1-methyl-8-{[5-nitro-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide | 1034615-45-6

• 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-nitro-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide
• 英文别名: 8-(5-nitro-2-trifluoromethoxy-phenylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide；1-methyl-8-[5-nitro-2-(trifluoromethoxy)anilino]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide
• CAS: 1034615-45-6
• 化学式: C₁₈H₁₄F₃N₇O₄
• 分子量: 449.349
• InChiKey: KVZAUEIJEVGGNG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  154
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  1-methyl-8-{[5-nitro-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 在 铁粉 、 氯化铵 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 4.5h， 生成 (S)-8-{5-[(pyrrolidine-2-carbonyl)-amino]-2-trifluoromethoxy-phenylamino}-1-methyl-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
• 作为产物：
  描述：

  8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 、 5-硝基-2-(三氟甲氧基)苯胺 在 palladium diacetate 、 potassium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-methyl-8-{[5-nitro-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

• SUBSTITUTED PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  申请人：Caruso Michele

  公开号：US20100216808A1

  公开（公告）日：2010-08-26

  Pyrazolo-quinazoline derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

  本发明揭示了式（I）中所定义的吡唑并喹唑啉衍生物及其药学上可接受的盐，以及它们的制备方法和包含它们的制药组合物；本发明中的化合物在治疗与蛋白激酶活性失调相关的疾病，如癌症中可能有用。
• Substituted pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
  申请人：Caruso Michele

  公开号：US08614220B2

  公开（公告）日：2013-12-24

  Pyrazolo-quinazoline derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

  本发明揭示了式（I）中定义的吡唑喹唑啉衍生物及其药学上可接受的盐，以及它们的制备方法和包含它们的制药组合物；本发明中的化合物可能在治疗与蛋白激酶活性失调有关的疾病（如癌症）中有用。
• 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.
• US8614220B2
  申请人：——

  公开号：US8614220B2

  公开（公告）日：2013-12-24
• [EN] SUBSTITUTED PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLO-QUINAZOLINE SUBSTITUÉS, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION EN TANT QU'INHIBITEURS DES KINASES
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2008074788A1

  公开（公告）日：2008-06-26

  [EN] Pyrazolo-quinazoline derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
  [FR] La présente invention concerne des dérivés de pyrazolo-quinazoline de formule (I) tels que définis dans le mémoire descriptif et leurs sels pharmaceutiquement acceptables, leur procédé de préparation et des compositions pharmaceutiques qui les comprennent. Les composés selon l'invention ont une utilisation thérapeutique pour le traitement de maladies associée à une activité protéine-kinase déréglée telles que le cancer.