1-(3,3-dimethylbutyl)-3-(4-methyl-3-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-(3,3-dimethylbutyl)-3-(4-methyl-3-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea
• 英文别名: 1-(3,3-Dimethylbutyl)-3-[4-methyl-3-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea；1-(3,3-dimethylbutyl)-3-[4-methyl-3-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea
• 化学式: C₂₄H₃₁N₅O
• 分子量: 405.543
• InChiKey: WLXZGXQZOPTKEN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  78.9
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(3,3-dimethylbutyl)-3-(4-methyl-3-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea 在 盐酸 作用下， 以 水 、 乙腈 为溶剂， 反应 0.33h， 以74%的产率得到1-(3,3-dimethylbutyl)-3-(4-methyl-3-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea hydrochloride
  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：

  4,6-二氯烟酸乙酯 在 吡啶 、 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 碳酸氢钠 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 potassium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 为溶剂， 反应 77.0h， 生成 1-(3,3-dimethylbutyl)-3-(4-methyl-3-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-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

文献信息

• [EN] RAF INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE RAF
  申请人：DECIPHERA PHARMACEUTICALS LLC

  公开号：WO2013134298A1

  公开（公告）日：2013-09-12

  This invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I); and use of a compound of Formula (I) for treating specified cancers.

  这项发明提供了化合物的公式(I)或其药用可接受的盐；包括公式(I)化合物的药物组合物；以及使用公式(I)化合物治疗特定癌症。
• RAF INHIBITOR COMPOUNDS
  申请人：Deciphera Pharmaceuticals, LLC

  公开号：US20150105367A1

  公开（公告）日：2015-04-16

  This invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I); and use of a compound of Formula (I) for treating specified cancers.

  该发明提供了式(I)的化合物或其药学上可接受的盐；包含式(I)化合物的制药组合物；以及使用式(I)化合物治疗特定癌症的方法。
• US9187474B2
  申请人：——

  公开号：US9187474B2

  公开（公告）日：2015-11-17
• Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-<i>d</i>]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against <i>BRAF</i> or <i>RAS</i> Mutant Tumor Cells
  作者：James R. Henry、Michael D. Kaufman、Sheng-Bin Peng、Yu Mi Ahn、Timothy M. Caldwell、Lakshminarayana Vogeti、Hanumaiah Telikepalli、Wei-Ping Lu、Molly M. Hood、Thomas J. Rutkoski、Bryan D. Smith、Subha Vogeti、David Miller、Scott C. Wise、Lawrence Chun、Xiaoyi Zhang、Youyan Zhang、Lisa Kays、Philip A. Hipskind、Aaron D. Wrobleski、Karen L. Lobb、Julia M. Clay、Jeffrey D. Cohen、Jennie L. Walgren、Denis McCann、Phenil Patel、David K. Clawson、Sherry Guo、Danalyn Manglicmot、Chris Groshong、Cheyenne Logan、James J. Starling、Daniel L. Flynn

  DOI：10.1021/acs.jmedchem.5b00067

  日期：2015.5.28

  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.