1-(1-benzyl-3,3-difluoro-piperidin-4-yl)-2-methyl-1,6-dihydro-1,3,5,6-tetraaza-as-indacene | 1315488-44-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(1-benzyl-3,3-difluoro-piperidin-4-yl)-2-methyl-1,6-dihydro-1,3,5,6-tetraaza-as-indacene
• 英文别名: 3-(1-Benzyl-3,3-difluoropiperidin-4-yl)-4-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaene
• CAS: 1315488-44-8
• 化学式: C₂₁H₂₁F₂N₅
• 分子量: 381.428
• InChiKey: KGGCWCHJSRDQHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  49.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(1-benzyl-3,3-difluoro-piperidin-4-yl)-2-methyl-1,6-dihydro-1,3,5,6-tetraaza-as-indacene 在 20 % Pd(OH)2/C 、 氢气 作用下， 以 四氢呋喃 为溶剂， 80.0 ℃ 、344.75 kPa 条件下， 以25 mg的产率得到(+/-)-1-(3,3-difluoropiperidin-4-yl)-2-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine
  参考文献：
  名称：

  Discovery and Optimization of C-2 Methyl Imidazopyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2

  摘要：

  Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

  DOI：

  10.1021/jm300628c
• 作为产物：
  描述：

  1-(苯磺酰基)-4-氯-5-硝基吡咯并[2,3-b]吡啶 在 水 、 铁粉 、 氯化铵 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 异丙醇 、 甲苯 为溶剂， 反应 42.2h， 生成 1-(1-benzyl-3,3-difluoro-piperidin-4-yl)-2-methyl-1,6-dihydro-1,3,5,6-tetraaza-as-indacene
  参考文献：
  名称：

  Discovery and Optimization of C-2 Methyl Imidazopyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2

  摘要：

  Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

  DOI：

  10.1021/jm300628c

文献信息

• [EN] TRICYCLIC HETEROCYCLIC COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES TRICYCLIQUES, LEURS COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2011086053A1

  公开（公告）日：2011-07-21

  The invention provides novel compounds of formula (I) having the general formula, wherein R1, R2, R3, X and Y are as described herein. Accordingly, the compounds may be provided in pharmaceutically acceptable compositions and used for the treatment of immunological or hyperproliferative disorders.

  该发明提供了具有通式（I）的新化合物，通式如下，其中R1、R2、R3、X和Y如本文所述。因此，这些化合物可以用于制备药学上可接受的组合物，并用于治疗免疫或过度增殖性疾病。
• TRICYCLIC HETEROCYCLIC COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
  申请人：Babu Srinivasan

  公开号：US20110201593A1

  公开（公告）日：2011-08-18

  The invention provides novel compounds of formula I having the general formula: wherein R 1 , R 2 , R 3 , X and Y are as described herein. Accordingly, the compounds may be provided in pharmaceutically acceptable compositions and used for the treatment of immunological or hyperproliferative disorders.

  本发明提供了具有以下一般式的新化合物I： 其中R1、R2、R3、X和Y如本文所述。因此，这些化合物可以在药学上可接受的组合物中提供，并用于治疗免疫或过度增生性疾病。
• US8461328B2
  申请人：——

  公开号：US8461328B2

  公开（公告）日：2013-06-11