2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl isocyanate | 1147504-83-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl isocyanate
• 英文别名: 2-morpholino-5-trifluoromethylphenyl isocyanate；2-(N-morpholyl)-5-(trifluoromethyl)phenyl isocyanate
• CAS: 1147504-83-3
• 化学式: C₁₂H₁₁F₃N₂O₂
• 分子量: 272.227
• InChiKey: XUYKFDBUZLWAIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.51
• 重原子数：
  19.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  41.9
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one 、 2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl isocyanate 以 四氢呋喃 为溶剂， 反应 14.0h， 以94%的产率得到1-(2-(N-morpholyl)-5-(trifluoromethyl)phenyl)-3-(3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)phenyl)urea
  参考文献：
  名称：

  BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring

  摘要：

  We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo-[4,5]pyridin-2-one scaffold and it substituted urea linker. Here, we present it new series of BRAY inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

  DOI：

  10.1021/jm901509a

文献信息

• Pyridoimidazolones as Novel Potent Inhibitors of v-Raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF)
  作者：Dan Niculescu-Duvaz、Catherine Gaulon、Harmen P. Dijkstra、Ion Niculescu-Duvaz、Alfonso Zambon、Delphine Ménard、Bart M. J. M. Suijkerbuijk、Arnaud Nourry、Lawrence Davies、Helen Manne、Frank Friedlos、Lesley Ogilvie、Douglas Hedley、Steven Whittaker、Ruth Kirk、Adrian Gill、Richard D. Taylor、Florence I. Raynaud、Javier Moreno-Farre、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm801509w

  日期：2009.4.23

  BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50−70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency

  BRAF是一种丝氨酸/苏氨酸激酶，在多种癌症（包括50％至70％的黑色素瘤）中都会发生突变，并且已被证实可作为治疗靶标。我们已经设计并合成了含有吡啶并咪唑酮作为新型铰链结合支架的BRAF突变体抑制剂。已经获得对突变BRAF具有低纳摩尔效能（对于化合物5i为12nM ）和对突变BRAF黑色素瘤细胞系WM266.4具有低微摩尔细胞效能的化合物。该系列得益于极低的新陈代谢，以及可以通过咪唑酮的NH基团的甲基化来调节的药代动力学（PK），从而使化合物具有更少的H-供体和更好的PK谱。这些化合物在治疗突变型BRAF黑色素瘤中具有巨大潜力。
• Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
  作者：Delphine Ménard、Ion Niculescu-Duvaz、Harmen P. Dijkstra、Dan Niculescu-Duvaz、Bart M. J. M. Suijkerbuijk、Alfonso Zambon、Arnaud Nourry、Esteban Roman、Lawrence Davies、Helen A. Manne、Frank Friedlos、Ruth Kirk、Steven Whittaker、Adrian Gill、Richard D. Taylor、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm900242c

  日期：2009.7.9

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.