3-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrrolo[2,3-b:5,4-c′]-dipyridine-6-carbonitrile | 1200127-66-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 3-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrrolo[2,3-b:5,4-c′]-dipyridine-6-carbonitrile
• 英文别名: 3-(4-(4-methylpiperazin-1-yl)phenyl)-9H-dipyrido[2,3-b:4',3']pyrrole-6-carbonitrile；3-[4-(4-Methylpiperazin-1-Yl)phenyl]-9h-Pyrrolo[2,3-B:5,4-C']dipyridine-6-Carbonitrile；12-[4-(4-methylpiperazin-1-yl)phenyl]-5,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene-4-carbonitrile
• CAS: 1200127-66-7
• 化学式: C₂₂H₂₀N₆
• 分子量: 368.441
• InChiKey: PVRJSOWSQUNARV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  71.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (αS)-α-氨基-1H-吡咯并[2,3-b]吡啶-3-丙酸 在 吡啶 、 selenium(IV) oxide 、 bis-triphenylphosphine-palladium(II) chloride 、 氯化亚砜 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氨 、 溴 、 sodium acetate 、 sodium carbonate 、 1-羟基苯并三唑 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸酐 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 3-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrrolo[2,3-b:5,4-c′]-dipyridine-6-carbonitrile
  参考文献：
  名称：

  Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1

  摘要：

  Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.10.063

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。
• Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
  作者：Lewis Gazzard、Karen Williams、Huifen Chen、Lorraine Axford、Elizabeth Blackwood、Brenda Burton、Kerry Chapman、Peter Crackett、Joy Drobnick、Charles Ellwood、Jennifer Epler、Michael Flagella、Emanuela Gancia、Matthew Gill、Simon Goodacre、Jason Halladay、Joanne Hewitt、Hazel Hunt、Samuel Kintz、Joseph Lyssikatos、Calum Macleod、Sarah Major、Guillaume Médard、Raman Narukulla、Judi Ramiscal、Stephen Schmidt、Eileen Seward、Christian Wiesmann、Ping Wu、Sharon Yee、Ivana Yen、Shiva Malek

  DOI：10.1021/acs.jmedchem.5b00464

  日期：2015.6.25

  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.
• US8501765B2
  申请人：——

  公开号：US8501765B2

  公开（公告）日：2013-08-06
• US9216980B2
  申请人：——

  公开号：US9216980B2

  公开（公告）日：2015-12-22