N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(2-cyanopropan-2-yl)benzamide | 1123580-75-5

• 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: N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(2-cyanopropan-2-yl)benzamide
• 英文别名: N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide；N-[3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl]-3-(2-cyanopropan-2-yl)benzamide
• CAS: 1123580-75-5
• 化学式: C₂₄H₁₉FN₄O₂S
• 分子量: 446.505
• InChiKey: AXABQOAUGMXTRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  129
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(2-cyanopropan-2-yl)benzamide 、 环丙基甲酰氯 在 碳酸氢钠 、 Brine 、 Sodium sulfate-III 、 silica gel 、 ethyl acetate n-hexane 、 Ethyl acetate;hexane;2-propan-2-yloxypropane 作用下， 以 吡啶 、 乙酸乙酯 为溶剂， 反应 4.0h， 以to give the title compound (118 mg, 51%) as a colorless solid的产率得到3-(1-cyano-1-methylethyl)-N-[3-({2-[(cyclopropylcarbonyl)amino]-5-fluoro-1,3-benzothiazol-6-yl}oxy)phenyl]benzamide
  参考文献：
  名称：

  HETEROCYCLIC COMPOUND AND USE THEREOF

  摘要：

  提供的是一种具有强烈Raf抑制活性的杂环化合物。该化合物由以下式表示：其中每个符号如规范中定义，或其盐。

  公开号：

  US20110172245A1
• 作为产物：
  描述：

  3-(1-cyano-1-methylethyl)-N-[3-(2-fluoro-4-nitrophenoxy)phenyl]benzamide 在 铁粉 、 溶剂黄146 、 calcium chloride 作用下， 以 乙醇 、 水 为溶剂， 反应 12.0h， 生成 N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(2-cyanopropan-2-yl)benzamide
  参考文献：
  名称：

  Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives

  摘要：

  With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E))and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

  DOI：

  10.1021/jm400778d

文献信息

• Heterocyclic compound and use thereof
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08324395B2

  公开（公告）日：2012-12-04

  Provided is a heterocyclic compound showing strong Raf inhibitory activity. A compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是一种具有较强Raf抑制活性的杂环化合物。该化合物由下式所表示：其中每个符号如规范中所定义，或其盐。
• 2-Carbonylaminobenzothiazoles and their use for the prophylaxis and treatment of cancer
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2181987B9

  公开（公告）日：2014-09-03
• US8324395B2
  申请人：——

  公开号：US8324395B2

  公开（公告）日：2012-12-04
• Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of <i>C</i>-7-Substituted 1,3-Benzothiazole Derivatives
  作者：Masanori Okaniwa、Masaaki Hirose、Takeo Arita、Masato Yabuki、Akito Nakamura、Terufumi Takagi、Tomohiro Kawamoto、Noriko Uchiyama、Akihiko Sumita、Shunichirou Tsutsumi、Tsuneaki Tottori、Yoshitaka Inui、Bi-Ching Sang、Jason Yano、Kathleen Aertgeerts、Sei Yoshida、Tomoyasu Ishikawa

  DOI：10.1021/jm400778d

  日期：2013.8.22

  With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E))and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.
• HETEROCYCLIC COMPOUND AND USE THEREOF
  申请人：Hirose Masaaki

  公开号：US20110172245A1

  公开（公告）日：2011-07-14

  Provided is a heterocyclic compound showing strong Raf inhibitory activity. A compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是一种具有强烈Raf抑制活性的杂环化合物。该化合物由以下式表示：其中每个符号如规范中定义，或其盐。