4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine | 1222076-90-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine
• 英文别名: 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine
• CAS: 1222076-90-5
• 化学式: C₁₁H₅ClF₂N₄
• 分子量: 266.637
• InChiKey: OOIYZRGSGWDFTF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.75
• 重原子数：
  18.0
• 可旋转键数：
  1.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  43.6
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N-cyclopropyl-3-hydroxy-4-methylbenzamide 、 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 2-二-叔丁膦基-2',4',6'-三异丙基联苯 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 生成 N-cyclopropyl-3-(1-(2,4-difluorophenyl)-1H-pyrazolo[4,3-d]pyridazin-4-yloxy)-4-methylbenzamide
  参考文献：
  名称：

  Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

  摘要：

  A novel class of pyrazolopyridazine p38 alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38 alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38 alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNF alpha production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.059
• 作为产物：
  描述：

  1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazin-4-ol 在 三氯氧磷 作用下， 生成 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyridazine
  参考文献：
  名称：

  Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

  摘要：

  A novel class of pyrazolopyridazine p38 alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38 alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38 alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNF alpha production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.059

文献信息

• [EN] IMIDAZOLE MACROCYCLES FOR THE TREATMENT OF AUTOIMMUNE DISEASE<br/>[FR] MACROCYCLES D'IMIDAZOLE POUR LE TRAITEMENT D'UNE MALADIE AUTO-IMMUNE
  申请人：[en]F. HOFFMANN-LA ROCHE AG

  公开号：WO2023148129A1

  公开（公告）日：2023-08-10

  The present invention relates to compounds of formula (Ia), (Ia), wherein R2, M1, M2, M3, Q1and Q2are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.