3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide | 1092394-94-9

• 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: 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide
• 英文别名: 3-(2-cyanopropan-2-yl)-N-[3-[6-[(4-methylphenyl)sulfonylamino]pyridin-3-yl]oxyphenyl]benzamide
• CAS: 1092394-94-9
• 化学式: C₂₉H₂₆N₄O₄S
• 分子量: 526.616
• InChiKey: KDARJMCPOWKJHM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 64.25h， 生成 N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x
• 作为产物：
  描述：

  2-nitro-5-(3-nitrophenoxy)pyridine 在 吡啶 、 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 乙酸乙酯 为溶剂， 反应 70.0h， 生成 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide
  参考文献：
  名称：

  Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

  摘要：

  To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

  DOI：

  10.1021/jm300126x

文献信息

• Fused heterocycle derivatives and use thereof
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08304557B2

  公开（公告）日：2012-11-06

  A compound represented by the formula (I): wherein Z1, Z2, Z3 and Z4 are the following combination, (Z1,Z2,Z3,Z4)=(CR4,N,CR5,C), (N,N,CR5,C), (N,C,CR5,N), (S,C,CR5,C) or (S,C,N,C); R1 and R2 are the same or different and each is (1) a hydrogen atom, (2) a halogen atom, (3) a group bonded via a carbon atom, (4) a group bonded via a nitrogen atom, (5) a group bonded via an oxygen atom or (6) a group bonded via a sulfur atom; R3 is an amino optionally having substituent(s); R4 and R5 are the same or different and each is (1) a hydrogen atom, (2) a halogen atom, (3) a group bonded via a carbon atom, (4) a group bonded via a nitrogen atom, (5) a group bonded via an oxygen atom or (6) a group bonded via a sulfur atom; R3 and R4 optionally form a ring optionally having substituent(s); and a group represented by the formula is a cyclic group optionally having substituent(s), or a salt thereof.

  化合物的化学式为 (I)：其中 Z1，Z2，Z3 和 Z4 是以下组合，(Z1，Z2，Z3，Z4) = (CR4，N，CR5，C)，(N，N，CR5，C)，(N，C，CR5，N)，(S，C，CR5，C) 或 (S，C，N，C)；R1 和 R2 相同或不同，且每个都是 (1) 氢原子，(2) 卤素原子，(3) 通过碳原子键合的基团，(4) 通过氮原子键合的基团，(5) 通过氧原子键合的基团或 (6) 通过硫原子键合的基团；R3 是氨基，可以有取代基；R4 和 R5 相同或不同，且每个都是 (1) 氢原子，(2) 卤素原子，(3) 通过碳原子键合的基团，(4) 通过氮原子键合的基团，(5) 通过氧原子键合的基团或 (6) 通过硫原子键合的基团；R3 和 R4 可选地形成一个环，可以有取代基；以及由以下式表示的基团是一个环状基团，可以有取代基，或其盐。
• HETEROCYCLIC COMPOUND AND USE THEREOF
  申请人：Hirose Masaaki

  公开号：US20100249119A1

  公开（公告）日：2010-09-30

  The present invention provides a heterocyclic compound having a strong Raf inhibitory activity, which is represented by the following formula wherein each substituent is as defined in the present specification, or a salt thereof.

  本发明提供了一种具有强烈的Raf抑制活性的杂环化合物，其由以下公式表示，其中每个取代基如本规范中所定义的，或其盐。
• Heterocyclic compound and use thereof
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08344135B2

  公开（公告）日：2013-01-01

  The present invention provides a heterocyclic compound having a strong Raf inhibitory activity, which is represented by the following formula wherein each substituent is as defined in the present specification, or a salt thereof.

  本发明提供了一种具有强烈的Raf抑制活性的杂环化合物，其表示为以下式子，其中每个取代基如本说明书中所定义的，或其盐。
• FUSED HETEROCYCLE DERIVATIVES AND USE THEREOF
  申请人：OGURO Yuya

  公开号：US20090163488A1

  公开（公告）日：2009-06-25

  A compound represented by the formula (I): wherein Z 1 , Z 2 , Z 3 and Z 4 are the following combination, (Z 1 ,Z 2 ,Z 3 ,Z 4 )=(CR 4 ,N,CR 5 ,C), (N,N,CR 5 ,C), (N,C,CR 5 ,N), (S,C,CR 5 ,C) or (S,C,N,C); R 1 and R 2 are the same or different and each is (1) a hydrogen atom, (2) a halogen atom, (3) a group bonded via a carbon atom, (4) a group bonded via a nitrogen atom, (5) a group bonded via an oxygen atom or (6) a group bonded via a sulfur atom; R 3 is an amino optionally having substituent(s); R 4 and R 5 are the same or different and each is (1) a hydrogen atom, (2) a halogen atom, (3) a group bonded via a carbon atom, (4) a group bonded via a nitrogen atom, (5) a group bonded via an oxygen atom or (6) a group bonded via a sulfur atom; R 3 and R 4 optionally form a ring optionally having substituent(s); and a group represented by the formula is a cyclic group optionally having substituent(s), or a salt thereof.

  化合物的分子式为（I）：其中Z1，Z2，Z3和Z4是以下组合，（Z1，Z2，Z3，Z4）=（CR4，N，CR5，C），（N，N，CR5，C），（N，C，CR5，N），（S，C，CR5，C）或（S，C，N，C）; R1和R2相同或不同，每个都是（1）氢原子，（2）卤原子，（3）通过碳原子键合的基团，（4）通过氮原子键合的基团，（5）通过氧原子键合的基团或（6）通过硫原子键合的基团; R3是氨基，可以有取代基; R4和R5相同或不同，每个都是（1）氢原子，（2）卤原子，（3）通过碳原子键合的基团，（4）通过氮原子键合的基团，（5）通过氧原子键合的基团或（6）通过硫原子键合的基团; R3和R4可以选择形成一个环，也可以有取代基; 以及由公式表示的基团是一个环状基团，可以有取代基，或其盐。
• HETEROBICYCLIC COMPOUNDS AS KINASE INHIBITORS
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2162445A1

  公开（公告）日：2010-03-17