(R)-4-((1,3-dimethyl-2-oxo-4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-4-((1,3-dimethyl-2-oxo-4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
• 英文别名: 4-[[(3R)-1,3-dimethyl-4-(oxan-4-yl)-2-oxo-3H-pyrido[2,3-b]pyrazin-6-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
• 化学式: C₂₈H₃₈N₆O₄
• 分子量: 522.648
• InChiKey: HSRXFQQYAZQIST-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  99.3
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,6-二氯-3-氨基吡啶 在 吡啶 、 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium acetate 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 三氟乙酸 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 74.0h， 生成 (R)-4-((1,3-dimethyl-2-oxo-4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
  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

文献信息

• BET-PROTEIN-INHIBITING DIHYDROPYRIDOPYRAZINONES
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160193206A1

  公开（公告）日：2016-07-07

  The present invention relates to BET protein-inhibitory, especially BRD4-inhibitory, dihydropyridopyrazinones of the general formula (I) in which A, X, R 1 , R 2 , R 3 , R 4 , R 4 , R 6 , R 7 and n have the meanings given in the description, to intermediates for preparation of the compounds according to the invention, to pharmaceutical compositions comprising the compounds according to the invention, and to the prophylactic and therapeutic use thereof in the case of hyperproliferative disorders, especially in the case of neoplastic disorders. This invention further relates to the use of BET protein inhibitors in viral infections, in neurodegenerative disorders, in inflammation diseases, in atherosclerotic disorders and in male fertility control.

  本发明涉及BET蛋白抑制剂，特别是BRD4抑制剂，通式（I）所示的二氢吡啶吡唑酮，其中A、X、R1、R2、R3、R4、R4、R6、R7和n在说明书中给出其含义，以及制备本发明化合物的中间体，包含本发明化合物的制药组合物，以及在高增殖性疾病，特别是恶性肿瘤疾病的预防和治疗中的预防和治疗用途。本发明还涉及在病毒感染、神经退行性疾病、炎症性疾病、动脉粥样硬化性疾病和男性生育控制中使用BET蛋白抑制剂。
• 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.