1-(3,3-dimethylbutyl)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea | 1454690-54-0

• 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: 1-(3,3-dimethylbutyl)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea
• 英文别名: 1-(3,3-Dimethylbutyl)-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea；1-(3,3-dimethylbutyl)-3-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
• CAS: 1454690-54-0
• 化学式: C₁₉H₃₀BFN₂O₃
• 分子量: 364.268
• InChiKey: AFHBIZHTNFFLLF-UHFFFAOYSA-N

物化性质

• 沸点：
  433.5±45.0 °C(Predicted)
• 密度：
  1.08±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.68
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  59.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-bromo-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine 、 1-(3,3-dimethylbutyl)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 以85%的产率得到1-(3,3-dimethylbutyl)-3-(2-fluoro-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea
  参考文献：
  名称：

  Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells

  摘要：

  The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation, Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS Mutation. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild. type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

  DOI：

  10.1021/acs.jmedchem.5b00067
• 作为产物：
  描述：

  3-氨基-4-氟苯硼酸频那醇酯 在 碳酸氢钠 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 6.0h， 生成 1-(3,3-dimethylbutyl)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea
  参考文献：
  名称：

  Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells

  摘要：

  The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation, Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS Mutation. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild. type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

  DOI：

  10.1021/acs.jmedchem.5b00067