N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}-cyclopropanecarboxamide | 1448850-83-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}-cyclopropanecarboxamide
• 英文别名: N-{7-Cyano-6-[4-Fluoro-3-({[3-(Trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-Benzothiazol-2-Yl}cyclopropanecarboxamide；N-[7-cyano-6-[4-fluoro-3-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
• CAS: 1448850-83-6
• 化学式: C₂₆H₁₇F₄N₅O₃S
• 分子量: 555.512
• InChiKey: IIKOGUBERFKZGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  39
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  144
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-[5-(4-amino-2-cyanophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide 在 吡啶 、 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.17h， 生成 N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}-cyclopropanecarboxamide
  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

• 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.