3-amino-4-methyl-N-(4-((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)benzamide | 1202649-62-4

• 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-((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)benzamide
• 英文别名: 3-amino-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide
• CAS: 1202649-62-4
• 化学式: C₂₁H₂₅F₃N₄O
• 分子量: 406.451
• InChiKey: FEIIOIKTXUDCIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  61.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-amino-4-methyl-N-(4-((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)benzamide 在 四(三苯基膦)钯 、 草酰氯 、 sodium carbonate 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.5h， 生成 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-(pyridin-3-yl)benzamido)benzamide
  参考文献：
  名称：

  Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

  摘要：

  Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.03.064
• 作为产物：
  描述：

  4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-nitrobenzamide 在 铁粉 、 氯化铵 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以1.6 g的产率得到3-amino-4-methyl-N-(4-((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)benzamide
  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

• SUBSTITUTED PENTA-FUSED HEXA-HETEROCYCLIC COMPOUNDS, PREPARATION METHOD THEREFOR, DRUG COMBINATION AND USE THEREOF
  申请人：Xiamen University

  公开号：US20200165246A1

  公开（公告）日：2020-05-28

  A type of substituted penta-fused hexa-heterocyclic compounds having selective inhibition for PIKfyve kinase, a pharmaceutically acceptable salt and pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.

  一种替代的五重融合六元杂环化合物，具有对PIKfyve激酶的选择性抑制作用，其药学上可接受的盐及其药学上可接受的溶剂，其制备方法，包括这些化合物的药物组合物，以及在制备用于预防或治疗与PIKfyve相关疾病的药物中使用这些化合物，特别是在制备用于预防或治疗肿瘤生长和转移的药物中。
• 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。
• SUBSTITUTED PENTA- AND HEXA-HETEROCYCLIC COMPOUNDS, PREPARATION METHOD THEREFOR, DRUG COMBINATION AND USE THEREOF
  申请人：Xiamen University

  公开号：EP3663293A1

  公开（公告）日：2020-06-10

  A type of substituted penta- fused hexa-heterocyclic compounds having selective inhibition for PIKfyve kinase, a pharmaceutically acceptable salt and pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.

  一种对PIKfyve激酶具有选择性抑制作用的取代五融合六杂环化合物、其药学上可接受的盐和药学上可接受的溶液、其制备方法、包含这些化合物的药物组合物，以及这些化合物在制造预防或治疗体内PIKfyve相关疾病的药物中的用途，特别是在制造预防或治疗肿瘤生长和转移的药物中的用途。
• Substituted penta-fused hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof
  申请人：Xiamen University

  公开号：US11352354B2

  公开（公告）日：2022-06-07

  A type of substituted penta-fused hexa-heterocyclic compounds having selective inhibition for PIKfyve kinase, a pharmaceutically acceptable salt and pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.

  一种对PIKfyve激酶具有选择性抑制作用的取代五融合六六环化合物、其药学上可接受的盐和药学上可接受的溶液、其制备方法、包含这些化合物的药物组合物，以及这些化合物在制造预防或治疗体内PIKfyve相关疾病的药物中的用途，特别是在制造预防或治疗肿瘤生长和转移的药物中的用途。