1-methyl-8-{[5-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide | 1034616-36-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-methyl-8-{[5-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide
• 英文别名: 1-methyl-8-(5-(2-(1-methylpyrrolidin-2-yl)ethylamino)-2-(trifluoromethoxy)phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide；1-methyl-8-[5-[2-(1-methylpyrrolidin-2-yl)ethylamino]-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide
• CAS: 1034616-36-8
• 化学式: C₂₅H₂₉F₃N₈O₂
• 分子量: 530.553
• InChiKey: JVZPJOJXJIONKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2-三氟甲氧基-5-溴苯胺 在 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium diacetate 、 potassium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 lithium hexamethyldisilazane 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-methyl-8-{[5-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide
  参考文献：
  名称：

  NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

  摘要：

  As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.03.054

文献信息

• 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors
  作者：Italo Beria、Barbara Valsasina、Maria Gabriella Brasca、Walter Ceccarelli、Maristella Colombo、Sabrina Cribioli、Gabriele Fachin、Ronald D. Ferguson、Francesco Fiorentini、Laura M. Gianellini、Maria L. Giorgini、Jurgen K. Moll、Helena Posteri、Daniele Pezzetta、Fulvia Roletto、Francesco Sola、Dania Tesei、Michele Caruso

  DOI：10.1016/j.bmcl.2010.09.060

  日期：2010.11

  A series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was optimized as Polo-like kinase 1 inhibitors. Extensive SAR afforded a highly potent and selective PLK1 compound. The compound showed good antiproliferative activity when tested in a panel of tumor cell lines with PLK1 related mechanism of action and with good in vivo antitumor efficacy in two xenograft models after iv administration. (C) 2010 Elsevier Ltd. All rights reserved.
• NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor
  作者：Italo Beria、Roberto T. Bossi、Maria Gabriella Brasca、Michele Caruso、Walter Ceccarelli、Gabriele Fachin、Marina Fasolini、Barbara Forte、Francesco Fiorentini、Enrico Pesenti、Daniele Pezzetta、Helena Posteri、Alessandra Scolaro、Stefania Re Depaolini、Barbara Valsasina

  DOI：10.1016/j.bmcl.2011.03.054

  日期：2011.5

  As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation. (C) 2011 Elsevier Ltd. All rights reserved.