N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide | 1260168-98-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
• 英文别名: N-[5-(5-chloro-2-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
• CAS: 1260168-98-6
• 化学式: C₂₃H₂₇ClN₆O₃Si
• 分子量: 499.044
• InChiKey: SJWHGZJWFAFQRY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.82
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  95.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 在 盐酸 、 caesium carbonate 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling

  摘要：

  Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

  DOI：

  10.1016/j.bmcl.2019.04.008
• 作为产物：
  描述：

  3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 在 4-二甲氨基吡啶 、 铁粉 乙醇 、 氯化铵 、 N,N-二异丙基乙胺 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  [EN] PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
  [FR] COMPOSÉS PYRAZOLOPYRIMIDINE INHIBITEURS DES JAK ET PROCÉDÉS

  摘要：

  公开号：

  WO2011003065A3

文献信息

• PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
  申请人：Gibbons Paul

  公开号：US20120190665A1

  公开（公告）日：2012-07-26

  A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 and R 3 are defined herein, are useful as inhibitors of one or more Janus kinases. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient are disclosed.

  公式I的化合物、对映异构体、顺反异构体、互变异构体或其药学上可接受的盐，其中R1、R2和R3的定义如本文所述，可用作一种或多种Janus激酶的抑制剂。本文还揭示了一种包括公式I的化合物和药学上可接受的载体、辅料或载体的药物组合物，以及治疗或减轻患者对Janus激酶活性抑制响应的疾病或状况的方法。
• Pyrazolopyrimidine JAK inhibitor compounds and methods
  申请人：Gibbons Paul

  公开号：US08999998B2

  公开（公告）日：2015-04-07

  A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are defined herein, are useful as inhibitors of one or more Janus kinases. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient are disclosed.

  公式I的化合物，对映异构体，顺反异构体，互变异构体或其药学上可接受的盐，其中R1、R2和R3在此定义中，可用作一种或多种JAK抑制剂。本发明还公开了一种包括公式I化合物和药学上可接受的载体、佐剂或载体的制药组合物，以及治疗或减轻患者对JAK活性抑制反应的疾病或病情的方法。