{2-[4-(5-{4-[1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-phenyl}-1-methoxymethyl-4-(pyridin-4-yl)-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethylamine | 1251931-54-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: {2-[4-(5-{4-[1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-phenyl}-1-methoxymethyl-4-(pyridin-4-yl)-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethylamine
• CAS: 1251931-54-0
• 化学式: C₃₈H₄₀N₆O₃
• 分子量: 628.774
• InChiKey: WHZDVSACXWJEGY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.05
• 重原子数：
  47.0
• 可旋转键数：
  13.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  79.46
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  {2-[4-(5-{4-[1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-phenyl}-1-methoxymethyl-4-(pyridin-4-yl)-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethylamine 在 三氟乙酸 作用下， 以 苯甲醚 为溶剂， 反应 4.0h， 以18%的产率得到dimethyl-[2-(4-{5-[4-(4-methyl-1H-pyrazol-3-yl)-phenyl]-4-(pyridin-4-yl)-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine
  参考文献：
  名称：

  Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

  摘要：

  V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin- 4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methylpiperazin- 1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.031
• 作为产物：
  描述：

  {2-[4-(4-bromo-1-methoxymethyl-5-pyridin-4-yl-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethyl-amine 、 1-(4-methoxybenzyl)-4-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole 在 palladium diacetate 、 potassium carbonate 、 三苯基膦 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 以73%的产率得到{2-[4-(5-{4-[1-(4-methoxybenzyl)-4-methyl-1H-pyrazol-3-yl]-phenyl}-1-methoxymethyl-4-(pyridin-4-yl)-1H-imidazol-2-yl)-phenoxy]-ethyl}-dimethylamine
  参考文献：
  名称：

  Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

  摘要：

  V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin- 4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methylpiperazin- 1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.031