7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one | 1463054-13-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one
• 英文别名: 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroindol-2-one
• CAS: 1463054-13-8
• 化学式: C₁₄H₁₇BFNO₃
• 分子量: 277.103
• InChiKey: ZYBYKEGJAYXQKM-UHFFFAOYSA-N

物化性质

• 沸点：
  417.6±45.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.62
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one 、 (R)-2-(5-bromo-pyridin-3-ylamino)-2-phenyl-ethanol 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 反应 10.0h， 以5 mg的产率得到7-fluoro-5-[5-((R)-2-hydroxy-1-phenylethylamino)pyridin-3-yl]-1,3-dihydroindol-2-one
  参考文献：
  名称：

  [EN] NOVEL BI-RING PHENYL-PYRIDINES/PYRAZINES FOR THE TREATMENT OF CANCER
  [FR] NOUVELLES PHÉNYLPYRIDINES/PYRAZINES À DEUX CYCLES POUR LE TRAITEMENT DU CANCER

  摘要：

  该发明提供了具有以下一般式的新化合物：其中R1、R2和R3如本文所述，包括该化合物的组合物以及使用该化合物的方法。

  公开号：

  WO2014090692A1
• 作为产物：
  描述：

  7-氟-2-吲哚酮 在 N-溴代丁二酰亚胺(NBS) 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 2.0h， 生成 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one
  参考文献：
  名称：

  Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8

  摘要：

  Glutamate mediates fast excitatory neurotransmission via ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of S-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP gamma-8, the primary TARP found in hippocampus. High-throughput screen lead 4 was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118.(1) Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (GluAl/gamma-8 pIC(50) = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiography (ED50 = 0.6 mg/kg, plasma EC50 = 9 ng/mL).

  DOI：

  10.1021/acsmedchemlett.8b00215

文献信息

• [EN] INDOLONE COMPOUNDS AND THEIR USE AS AMPA RECEPTOR MODULATORS<br/>[FR] COMPOSÉS INDOLONES ET UTILISATION DE CES DERNIERS EN TANT QUE MODULATEURS DES RÉCEPTEURS AMPA
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2016176463A1

  公开（公告）日：2016-11-03

  Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof, Formula (I). Also provided herein are pharmaceutical compositions, comprising compounds of Formula (I), and methods of using compounds of Formula (I).

  本文提供的是化合物的化学式(I)，以及其药用盐、N-氧化物或溶剂化合物(I)。本文还提供了包含化合物的药物组合物(I)和使用化合物(I)的方法。
• NOVEL BI-RING PHENYL-PYRIDINES/PYRAZINES FOR THE TREATMENT OF CANCER
  申请人：HOFFMANN-LA ROCHE INC.

  公开号：US20150266878A1

  公开（公告）日：2015-09-24

  The invention provides novel compounds having the general formula: wherein R 1 , R 2 and R 3 are as described herein, compositions including the compounds and methods of using the compounds.

  本发明提供了具有下列通式的新化合物：其中R1、R2和R3如本文所述，包括这些化合物的组合物和使用这些化合物的方法。
• [EN] NOVEL BI-RING PHENYL-PYRIDINES/PYRAZINES FOR THE TREATMENT OF CANCER<br/>[FR] NOUVELLES PHÉNYLPYRIDINES/PYRAZINES À DEUX CYCLES POUR LE TRAITEMENT DU CANCER
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014090692A1

  公开（公告）日：2014-06-19

  The invention provides novel compounds having the general formula: wherein R1, R2 and R3 are as described herein, compositions including the compounds and methods of using the compounds.

  该发明提供了具有以下一般式的新化合物：其中R1、R2和R3如本文所述，包括该化合物的组合物以及使用该化合物的方法。
• Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8
  作者：Suchitra Ravula、Brad M. Savall、Nyantsz Wu、Brian Lord、Kevin Coe、Kai Wang、Mark Seierstad、Devin M. Swanson、Jeannie Ziff、Minh Nguyen、Perry Leung、Ray Rynberg、David La、Daniel J. Pippel、Tatiana Koudriakova、Timothy W. Lovenberg、Nicholas I. Carruthers、Michael P. Maher、Michael K. Ameriks

  DOI：10.1021/acsmedchemlett.8b00215

  日期：2018.8.9

  Glutamate mediates fast excitatory neurotransmission via ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of S-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP gamma-8, the primary TARP found in hippocampus. High-throughput screen lead 4 was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118.(1) Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (GluAl/gamma-8 pIC(50) = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiography (ED50 = 0.6 mg/kg, plasma EC50 = 9 ng/mL).