1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2hquinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4hpyrazolo[4,3-c]pyridin-5-yl]ethanone | 1936421-45-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2hquinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4hpyrazolo[4,3-c]pyridin-5-yl]ethanone
• 英文别名: 1-[3-[7-Chloro-3,4-dihydro-6-(1-methyl-1H-pyrazol-4-yl)-1(2H)-quinolinyl]-1,4,6,7-tetrahydro-1-[(3S)-tetrahydro-3-furanyl]-5H-pyrazolo[4,3-c]pyridin-5-yl]ethanone；1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-oxolan-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone
• CAS: 1936421-45-2
• 化学式: C₂₅H₂₉ClN₆O₂
• 分子量: 480.997
• InChiKey: NYOUQHHVBLJFPS-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  68.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2hquinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4hpyrazolo[4,3-c]pyridin-5-yl]ethanone 、 甲基三氟硼酸钾 在 palladium diacetate 、 caesium carbonate 、 正丁基二(1-金刚烷基)膦 作用下， 以 水 、 甲苯 为溶剂， 反应 18.0h， 以15%的产率得到1-[3-[7-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone
  参考文献：
  名称：

  [EN] 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
  [FR] COMPOSÉS 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE UTILISÉS COMME INHIBITEURS DE CBP ET/OU DE EP300

  摘要：

  公开号：

  WO2016086200A9
• 作为产物：
  描述：

  ethyl 3-((tert-butoxycarbonyl)(2-cyanoethyl)amino)propanoate 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium hydride 、 caesium carbonate 、 一水合肼 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 、 copper(ll) bromide 、 sodium t-butanolate 、 亚硝酸异戊酯 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 44.33h， 生成 1-[3-[7-chloro-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2hquinolin-1-yl]-1-[(3S)-tetrahydrofuran-3-yl]-6,7-dihydro-4hpyrazolo[4,3-c]pyridin-5-yl]ethanone
  参考文献：
  名称：

  [EN] 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
  [FR] COMPOSÉS 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE UTILISÉS COMME INHIBITEURS DE CBP ET/OU DE EP300

  摘要：

  公开号：

  WO2016086200A9

文献信息

• THERAPEUTIC COMPOUNDS AND USES THEREOF
  申请人：Constellation Pharmaceuticals, Inc.

  公开号：US20160158207A1

  公开（公告）日：2016-06-09

  The present invention relates to compounds of formula (I) or formula (II): and to salts thereof, wherein R 1 -R 4 of formula (I) and R 1 -R 3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

  本发明涉及公式（I）或公式（II）的化合物及其盐，其中公式（I）的R1-R4和公式（II）的R1-R3具有以下定义的任何值，以及其组合物和用途。这些化合物可用作CBP和/或EP300的抑制剂。还包括含有公式（I）或公式（II）的化合物或其药学上可接受的盐的制药组合物，以及使用这些化合物和盐治疗各种CBP和/或EP300介导的疾病的方法。
• 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
  申请人：GENENTECH, INC.

  公开号：EP3632915A1

  公开（公告）日：2020-04-08

  The present invention relates to compounds of formula (I) or formula (II): and to salts thereof, wherein R1-R4 of formula (I) and R1-R3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

  本发明涉及式 (I) 或式 (II) 的化合物： 及其盐，其中式(I)的 R1-R4 和式(II)的 R1-R3 具有本文定义的任一值，以及其组合物和用途。这些化合物可用作 CBP 和/或 EP300 的抑制剂。还包括包含式(I)的式(II)的化合物或其药学上可接受的盐的药物组合物，以及使用这种化合物和盐治疗各种CBP和/或EP300介导的疾病的方法。
• GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
  作者：F. Anthony Romero、Jeremy Murray、Kwong Wah Lai、Vickie Tsui、Brian K. Albrecht、Le An、Maureen H. Beresini、Gladys de Leon Boenig、Sarah M. Bronner、Emily W. Chan、Kevin X. Chen、Zhongguo Chen、Edna F. Choo、Kyle Clagg、Kevin Clark、Terry D. Crawford、Patrick Cyr、Denise de Almeida Nagata、Karen E. Gascoigne、Jane L. Grogan、Georgia Hatzivassiliou、Wei Huang、Thomas L. Hunsaker、Susan Kaufman、Stefan G. Koenig、Ruina Li、Yingjie Li、Xiaorong Liang、Jiangpeng Liao、Wenfeng Liu、Justin Ly、Jonathan Maher、Colin Masui、Mark Merchant、Yingqing Ran、Alexander M. Taylor、John Wai、Fei Wang、Xiaocang Wei、Dong Yu、Bing-Yan Zhu、Xiaoyu Zhu、Steven Magnuson

  DOI：10.1021/acs.jmedchem.7b00796

  日期：2017.11.22

  Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nM) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.
• 4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
  申请人：Genentech, Inc.

  公开号：EP3224258B1

  公开（公告）日：2019-08-14
• US9763922B2
  申请人：——

  公开号：US9763922B2

  公开（公告）日：2017-09-19