99-1

• 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: 6-(azetidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
• 英文别名: 6-(3-Azetidinyloxy)-N-(3-chloro-2-fluorophenyl)-7-methoxy-4-quinazolinamine；6-(azetidin-3-yloxy)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine
• CAS: 1441146-99-1
• 化学式: C₁₈H₁₆ClFN₄O₂
• 分子量: 374.802
• InChiKey: NCROSNKUVIUXLV-UHFFFAOYSA-N

物化性质

• 沸点：
  501.0±50.0 °C(Predicted)
• 密度：
  1.423±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  68.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-氯-N-甲基乙酰胺 、 6-(azetidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline 在 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 1.0h， 以62%的产率得到4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)azetidin-3-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 ammonium hydroxide 、 偶氮二甲酸二叔丁酯 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 异丙醇 为溶剂， 反应 30.25h， 生成 6-(azetidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
  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