3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol | 1062158-90-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol
• 英文别名: 3-(4-Morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-phenol；3-(4-morpholin-4-yl-1-piperidin-4-ylpyrazolo[3,4-d]pyrimidin-6-yl)phenol
• CAS: 1062158-90-0
• 化学式: C₂₀H₂₄N₆O₂
• 分子量: 380.45
• InChiKey: WCZSBHYATWRXOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  88.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  烟酰氯 、 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 3-{4-morpholin-4-yl-1-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenol
  参考文献：
  名称：

  Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase

  摘要：

  The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3K gamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3K alpha IC50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORCl (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.

  DOI：

  10.1021/jm9012642
• 作为产物：
  描述：

  3-[1-(1-benzylpiperidin-4-yl)-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol 在 氢氧化钯 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以leaving a white solid (148 mg)的产率得到3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol
  参考文献：
  名称：

  PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS

  摘要：

  本发明涉及吡唑并嘧啶类似物，制备吡唑并嘧啶类似物的方法，包含吡唑并嘧啶类似物的组合物，以及治疗与mTOR相关疾病的方法，包括向需要治疗的受试者施用有效量的吡唑并嘧啶类似物。本发明还涉及治疗PI3K相关疾病的方法，包括向需要治疗的受试者施用有效量的吡唑并嘧啶类似物。

  公开号：

  US20080234262A1

文献信息

• PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
  申请人：Zask Arie

  公开号：US20080234262A1

  公开（公告）日：2008-09-25

  The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.

  本发明涉及吡唑吡嘧啶类似物，制备吡唑吡嘧啶类似物的方法，包含吡唑吡嘧啶类似物的组合物，以及治疗mTOR相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。该发明还涉及治疗PI3K相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。
• [EN] PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS<br/>[FR] ANALOGUES DE PYRAZOLOPYRIMIDINE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE KINASE MTOR ET KINASE PI3
  申请人：WYETH CORP

  公开号：WO2008115974A2

  公开（公告）日：2008-09-25

  [EN] The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.
  [FR] La présente invention concerne des analogues de pyrazolopyrimidine, des procédés de préparation d'analogues de pyrazolopyrimidine et des compositions comprenant un analogue de pyrazolopyrimidine et des procédés de traitement de troubles liés au mTOR comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine. L'invention concerne également le traitement de troubles liés au PI3K comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine.
• Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase
  作者：Pawel Nowak、Derek C. Cole、Natasja Brooijmans、Matthew G. Bursavich、Kevin J. Curran、John W. Ellingboe、James J. Gibbons、Irwin Hollander、YongBo Hu、Joshua Kaplan、David J. Malwitz、Lourdes Toral-Barza、Jeroen C. Verheijen、Arie Zask、Wei-Guo Zhang、Ker Yu

  DOI：10.1021/jm9012642

  日期：2009.11.26

  The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3K gamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3K alpha IC50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORCl (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.
• Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-α: Hit to lead studies
  作者：Adam M. Gilbert、Pawel Nowak、Natasja Brooijmans、Matthew G. Bursavich、Christoph Dehnhardt、Efren Delos Santos、Larry R. Feldberg、Irwin Hollander、Stephen Kim、Sabrina Lombardi、Kaapjoo Park、Aranapakam M. Venkatesan、Robert Mallon

  DOI：10.1016/j.bmcl.2009.11.051

  日期：2010.1

  Series of purine and pyrazolo[3,4-d] pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110 alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110 gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells. (C) 2009 Elsevier Ltd. All rights reserved.