[(4-bromo-2,5-dimethoxyphenyl)methyl]dimethylamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: [(4-bromo-2,5-dimethoxyphenyl)methyl]dimethylamine
• 英文别名: 1-(4-bromo-2,5-dimethoxyphenyl)-N,N-dimethylmethanamine；[(4-Bromo-2,5-dimethoxyphenyl)methyl]dimethylamine
• 化学式: C₁₁H₁₆BrNO₂
• 分子量: 274.158
• InChiKey: AAPPLJBOAYSLSV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [(4-bromo-2,5-dimethoxyphenyl)methyl]dimethylamine 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 32.0h， 生成 (R)-4-cyclopentyl-6-(4-((dimethylamino)methyl)-2,5-dimethoxyphenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one
  参考文献：
  名称：

  Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold

  摘要：

  Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

  DOI：

  10.1021/acsmedchemlett.9b00243
• 作为产物：
  描述：

  4-溴-2,5-二甲氧基苯甲醛 、 盐酸二甲胺 在 sodium acetate 、 溶剂黄146 、 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 16.67h， 以89%的产率得到[(4-bromo-2,5-dimethoxyphenyl)methyl]dimethylamine
  参考文献：
  名称：

  体内主动选择性BRD9抑制剂的基于结构的设计。

  摘要：

  染色质重塑开关/不可发酵蔗糖（SWI / SNF）复合物的成分在肿瘤中反复突变，表明改变复合物的活性在肿瘤发生中起作用。但是，各个亚基在这一过程中所起的作用尚不清楚。我们着手开发针对BRD9溴结构域的抑制剂化合物，以评估其在SWI / SNF复合物中的功能。在这里，我们介绍基于新型吡啶酮类支架的有效和选择性BRD9溴结构域抑制剂系列的发现和开发。关于与BRD9结合的抑制剂的晶体学信息指导了他们在BRD9效力和对BRD4选择性方面的发展。这些化合物调节BRD9溴结构域的细胞功能，并在AML异种移植模型中显示抗肿瘤活性。

  DOI：

  10.1021/acs.jmedchem.5b01865

文献信息

• New Pyridinones and Isoquinolinones as Inhibitors of the Bromodomain BRD9
  申请人：Boehringer Ingelheim International GmbH

  公开号：US20180044335A1

  公开（公告）日：2018-02-15

  The present invention encompasses compounds of general formula (I) wherein the groups R 1 to R 9 , X 1 and X 2 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, e.g. cancer, pharmaceutical preparations containing such compounds and their uses as a medicament.

  本发明涵盖了一般式（I）的化合物，其中基团R1至R9，X1和X2的含义如权利要求和说明书中所述。本发明的化合物适用于治疗由细胞过度或异常增殖所特征化的疾病，例如癌症，含有这种化合物的制药制剂以及它们作为药物的用途。
• Pyridinones and isoquinolinones as inhibitors of the bromodomain BRD9
  申请人：Boehringer Ingelheim International GmbH

  公开号：US11319318B2

  公开（公告）日：2022-05-03

  The present invention encompasses compounds of general formula (I) wherein the groups R1 to R9, X1 and X2 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, e.g. cancer, pharmaceutical preparations containing such compounds and their uses as a medicament.

  本发明包括通式（I）的化合物，其中基团 R1 至 R9、X1 和 X2 具有权利要求书和说明书中给出的含义。本发明的化合物适用于治疗以细胞过度增殖或异常增殖为特征的疾病（如癌症）、含有此类化合物的药物制剂及其作为药物的用途。
• NEW PYRIDINONES AND ISOQUINOLINONES AS INHIBITORS OF THE BROMODOMAIN BRD9
  申请人：Boehringer Ingelheim International GmbH

  公开号：EP3265453B1

  公开（公告）日：2022-06-29
• Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold
  作者：David Remillard、Dennis L. Buckley、Hyuk-Soo Seo、Fleur M. Ferguson、Sirano Dhe-Paganon、James E. Bradner、Nathanael S. Gray

  DOI：10.1021/acsmedchemlett.9b00243

  日期：2019.10.10

  Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.
• Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor
  作者：Laetitia J. Martin、Manfred Koegl、Gerd Bader、Xiao-Ling Cockcroft、Oleg Fedorov、Dennis Fiegen、Thomas Gerstberger、Marco H. Hofmann、Anja F. Hohmann、Dirk Kessler、Stefan Knapp、Petr Knesl、Stefan Kornigg、Susanne Müller、Herbert Nar、Catherine Rogers、Klaus Rumpel、Otmar Schaaf、Steffen Steurer、Cynthia Tallant、Christopher R. Vakoc、Markus Zeeb、Andreas Zoephel、Mark Pearson、Guido Boehmelt、Darryl McConnell

  DOI：10.1021/acs.jmedchem.5b01865

  日期：2016.5.26

  potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display antitumor activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.

  染色质重塑开关/不可发酵蔗糖（SWI / SNF）复合物的成分在肿瘤中反复突变，表明改变复合物的活性在肿瘤发生中起作用。但是，各个亚基在这一过程中所起的作用尚不清楚。我们着手开发针对BRD9溴结构域的抑制剂化合物，以评估其在SWI / SNF复合物中的功能。在这里，我们介绍基于新型吡啶酮类支架的有效和选择性BRD9溴结构域抑制剂系列的发现和开发。关于与BRD9结合的抑制剂的晶体学信息指导了他们在BRD9效力和对BRD4选择性方面的发展。这些化合物调节BRD9溴结构域的细胞功能，并在AML异种移植模型中显示抗肿瘤活性。