2-(4-(4-hydroxypiperidin-1-yl)-2-methoxyphenylamino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one | 1234480-51-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 2-(4-(4-hydroxypiperidin-1-yl)-2-methoxyphenylamino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one
• 英文别名: 2-((4-(4-hydroxypiperidin-1-yl)-2-methoxyphenyl)amino-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one；2-[4-(4-hydroxypiperidin-1-yl)-2-methoxyanilino]-5,11-dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one
• CAS: 1234480-51-3
• 化学式: C₂₅H₂₈N₆O₃
• 分子量: 460.536
• InChiKey: YSFFGUHMDPYPAW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  94.1
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(4-(4-hydroxypiperidin-1-yl)-2-methoxyphenylamino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one 、 (2S,4R)-1-((S)-2-(6-bromohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 以10 %的产率得到(2S,4R)-1-((S)-2-(6-((1-(4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)-amino)-3-methoxyphenyl)piperidin-4-yl)oxy)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)-phenyl)ethyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  作为细胞外信号调节激酶 5 的高选择性和高效降解剂的蛋白水解靶向嵌合体的设计、合成和生物学评价

  摘要：

  细胞外信号调节激酶 5 (ERK5) 被认为是丝裂原激活蛋白激酶家族的关键成员，参与肿瘤生长、迁移和血管生成。然而，多项研究中ERK5抑制的结果存在争议，需要高度特异性的ERK5靶向剂来确认生理功能。利用蛋白水解靶向嵌合体技术，我们设计了选择性ERK5降解剂PPM-3，并检测了其对癌细胞的生物学效应。有趣的是， PPM-3选择性降解ERK5并不会直接影响肿瘤细胞的生长。根据蛋白质组学分析，ERK5缺失可能与肿瘤免疫相关。PPM-3通过影响巨噬细胞的分化来影响肿瘤的发展。因此，PPM-3是研究ERK5的有效小分子工具，也是一种有前途的免疫治疗候选药物。

  DOI：

  10.1021/acs.jmedchem.3c00864

文献信息

• Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
  申请人：Brown Dennis M.

  公开号：US10383847B2

  公开（公告）日：2019-08-20

  The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo. In particular, the therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo, are effective Nek9 inhibitors. The active agent, such as meisoindigo, can act as a Nek9 inhibitor. The active agent can be used together with Nek9 inhibitors or agents that inhibit the expression of Nek9.

  本发明描述了通过提高单一疗法的疗效或减少副作用来提高以前受次优治疗性能限制的治疗活性制剂的疗效的方法和组合物。这种方法和组合物特别适用于选自以下组别的治疗活性剂：(i) 靛红素；(ii) 靛红素的类似物；(iii) 靛红素或靛红素类似物的衍生物；(iv) 包含靛红素、靛红素类似物或靛红素或靛红素类似物衍生物的药物组合物，特别是甲异靛。特别是，选自以下组别的治疗活性剂是有效的 Nek9 抑制剂：(i) 靛红素；(ii) 靛红素的类似物；(iii) 靛红素的衍生物或靛红素的类似物；以及 (iv) 由靛红素、靛红素的类似物或靛红素的衍生物或靛红素的类似物，特别是 meisoindigo 组成的药物组合物。活性剂，如 meisoindigo，可作为 Nek9 抑制剂。活性剂可与 Nek9 抑制剂或抑制 Nek9 表达的制剂一起使用。
• Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10570154B2

  公开（公告）日：2020-02-25

  The present invention relates to novel pyrimido-diazepinone compounds, methods of modulating protein kinases, including MPS1 (TTK), ERK5 (BMK1, MAPK7), polo kinase 1, 2, 3, or 4, Ack1, Ack2, Abl, DCAMKL1, ABL1, Abl mutants, DCAMKL2, ARK5, BRK, MKNK2, FGFR4, TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS1, RPS6KA6, TAOK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, Axl, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, ROCK-H, Rsk1, SGK, TrkA, TrkB and TrkC, and the use of such compounds in the treatment of various diseases, disorders or conditions.

  本发明涉及新型嘧啶类二氮杂卓酮化合物、调节蛋白激酶的方法，包括MPS1（TTK）、ERK5（BMK1、MAPK7）、polo 激酶 1、2、3 或 4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl 突变体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3, ROS1, RPS6KA6, TAOK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, Axl, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR、PKB、PKC、Raf、ROCK-H、Rsk1、SGK、TrkA、TrkB 和 TrkC。
• PYRIMIDO-DIAZEPINONE KINASE SCAFFOLD COMPOUNDS AND METHODS OF TREATING DISORDERS
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：EP2379559B1

  公开（公告）日：2017-10-25
• COMPOSITIONS AND METHODS TO IMPROVE THE THERAPEUTIC BENEFIT OF INDIRUBIN AND ANALOGS THEREOF, INCLUDING MEISOINDIGO
  申请人：BROWN Dennis M.

  公开号：US20160243077A1

  公开（公告）日：2016-08-25

  The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo. In particular, the therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo, are effective Nek9 inhibitors. The active agent, such as meisoindigo, can act as a Nek9 inhibitor. The active agent can be used together with Nek9 inhibitors or agents that inhibit the expression of Nek9.
• US9266890B2
  申请人：——

  公开号：US9266890B2

  公开（公告）日：2016-02-23