N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride

• 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: N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride
• 英文别名: 7-[[(3R,9aS)-3,4,6,7,9,9a-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-yl]methoxy]-N-(4-bromo-3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine;hydrochloride
• 化学式: C₂₃H₂₃BrClFN₄O₄*(x)ClH
• 分子量: 590.3
• InChiKey: YKDOJZIQVDJIDD-LMRHVHIWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.84
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  78
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3(R)-羟基甲基吗啉 在 甲醇 、 sodium methylate 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 57.58h， 生成 N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride
  参考文献：
  名称：

  Receptor-Type Kinase Modulators and Methods of Use

  摘要：

  本发明提供了用于调节受体激酶活性的化合物，特别是ephrin和EGFR，并利用这些化合物及其药物组合物治疗由受体激酶活性介导的疾病的方法。由受体激酶活性介导的疾病包括但不限于部分表现为细胞增殖异常水平（即肿瘤生长）、程序性细胞死亡（凋亡）、细胞迁移和侵袭以及与肿瘤生长相关的血管生成的疾病。本发明的化合物包括“谱选择性”激酶调节剂，这些化合物抑制、调节和/或调节跨受体型酪氨酸激酶亚家族的信号传导，包括ephrin和EGFR。

  公开号：

  US20160129032A1

文献信息

• Receptor-type kinase modulators and methods of use
  申请人：Rice D Kenneth

  公开号：US20060069077A1

  公开（公告）日：2006-03-30

  The present invention provides compounds for modulating receptor kinase activity, particularly ephrin and EGFR, and methods of treating diseases mediated by receptor kinase activity utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds of the invention include “spectrum selective” kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR.

  本发明提供了用于调节受体激酶活性的化合物，特别是调节ephrin和EGFR等受体激酶活性的化合物，并利用这些化合物和其制剂治疗由受体激酶活性介导的疾病的方法。由受体激酶活性介导的疾病包括但不限于部分表现为细胞增殖异常水平（即肿瘤生长）、程序性细胞死亡（凋亡）、细胞迁移和侵袭以及与肿瘤生长相关的血管生成的疾病。本发明的化合物包括“光谱选择性”激酶调节剂，可以抑制、调节和/或调节受体型酪氨酸激酶亚家族之间的信号转导，包括ephrin和EGFR。
• Processes for the preparation of substituted quinazolines
  申请人：Symphony Evolution, Inc.

  公开号：US09163006B2

  公开（公告）日：2015-10-20

  The present disclosure provides compounds for modulating receptor kinase activity, particularly ephrin and EGFR, and methods of treating diseases mediated by receptor kinase activity utilizing the compounds and pharmaceutical compositions thereof. The compounds are generally of formula (I): Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds of the invention include “spectrum selective” kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR. Also disclosed are methods of making compounds for formula 8: comprising introducing group E2 into a compound of formula 7: wherein Ar, Z, P, and E2 are defined herein.

  本公开提供用于调节受体激酶活性的化合物，特别是ephrin和EGFR，并利用这些化合物和其药物组合物治疗受受体激酶活性介导的疾病的方法。这些化合物通常具有式（I）：受受体激酶活性介导的疾病包括但不限于疾病的特征部分为细胞增殖异常（即肿瘤生长）、程序性细胞死亡（凋亡）、细胞迁移和侵袭以及与肿瘤生长相关的血管生成。本发明的化合物包括“光谱选择性”激酶调节剂，这些化合物抑制、调节和/或调节受体型酪氨酸激酶亚家族之间的信号转导，包括ephrin和EGFR。还公开了制备式8化合物的方法：包括将E2基团引入式7化合物中：其中Ar、Z、P和E2在此处定义。
• Process for preparing receptor-type kinase modulators
  申请人：Symphony Evolution, Inc.

  公开号：EP2280003A2

  公开（公告）日：2011-02-02

  The present invention provides a process for preparing compounds for modulating receptor kinase activity, particularly ephrin and EGFR. Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds provided by the process of the invention include "spectrum selective" kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR.

  本发明提供了一种用于制备调节受体激酶活性（尤其是表皮生长因子受体和表皮生长因子受体）的化合物的工艺。由受体激酶活性介导的疾病包括但不限于部分以异常水平的细胞增殖（即肿瘤生长）、程序性细胞死亡（凋亡）、细胞迁移和侵袭以及与肿瘤生长相关的血管生成为特征的疾病。本发明工艺提供的化合物包括 "谱系选择性 "激酶调节剂，即抑制、调节和/或调控包括表皮生长因子受体和表皮生长因子受体在内的各受体型酪氨酸激酶亚家族信号转导的化合物。
• Compounds, pharmaceutical compositions thereof and their use in treating cancer
  申请人：Symphony Evolution, Inc.

  公开号：EP2277867A2

  公开（公告）日：2011-01-26

  The present invention provides compounds which can modulate receptor kinase activity, particularly ephrin and EGFR, pharmaceutical compositions thereof and such compounds for use in treating cancer. The compounds comprise N-(3,4-dichloro-2-fluorophenyl)-7-([(3aR,5r,6aS)-2-methyloctahydrocyclopenta [c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine and N-(3,4-dichloro-2-fluorophenyl)-7-([(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine.

  本发明提供了可调节受体激酶活性的化合物，特别是表皮生长因子受体和表皮生长因子受体，其药物组合物和用于治疗癌症的此类化合物。这些化合物包括N-(3,4-二氯-2-氟苯基)-7-([(3aR,5r,6aS)-2-甲基八氢环戊并[c]吡咯-5-基]甲基}氧基)-6-(甲氧基)喹唑啉-4-胺和N-(3、N-(3,4-二氯-2-氟苯基)-7-([(3aR,5s,6aS)-2-甲基八氢环戊并[c]吡咯-5-基]甲基}氧基)-6-(甲氧基)喹唑啉-4-胺。
• Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
  申请人：Symphony Evolution, Inc.

  公开号：US10266518B2

  公开（公告）日：2019-04-23

  The present invention provides compounds of Formula I, for modulating receptor kinase activity, particularly ephrin and EGFR, and methods of treating diseases mediated by receptor kinase activity utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds of the invention include “spectrum selective” kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR.

  本发明提供了式 I 的化合物、 用于调节受体激酶活性，特别是表皮生长因子受体和表皮生长因子受体，以及利用其化合物和药物组合物治疗由受体激酶活性介导的疾病的方法。由受体激酶活性介导的疾病包括但不限于部分以异常水平的细胞增殖（即肿瘤生长）、程序性细胞死亡（凋亡）、细胞迁移和侵袭以及与肿瘤生长相关的血管生成为特征的疾病。本发明的化合物包括 "谱系选择性 "激酶调节剂，即抑制、调节和/或调节包括表皮生长因子受体和表皮生长因子受体在内的受体型酪氨酸激酶亚家族信号转导的化合物。