1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-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-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea
• 英文别名: 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea；1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-(7-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidin-6-yl)phenyl]urea
• 化学式: C₂₃H₂₈FN₅OS
• 分子量: 441.573
• InChiKey: LWLLTMSZMKVUNY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea 在 间氯过氧苯甲酸 、 氨 作用下， 以 二氯甲烷 、 1,4-二氧六环 、 甲醇 为溶剂， 反应 2.0h， 以24%的产率得到1-(5-(2-amino-7-methylpyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)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：

  4-氨基-2-甲巯基嘧啶-5-甲醛 在 吡啶 、 四(三苯基膦)钯 、 potassium carbonate 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)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

文献信息

• [EN] OXAZOLIDINONE COMPOUNDS AND DERIVATIVES THEREOF<br/>[FR] COMPOSÉS D'OXAZOLIDINONE ET LEURS DÉRIVÉS
  申请人：AMGEN INC

  公开号：WO2013134079A1

  公开（公告）日：2013-09-12

  Compounds of Formula (I) and Formula (II) are useful inhibitors of tankyrase. Compounds of Formula (I) and Formula (II) have the following structure: where the definitions of the variables are provided herein.

  式(I)和式(II)的化合物是坦克酶的有用抑制剂。式(I)和式(II)的化合物具有以下结构：其中变量的定义在此提供。
• [EN] 2-AMINO, 6 - PHENYL SUBSTITUTED PYRIDO [2, 3 - D] PYRIMIDINE DERIVATIVES USEFUL AS RAF KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE PYRIMIDINE PYRIDO [2, 3-D] SUBSTITUÉS À 2-AMINO, 6-PHÉNYLE UTILES COMME INHIBITEURS DE RAF KINASE
  申请人：LILLY CO ELI

  公开号：WO2013134252A1

  公开（公告）日：2013-09-12

  This invention provides compounds of Formula I: (Formula I should be inserted here) 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.

  本发明提供了I式化合物：（应在此处插入I式化合物），或其药学上可接受的盐；包括I式化合物的制药组合物；以及使用I式化合物治疗特定癌症的方法。
• RAF INHIBITOR COMPOUNDS
  申请人：Deciphera Pharmaceuticals, LLC

  公开号：US20150119392A1

  公开（公告）日：2015-04-30

  This invention provides compounds of Formula I: (Formula I should be inserted here) 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.

  本发明提供了I式化合物：（应在此处插入I式）或其药学上可接受的盐；包括I式化合物的制药组合物；以及使用I式化合物治疗特定癌症的方法。
• OXAZOLIDINONE COMPOUNDS AND DERIVATIVES THEREOF
  申请人：AMGEN INC.

  公开号：US20150045368A1

  公开（公告）日：2015-02-12

  Compounds of Formula (I) and Formula (II) are useful inhibitors of tankyrase. Compounds of Formula (I) and Formula (II) have the following structure: where the definitions of the variables are provided herein.

  式(I)和式(II)的化合物是坦克酰酶的有用抑制剂。式(I)和式(II)的化合物具有以下结构：其中变量的定义在此提供。
• RAF inhibitor compounds
  申请人：Deciphera Pharmaceuticals, LLC

  公开号：US09334267B2

  公开（公告）日：2016-05-10

  This invention provides compounds of Formula I: (Formula I should be inserted here) 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.

  本发明提供了式I的化合物：（应在此处插入公式I），或其药学上可接受的盐；包括化合物I的药物组合物；以及使用化合物I治疗特定癌症。