4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine

• 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: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine
• 英文别名: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine
• 化学式: C₁₄H₁₉BN₂O₂
• 分子量: 258.128
• InChiKey: WWQZWYMCVVCLJL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.05
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  60.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-2-(1-((5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 、 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 反应 16.0h， 以52%的产率得到(S)-2-(1-((5-(6-amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one
  参考文献：
  名称：

  Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases

  摘要：

  Oral PI3K delta inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3K delta inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

  DOI：

  10.1021/acs.jmedchem.8b00873
• 作为产物：
  描述：

  4-溴-6-氨基吲哚 、 联硼酸频那醇酯 、 potassium acetate 、 、 碳酸氢钠 在 1,1'-双(二苯基膦)二茂铁 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 氩 、 乙酸乙酯 、 水 、 Brine 、 Sodium sulfate-III 、 dichloromethane diethyl ether 作用下， 以 叔丁醇 、 水 为溶剂， 反应 16.0h， 以to give 110 mg (30% yield) of the title compound的产率得到4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine
  参考文献：
  名称：

  PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS

  摘要：

  本发明揭示了具有化学结构式（I）的新吡咯三唑酮衍生物；以及其制备过程，包括它们的药物组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。

  公开号：

  US20150291595A1

文献信息

• [EN] PYRROLOPYRIMIDINE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE PYRROLOPYRIMIDINE UTILISÉS EN TANT QU'INHIBITEURS DE PI3K
  申请人：ALMIRALL SA

  公开号：WO2015091532A1

  公开（公告）日：2015-06-25

  New pyrrolopyrimidine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

  揭示了具有化学结构式(I)的新吡咯吡嘧啶衍生物；以及它们的制备方法、包含它们的药物组合物以及它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。
• Pyrrolotriazinone derivatives as PI3K inhibitors
  申请人：ALMIRALL, S.A.

  公开号：US09388189B2

  公开（公告）日：2016-07-12

  New pyrrolotriazinone derivatives having the chemical structure of Formula (I) are disclosed; as well as process for theft preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

  本发明揭示了具有化学结构式（I）的新吡咯三嗪衍生物；以及制备它们的方法，包括含有它们的制药组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。
• Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases
  作者：Montse Erra、Joan Taltavull、Francisco Javier Bernal、Juan Francisco Caturla、Marta Carrascal、Lluís Pagès、Marta Mir、Sònia Espinosa、Jordi Gràcia、María Domínguez、Mar Sabaté、Stéphane Paris、Mónica Maldonado、Begoña Hernández、Mónica Bravo、Elena Calama、Montserrat Miralpeix、Martin D. Lehner、Marta Calbet

  DOI：10.1021/acs.jmedchem.8b00873

  日期：2018.11.8

  Oral PI3K delta inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3K delta inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.
• PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS
  申请人：ALMIRALL, S.A.

  公开号：US20150291595A1

  公开（公告）日：2015-10-15

  New pyrrolotriazinone derivatives having the chemical structure of Formula (I) are disclosed; as well as process for theft preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).

  本发明揭示了具有化学结构式（I）的新吡咯三唑酮衍生物；以及其制备过程，包括它们的药物组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的用途。