(2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzyl]piperidine | 1200131-04-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzyl]piperidine
• 英文别名: (2S,6R)-2,6-dimethyl-1-(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl)piperidine；(2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]piperidine；(2S,6R)-2,6-dimethyl-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperidine
• CAS: 1200131-04-9
• 化学式: C₂₀H₃₂BNO₂
• 分子量: 329.291
• InChiKey: JJYRXEVQAUYIQL-IYBDPMFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.75
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-bromo-9H-pyrrolo[2,3-b:5,4-c′]dipyridine-6-carbonitrile 、 (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzyl]piperidine 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 8.0h， 生成 3-(4-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)phenyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridine-6-carbonitrile
  参考文献：
  名称：

  Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

  摘要：

  Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

  DOI：

  10.1021/acs.jmedchem.5b00464
• 作为产物：
  描述：

  对溴溴苄 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二甲基亚砜 、 乙腈 为溶剂， 反应 2.5h， 生成 (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzyl]piperidine
  参考文献：
  名称：

  Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

  摘要：

  Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

  DOI：

  10.1021/acs.jmedchem.5b00464

文献信息

• DIAZACARBAZOLES AND METHODS OF USE
  申请人：Chen Huifen

  公开号：US20110118230A1

  公开（公告）日：2011-05-19

  The invention relates to 1,7-diazacarbazole compounds of Formula (I), (I-a) and (I-b) which are useful as kinase inhibitors, more specifically useful as checkpoint kinase 1 (chk1) inhibitors, thus useful as cancer therapeutics. The invention also relates to compositions, more specifically pharmaceutical compositions comprising these compounds and methods of using the same to treat various forms of cancer and hyperproliferative disorders, as well as methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

  本发明涉及式（I），（I-a）和（I-b）的1,7-二氮杂咔唑化合物，其作为激酶抑制剂有用，更具体地作为检查点激酶1（chk1）抑制剂有用，因此可用作癌症治疗剂。本发明还涉及包含这些化合物的组合物，更具体地是药物组合物，并使用它们治疗各种形式的癌症和增生性疾病的方法，以及使用这些化合物进行哺乳动物细胞的体外、原位和体内诊断或治疗的方法，或相关的病理条件。
• METHODS OF USE OF DIAZACARBAZOLES FOR TREATING CANCER
  申请人：Genentech, Inc.

  公开号：US20130261104A1

  公开（公告）日：2013-10-03

  Methods of use of compounds of formula (I) for treating cancer: wherein X, Y, X, R 3 , R 5 and R 6 are as defined herein.

  使用式(I)化合物治疗癌症的方法：其中X、Y、X、R3、R5和R6的定义如本文所述。
• Diazacarbazoles and methods of use
  申请人：Chen Huifen

  公开号：US08501765B2

  公开（公告）日：2013-08-06

  The invention relates to 1,7-diazacarbazole compounds of Formula (I), which are useful as kinase inhibitors, more specifically useful as checkpoint kinase I (chk1) inhibitors, thus useful as cancer therapeutics.

  本发明涉及式(I)的1,7-二氮杂咔唑化合物，其作为激酶抑制剂具有用途，更具体地作为检查点激酶I（chk1）抑制剂有用，因此作为癌症治疗药物有用。
• Methods of use of diazacarbazoles for treating cancer
  申请人：Genentech, Inc.

  公开号：US09216980B2

  公开（公告）日：2015-12-22

  Methods of use of compounds of formula (I) for treating cancer: wherein X, Y, X, R3, R5 and R6 are as defined herein.

  使用式(I)化合物治疗癌症的方法：其中X、Y、X、R3、R5和R6的定义如本文所述。
• [EN] DIAZACARBAZOLES AND METHODS OF USE<br/>[FR] DIAZACARBAZOLES ET PROCÉDÉS D'UTILISATION
  申请人：GENENTECH INC

  公开号：WO2009151598A8

  公开（公告）日：2010-05-06