1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylamino)phenyl)urea | 1402747-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylamino)phenyl)urea
• 英文别名: 1-(3-(trifluoromethyl)chlorophenyl)-3-(3-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-4-yl-amino)phenyl)urea；1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-[3-[[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino]phenyl]urea
• CAS: 1402747-15-2
• 化学式: C₂₄H₂₅ClF₃N₇O
• 分子量: 519.957
• InChiKey: ITLPVLLAPQMEHN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  85.4
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-methyl-6-(4-methylpiperazin-1-yl)-N-(3-nitrophenyl)pyrimidin-4-amine 在 铁粉 、 氯化铵 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.5h， 生成 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylamino)phenyl)urea
  参考文献：
  名称：

  Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

  摘要：

  V‐RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4‐phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non‐small‐cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG‐out conformation of BRAF.

  DOI：

  10.1111/cbdd.12198

文献信息

• [EN] UREA COMPOUNDS AS WELL AS PREPARATION METHODS, INTERMEDIATES AND USES THEREOF<br/>[FR] COMPOSÉS D'URÉE AINSI QUE LEURS PROCÉDÉS DE PRÉPARATION, INTERMÉDIAIRES ET UTILISATIONS
  申请人：SHANGHAI INSITITUTE OF PHARMACEUTICAL INDUSTRY

  公开号：WO2012139499A1

  公开（公告）日：2012-10-18

  本发明公开了一种如式I所示的脲类化合物或其药学上可接受的盐、多晶型物、溶剂合物或立体异构体；以及其制备方法，其中间体及其应用。本发明的脲类化合物在生物学测试中，对于多种蛋白激酶具有不同程度的抑制活性，并且在体外抗人肿瘤细胞系和人脐静脉内皮细胞（HUVEC）增殖试验中分别显示具有不同程度的抗肿瘤细胞生长和抗血管新生活性，在动物体内也显示出较佳的抗肿瘤活性。
• Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores
  作者：Qingwen Zhang、Juan Wang、Fei Wang、Xiuhua Chen、Yunsong He、Qidong You、Houyuan Zhou

  DOI：10.1111/cbdd.12198

  日期：2014.1

  V‐RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4‐phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non‐small‐cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG‐out conformation of BRAF.