N-(4-chloro-3-(trifluoromethyl)phenyl)-3-aminobenzamide

• 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: N-(4-chloro-3-(trifluoromethyl)phenyl)-3-aminobenzamide
• 英文别名: 3-amino-N-(4-chloro-3-(trifluoromethyl)phenyl)benzamide；3-amino-N-[4-chloro-3-(trifluoromethyl)phenyl]benzamide
• 化学式: C₁₄H₁₀ClF₃N₂O
• 分子量: 314.694
• InChiKey: YKBKENVAJHOCDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine 、 N-(4-chloro-3-(trifluoromethyl)phenyl)-3-aminobenzamide 在 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 6.17h， 生成 3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-N-(4-chloro-3-(trifluoromethyl)phenyl)benzamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors

  摘要：

  By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-Raf(V600E) inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-Raf(V600E)) cell lines with IC50 values of 3.190, 2276, 1.856, 1.632 mu M and 1.839 mu M, respectively, comparable with the positive control Vemurafenib (IC50 = 3.32 mu M). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-Raf(V600E)) and SK-MEL-2 (B-Raf(WT)) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-Raf(V600E)) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-Rat(WT)). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.10.039
• 作为产物：
  描述：

  间硝基苯甲酸 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 10.0h， 生成 N-(4-chloro-3-(trifluoromethyl)phenyl)-3-aminobenzamide
  参考文献：
  名称：

  设计，合成和评估基于嘧啶骨架的衍生物，作为有效的Pan-Raf抑制剂来克服耐药性。

  摘要：

  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，

  DOI：

  10.1016/j.ejmech.2017.02.041

文献信息

• 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..
• 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，
• Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors
  作者：Weimin Yang、Yadong Chen、Xiang Zhou、Yazhou Gu、Wenqi Qian、Fan Zhang、Wei Han、Tao Lu、Weifang Tang

  DOI：10.1016/j.ejmech.2014.10.039

  日期：2015.1

  By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-Raf(V600E) inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-Raf(V600E)) cell lines with IC50 values of 3.190, 2276, 1.856, 1.632 mu M and 1.839 mu M, respectively, comparable with the positive control Vemurafenib (IC50 = 3.32 mu M). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-Raf(V600E)) and SK-MEL-2 (B-Raf(WT)) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-Raf(V600E)) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-Rat(WT)). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C = 44.37%), compared to Sorafenib (T/C = 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss. (C) 2014 Elsevier Masson SAS. All rights reserved.