5-(difluoromethoxy)-1,3-difluoro-2-nitrobenzene | 1226805-60-2

• 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: 5-(difluoromethoxy)-1,3-difluoro-2-nitrobenzene
• CAS: 1226805-60-2
• 化学式: C₇H₃F₄NO₃
• 分子量: 225.099
• InChiKey: YBKKJJGVZSZDDE-UHFFFAOYSA-N

物化性质

• 沸点：
  250.3±35.0 °C(Predicted)
• 密度：
  1.552±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-(difluoromethoxy)-1,3-difluoro-2-nitrobenzene 在 盐酸 、 甲醇 、 sodium tetrahydroborate 、 potassium phosphate 、 N-溴代丁二酰亚胺(NBS) 、 N-碘代丁二酰亚胺 、 四(三苯基膦)钯 、 sodium azide 、 Zn(BH3CN)2 、 palladium 10% on activated carbon 、 (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1 ‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate 、 氢气 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三氟乙酸 、 nickel dichloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 95.0 ℃ 、103.42 kPa 条件下， 反应 33.0h， 生成 (4-amino-3,5-difluorophenyl)(7-(difluoromethoxy)-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]azocino[4,5,6-hi]indolizin-2-yl)methanone
  参考文献：
  名称：

  [EN] SMALL MOLECULE INHIBITORS OF KRAS G12C MUTANT
  [FR] INHIBITEURS À PETITES MOLÉCULES DE MUTANT DE KRAS G12C

  摘要：

  式(I)或(la)的化合物或其药学上可接受的盐可以抑制Kirsten大鼠肉瘤(G12C突变体)蛋白，并有望作为治疗剂用于治疗癌症。本发明还提供了包含式(I)或(la)的化合物或其药学上可接受的盐的制药组合物。本发明还涉及使用这些化合物或其药学上可接受的盐在癌症治疗和预防以及为此制备制药的方法。

  公开号：

  WO2022232318A1
• 作为产物：
  描述：

  3,5-二氟苯酚 在 硝酸 、 potassium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 5-(difluoromethoxy)-1,3-difluoro-2-nitrobenzene
  参考文献：
  名称：

  Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors

  摘要：

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

  DOI：

  10.1021/jm2009138

文献信息

• IMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASES
  申请人：Stange Hans

  公开号：US20100120763A1

  公开（公告）日：2010-05-13

  The invention relates to imidazo[5,1-c][1,2,4]benzotriazine derivatives of formula I: which are inhibitors of phosphodiesterase 2 or 10 useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.

  本发明涉及式I的咪唑并[5,1-c][1,2,4]苯并三嗪衍生物：它们是磷酸二酯酶2或10的抑制剂，可用于治疗精神病等中枢神经系统疾病，以及例如肥胖、2型糖尿病、代谢综合征、葡萄糖耐受不良和疼痛。
• [EN] IMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASES<br/>[FR] DÉRIVÉS D'IMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE EN TANT QU'INHIBITEURS DE PHOSPHODIESTÉRASES
  申请人：STANGE HANS

  公开号：WO2010054260A1

  公开（公告）日：2010-05-14

  The invention relates to imidazo[5,1-c][1,2,4]benzotriazine derivatives of formula (I): which are inhibitors of phosphodiesterase 2 or 10 useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.
• Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors
  作者：Michael S. Malamas、Yike Ni、James Erdei、Hans Stange、Rudolf Schindler、Hans-Joachim Lankau、Christian Grunwald、Kristi Yi Fan、Kevin Parris、Barbara Langen、Ute Egerland、Thorsten Hage、Karen L. Marquis、Steve Grauer、Julie Brennan、Rachel Navarra、Radka Graf、Boyd L. Harrison、Albert Robichaud、Thomas Kronbach、Menelas N. Pangalos、Norbert Hoefgen、Nicholas J. Brandon

  DOI：10.1021/jm2009138

  日期：2011.11.10

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
• [EN] SMALL MOLECULE INHIBITORS OF KRAS G12C MUTANT<br/>[FR] INHIBITEURS À PETITES MOLÉCULES DE MUTANT DE KRAS G12C
  申请人：MERCK SHARP & DOHME

  公开号：WO2022232318A1

  公开（公告）日：2022-11-03

  Compounds of Formula (I) or (la) or their pharmaceutically acceptable salts can inhibit the G12C mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds of Formula (I) or (la) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

  式(I)或(la)的化合物或其药学上可接受的盐可以抑制Kirsten大鼠肉瘤(G12C突变体)蛋白，并有望作为治疗剂用于治疗癌症。本发明还提供了包含式(I)或(la)的化合物或其药学上可接受的盐的制药组合物。本发明还涉及使用这些化合物或其药学上可接受的盐在癌症治疗和预防以及为此制备制药的方法。