3-amino-4-methyl-N-(4-morpholino-3-(trifluoromethyl)phenyl)benzamide | 1393911-16-4

• 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-morpholino-3-(trifluoromethyl)phenyl)benzamide
• 英文别名: 3-amino-4-methyl-N-[4-morpholin-4-yl-3-(trifluoromethyl)phenyl]benzamide
• CAS: 1393911-16-4
• 化学式: C₁₉H₂₀F₃N₃O₂
• 分子量: 379.382
• InChiKey: PVLUDJWCOLIWBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 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：

  (E)-3-(pyridin-3-yl)acryloyl chloride hydrochloride 、 3-amino-4-methyl-N-(4-morpholino-3-(trifluoromethyl)phenyl)benzamide 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以88%的产率得到(E)-4-methyl-N-(4-morpholino-3-(trifluoromethyl)phenyl)-3-(3-(pyridin-3-yl)acrylamido)benzamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR–ABL kinase

  摘要：

  A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC50 value as low as 20.6 nM in ABL kinase inhibition and an IC50 value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.06.044
• 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 、 N,N-二甲基甲酰胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 7.0h， 生成 3-amino-4-methyl-N-(4-morpholino-3-(trifluoromethyl)phenyl)benzamide
  参考文献：
  名称：

  发现具有更高溶解度的有效Pan-Raf抑制剂以克服耐药性

  摘要：

  尽管激酶抑制剂在肿瘤学和炎性疾病中有各种应用，但耐药性的出现仍然仍然是实现癌症治疗中长期缓解的主要障碍。为了克服IIB型BRaf V600E选择性抑制剂vemurafenib诱导的耐药性，并进一步改善其抗增殖活性，设计了一种基于吡咯并[2,3- d ]嘧啶支架的新型IIA Pan-Raf抑制剂Ia – Io，并在这项工作中进行了评估。在本文中，我们试图通过增加目标化合物的溶解度来改善它们的细胞效力。其中，Il，其溶解度为0.107 mg / mL，显示出对维拉非尼耐药性癌细胞（包括BRaf WT表型黑色素瘤SK-MEL-2和BRaf V600E表型结直肠癌HT-29细胞系）具有良好的细胞活性。基于良好的溶解度，与索拉非尼相比，II具有良好的代谢稳定性，并在大鼠中具有良好的药代动力学特征。至于生物学机制研究，II在A375和SK-Mel-2细胞中具有与我们先前的P-2相似的P-ERK激酶抑制

  DOI：

  10.1016/j.ejmech.2018.11.033

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，
• Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance
  作者：Lu Wang、Gaoyuan Zhu、Qing Zhang、Chunqi Duan、Yanmin Zhang、Zhimin Zhang、Yujun Zhou、Tao Lu、Weifang Tang

  DOI：10.1039/c7ob00518k

  日期：——

  Herein, we describe the design and characterization of a series of compounds I-01–I-22, based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors. Among them, I-15 binds to all Raf protomers with IC50 values of 12.6 nM (BRafV600E), 30.1 nM (ARaf), 19.7 nM (BRafWT) and 17.5 nM (CRaf) and demonstrates cellular activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colorectal

  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
• 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..
• Discovery of potent Pan-Raf inhibitors with increased solubility to overcome drug resistance
  作者：Lu Wang、Yanmin Zhang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Chunqi Duan、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2018.11.033

  日期：2019.2

  applications of kinase inhibitors in oncology and inflammatory diseases, the emergence of resistance still remains the major barrier to achieve long-term remission in cancer treatment. With the aim of overcoming the resistance induced by type IIB BRaf V600E selective inhibitor vemurafenib, and further ameliorating the antiproliferative activity, a novel type IIA Pan-Raf inhibitors Ia–Io based on pyrrolo[2

  尽管激酶抑制剂在肿瘤学和炎性疾病中有各种应用，但耐药性的出现仍然仍然是实现癌症治疗中长期缓解的主要障碍。为了克服IIB型BRaf V600E选择性抑制剂vemurafenib诱导的耐药性，并进一步改善其抗增殖活性，设计了一种基于吡咯并[2,3- d ]嘧啶支架的新型IIA Pan-Raf抑制剂Ia – Io，并在这项工作中进行了评估。在本文中，我们试图通过增加目标化合物的溶解度来改善它们的细胞效力。其中，Il，其溶解度为0.107 mg / mL，显示出对维拉非尼耐药性癌细胞（包括BRaf WT表型黑色素瘤SK-MEL-2和BRaf V600E表型结直肠癌HT-29细胞系）具有良好的细胞活性。基于良好的溶解度，与索拉非尼相比，II具有良好的代谢稳定性，并在大鼠中具有良好的药代动力学特征。至于生物学机制研究，II在A375和SK-Mel-2细胞中具有与我们先前的P-2相似的P-ERK激酶抑制
• Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR–ABL kinase
  作者：Shuxin Li、Zhenglin Yao、Yanjin Zhao、Wei Chen、Huijia Wang、Xianzhao Kuang、Wenhu Zhan、Shan Yao、Shanyou Yu、Wenxiang Hu

  DOI：10.1016/j.bmcl.2012.06.044

  日期：2012.8

  A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC50 value as low as 20.6 nM in ABL kinase inhibition and an IC50 value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development. (c) 2012 Elsevier Ltd. All rights reserved.