3-amino-4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl) phenyl)benzamide | 1086423-48-4

• 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: 3-amino-4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl) phenyl)benzamide
• 英文别名: 3-amino-4-methyl-N-[4-(morpholin-4-ylmethyl)-3-(trifluoromethyl)phenyl]benzamide
• CAS: 1086423-48-4
• 化学式: C₂₀H₂₂F₃N₃O₂
• 分子量: 393.409
• InChiKey: JIJGGWHWRDWVFN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  67.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(三异丙基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-羧酸 、 3-amino-4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl) phenyl)benzamide 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 水 为溶剂， 反应 168.53h， 生成 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2-methyl-5-(4-morpholin-4-ylmethyl-3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide
  参考文献：
  名称：

  WO2008/144253

  摘要：

  公开号：
• 作为产物：
  描述：

  4-甲基-3-硝基苯甲酸 在 草酰氯 、 铁粉 、 氯化铵 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 3-amino-4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl) phenyl)benzamide
  参考文献：
  名称：

  克服阻力的Pan-Raf抑制剂的合理设计，合成和生物学评估†

  摘要：

  具有DFG-in构象的选择性BRaf V600E抑制剂已被证明对黑色素瘤的一部分有效。然而，代表性抑制剂维罗非尼通过CRaf或BRAf WT依赖性方式迅速获得BRAf WT细胞的抗性。同时靶向Raf蛋白的所有亚型提供了增强功效以及降低获得性抗药性的前景。本文中，我们基于具有DFG-out构象的嘧啶支架作为泛Raf抑制剂，描述了一系列化合物I-01–I-22的设计和表征。其中，I-15结合所有Raf启动子，IC 50值为12.6 nM（BRaf V600E），30.1 nM（ARaf），19.7 nM（BRaf WT）和17.5 nM（CRaf），并证明了针对BRaf WT表型黑素瘤和BRaf V600E表型结直肠癌细胞的细胞活性。Western blot检测人黑素瘤SK-Mel-2细胞系中P-Erk的抑制作用表明，I-15在低至400 nM的浓度下抑制SK-Mel-2细胞系的增殖，而没有E

  DOI：

  10.1039/c7ob00518k

文献信息

• Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
  作者：Lu Wang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Yanle Zhi、Li Zhang、Tianxiao Mao、Xiang Zhou、Yadong Chen、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2017.02.041

  日期：2017.4

  isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western

  同时靶向所有Raf同工型提供了增强的功效以及降低的抗药性的前景。本文描述了一系列具有强力泛肽抑制剂的具有DFG-out构象的嘧啶支架的发现和表征。其中，具有优异泛泛效能的I-41表现出对BRafWT表型黑素瘤和BRafV600E表型结肠细胞的抑制活性。Western blotting结果显示，人黑素瘤SK-Mel-2细胞系中Erk的抑制作用表明I-41抑制了SK-Mel-2细胞的增殖而没有Erk的反常激活，这支持I-41可能成为良好的候选化合物。克服黑素瘤对当前BRafV600E抑制剂疗法的耐药性。I-41在大鼠中也具有良好的药代动力学特征。合成，SAR，线索选择，
• Compounds and Compositions as Protein Kinase Inhibitors
  申请人：Okram Barun

  公开号：US20080287432A1

  公开（公告）日：2008-11-20

  The invention provides a novel class of compounds of formula I, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the AbI, Bcr-AbI, Aurora-A, SGK, Tie-2, Trk-B, FGFR3, c-kit, b-RAF, c-RAF, DYRK2, Fms, Fyn and PDGFRalpha and PDGFR&bgr; kinases.

  本发明提供了一种新型的I类化合物，包括这些化合物的药物组合物以及使用这些化合物治疗或预防与异常或失调激酶活性相关的疾病或障碍的方法，尤其是涉及AbI、Bcr-AbI、AuroRA-A、SGK、Tie-2、Trk-B、FGFR3、c-kit、b-RAF、c-RAF、DYRK2、Fms、Fyn和PDGFRAlpha和PDGFR&bgr;激酶异常激活的疾病或障碍。
• COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
  申请人：Sim Taebo

  公开号：US20090105250A1

  公开（公告）日：2009-04-23

  The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, Bcr-Abl, FGFR3, PDGFRβ and b-Raf kinases.

  本发明提供了一类新颖的化合物、包含这些化合物的制药组合物以及使用这些化合物治疗或预防与异常或失调激酶活性有关的疾病或障碍的方法，特别是涉及Abl、Bcr-Abl、FGFR3、PDGFRβ和b-Raf激酶异常激活的疾病或障碍。
• Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
  作者：Yanmin Zhang、Lu Wang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Xiang Zhou、Yadong Chen、Tao Lu、Weifang Tang

  DOI：10.1021/acs.jcim.6b00795

  日期：2017.6.26

  While selective BRaf(V600E) inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway, Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-1-18 were designed and synthesized. The most promising compound I-16 potently inhibits subtypes of Rafs with IC50 values of 3.49 (BRaf(V600E)), 8.86 (ARaf), 5.78 (BRaf(WT)), and 1.65 nM (CRaf); respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRaf(WT) with IC50 values of 0.93 mu M. The Western blot results for: the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRar(V600E) inhibitors..
• US7589101B2
  申请人：——

  公开号：US7589101B2

  公开（公告）日：2009-09-15