4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid | 1234480-80-8

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid
• 英文别名: 4-[(5,11-dimethyl-6-oxopyrimido[4,5-b][1,4]benzodiazepin-2-yl)amino]-3-methoxybenzoic acid
• CAS: 1234480-80-8
• 化学式: C₂₁H₁₉N₅O₄
• 分子量: 405.413
• InChiKey: WSLOEKAMNQLCHA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid 、 N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide trifluoroacetate 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 反应 22.0h， 以39%的产率得到
  参考文献：
  名称：

  [EN] REGULATING CHIMERIC ANTIGEN RECEPTORS
  [FR] RÉGULATION DE RÉCEPTEURS D'ANTIGÈNES CHIMÉRIQUES

  摘要：

  这项发明涉及用于调节嵌合抗原受体免疫效应细胞（例如T细胞（CAR-T））治疗以调节相关的不良炎症反应的组合物和方法，例如细胞因子释放综合征和肿瘤溶解综合征，通过靶向蛋白质降解。

  公开号：

  WO2018148440A1
• 作为产物：
  描述：

  2-氯-5,11-二甲基-5H-苯并[E]嘧啶并[5,4-B][1,4]二氮杂-6(11H)- 在 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium carbonate 、 lithium hydroxide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 甲醇 、 水 、 叔丁醇 为溶剂， 反应 65.0h， 生成 4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)-3-methoxybenzoic acid
  参考文献：
  名称：

  METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES

  摘要：

  本申请提供了作为蛋白质降解诱导基团的双功能化合物。本申请还涉及通过使用将结合脑白质蛋白的基团与能够结合到靶向蛋白的配体相连的双功能化合物来实现内源蛋白的靶向降解的方法，该方法可用于治疗增殖性疾病。本申请还提供了制备本申请化合物及其中间体的方法。

  公开号：

  US20160176916A1

文献信息

• METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US20160176916A1

  公开（公告）日：2016-06-23

  The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

  本申请提供了作为蛋白质降解诱导基团的双功能化合物。本申请还涉及通过使用将结合脑白质蛋白的基团与能够结合到靶向蛋白的配体相连的双功能化合物来实现内源蛋白的靶向降解的方法，该方法可用于治疗增殖性疾病。本申请还提供了制备本申请化合物及其中间体的方法。
• [EN] TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS<br/>[FR] DÉGRADATION MODULABLE DE PROTÉINE ENDOGÈNE AVEC DES COMPOSÉS HÉTÉROBIFONCTIONNELS
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2018148443A1

  公开（公告）日：2018-08-16

  The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.

  本发明提供了一种在体内调节基因表达的方法，避免了与CRISPR内源蛋白敲除或敲入策略以及提供单个核苷酸修正或改变的策略相关的问题。该发明包括将编码靶向蛋白（dTAG）的异双功能化合物的核苷酸插入基因组中，与编码感兴趣的内源表达蛋白的基因的核苷酸序列同框，表达后产生内源蛋白-dTAG杂交蛋白。这允许使用异双功能化合物对dTAG和融合的内源蛋白进行靶向蛋白降解。
• Methods to induce targeted protein degradation through bifunctional molecules
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10125114B2

  公开（公告）日：2018-11-13

  The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

  本申请提供了作为蛋白质降解诱导分子的双功能化合物。本申请还涉及通过使用双官能化合物靶向降解内源性蛋白质的方法，该双官能化合物将脑龙结合分子与能够与靶向蛋白质结合的配体连接起来，可用于治疗增殖性疾病。本申请还提供了制造本申请化合物及其中间体的方法。
• 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。