9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine | 1282516-68-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
• 英文别名: 9-bromo-2,3-diiodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine
• CAS: 1282516-68-0
• 化学式: C₁₁H₇BrI₂N₂O
• 分子量: 516.902
• InChiKey: BOLGNRXJXPPVJO-UHFFFAOYSA-N

物化性质

• 沸点：
  540.5±60.0 °C(Predicted)
• 密度：
  2.66±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 在 bis-triphenylphosphine-palladium(II) chloride 、 四(三苯基膦)钯 、 乙基溴化镁 、 potassium acetate 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 乙醚 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 6.33h， 生成 PI3K抑制剂(GDC-0032)
  参考文献：
  名称：

  Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

  摘要：

  Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively, suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

  DOI：

  10.1021/jm4003632
• 作为产物：
  描述：

  2-(5-bromo-2-cyanophenoxy)ethan-1-aminium chloride 在 N-碘代丁二酰亚胺 、 magnesium ethylate 、 potassium hydrogencarbonate 作用下， 以 2-甲基四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 71.5h， 生成 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF (S)-2-((2-((S)-4-(DIFLUOROMETHYL)-2-OXOOXAZOLIDIN-3-YL)-5,6-DIHYDROBENZO[F]IMIDAZO[1,2-D][1,4]OXAZEPIN-9-YL)AMINO) PROPANAMIDE
  [FR] PROCÉDÉ DE PRÉPARATION DE (S)-2-((2-((S)-4-(DIFLUOROMÉTHYL)-2-OXOOXAZOLIDIN-3-YL)-5,6-DIHYDROBENZO[F]IMIDAZO[1,2-D][1,4]OXAZÉPIN-9-YL)AMINO) PROPANAMIDE

  摘要：

  制备苯并噁唑啉酮化合物的方法以及合成中间体被描述，包括具有结构（I）的化合物18。

  公开号：

  WO2018109204A1

文献信息

• BENZOXAZEPIN COMPOUNDS SELECTIVE FOR PI3K P110 DELTA AND METHODS OF USE
  申请人：Heffron Timothy

  公开号：US20120245144A1

  公开（公告）日：2012-09-27

  Benzoxazepin Formula I compounds, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological disorders, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  本句翻译为中文是：苯并恶唑啉I型化合物，包括立体异构体、几何异构体、互变异构体、代谢物以及药学上可接受的盐，对于抑制PI3K的δ异构体以及治疗由脂质激酶介导的疾病如炎症、免疫疾病和癌症是有用的。公开了使用I型化合物公式进行体外、原位和体内诊断、预防或治疗哺乳动物细胞中此类疾病或相关病理状况的方法。
• [EN] BENZOXAZEPIN OXAZOLIDINONE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE BENZOXAZÉPINE OXAZOLIDINONE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2017001645A1

  公开（公告）日：2017-01-05

  Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide- 3 kinase (PI3K) modulation activity or function having the Formula (I) structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

  本发明描述了具有磷脂酰肌醇-3激酶（PI3K）调节活性的苯并恶唑啉恶唑烷酮化合物，其具有如下公式（I）结构：或立体异构体、互变异构体或药用可接受的盐，以及具有本发明所述的取代基和结构特征。还描述了包括公式I化合物的药物组合物和药物，以及使用此类PI3K调节剂的方法，单独使用或与其他治疗剂联合使用，用于治疗由PI3K失调介导或依赖的疾病或病症。
• Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino acids
  作者：Chong Han、Sean M. Kelly、Theresa Cravillion、Scott J. Savage、Tina Nguyen、Francis Gosselin

  DOI：10.1016/j.tet.2019.04.057

  日期：2019.8

  An efficient synthesis of PI3K inhibitor GDC-0077, featuring two consecutive Cu-catalyzed CN coupling reactions, is reported. The described synthetic route involves a chemoselective Ullmann-type coupling of a chiral difluoromethyl-substituted oxazolidinone, a Cu-catalyzed N-arylation of l-alanine with high stereochemical integrity, and a high-yielding final amide bond formation step to produce GDC-0077

  据报道，PI3K抑制剂GDC-0077的有效合成具有两个连续的Cu催化的C N偶联反应。所述的合成途径涉及手性二氟甲基取代的恶唑烷酮的化学选择性乌尔曼型偶联，具有高立体化学完整性的Cu催化的1-丙氨酸的N-芳基化以及高产率的最终酰胺键形成步骤以产生GDC-0077在＞ 99.5面积％的HPLC纯度中。
• BENZOXAZEPIN OXAZOLIDINONE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20170002022A1

  公开（公告）日：2017-01-05

  Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

  本发明描述了具有磷脂酰肌醇-3激酶（PI3K）调节活性的苯并恶唑啉恶唑烷酮化合物，其具有如下公式I结构：或其立体异构体、互变异构体或药用可接受的盐，以及本发明所述的取代基和结构特征。还描述了包括公式I化合物的药物组合物和药物，以及使用这样的PI3K调节剂的方法，单独使用或与其他治疗剂联合使用，用于治疗由PI3K失调介导或依赖的疾病或病症。
• BENZOXAZEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
  申请人：Blaquiere Nicole

  公开号：US20110076292A1

  公开（公告）日：2011-03-31

  Benzoxazepin compounds of Formula I, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z 1 is CR 1 or N; Z 2 is CR 2 or N; Z 3 is CR 3 or N; Z 4 is CR 4 or N; and B is a pyrazolyl, imidazolyl, or triazolyl ring fused to the benzoxepin ring, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  方程式I中的苯并噁唑啉化合物，包括立体异构体、几何异构体、互变异构体、溶剂合物、代谢物及其药用可接受盐，其中：Z1为CR1或N；Z2为CR2或N；Z3为CR3或N；Z4为CR4或N；B为与苯并噁唑啉环融合的吡唑基、咪唑基或三唑基环，用于抑制脂质激酶包括p110 alpha和PI3K的其他同系物，并用于治疗由脂质激酶介导的癌症等疾病。公开了使用方程式I中的化合物在哺乳动物细胞中进行体外、体内和体内诊断、预防或治疗此类疾病或相关病理条件的方法。