(4as,5ar)-N-{1-[(R)-[(2r)-1,1-Dioxidotetrahydro-2h-Thiopyran-2-Yl](Phenyl)methyl]-1h-Pyrazol-4-Yl}-5,5-Difluoro-5a-Methyl-1,4,4a,5,5a,6-Hexahydrocyclopropa[f]indazole-3-Carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4as,5ar)-N-{1-[(R)-[(2r)-1,1-Dioxidotetrahydro-2h-Thiopyran-2-Yl](Phenyl)methyl]-1h-Pyrazol-4-Yl}-5,5-Difluoro-5a-Methyl-1,4,4a,5,5a,6-Hexahydrocyclopropa[f]indazole-3-Carboxamide
• 英文别名: (4aS,5aR)-N-[1-[(R)-[(2R)-1,1-dioxothian-2-yl]-phenylmethyl]pyrazol-4-yl]-5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]indazole-3-carboxamide
• 化学式: C₂₅H₂₇F₂N₅O₃S
• 分子量: 515.584
• InChiKey: JNRFIKALOWSUBG-DAVFGYKESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  硫代环己酮 在 正丁基锂 、 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三苯基膦 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， -78.0~25.0 ℃ 、101.33 kPa 条件下， 反应 14.0h， 生成 (4as,5ar)-N-{1-[(R)-[(2r)-1,1-Dioxidotetrahydro-2h-Thiopyran-2-Yl](Phenyl)methyl]-1h-Pyrazol-4-Yl}-5,5-Difluoro-5a-Methyl-1,4,4a,5,5a,6-Hexahydrocyclopropa[f]indazole-3-Carboxamide
  参考文献：
  名称：

  Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo

  摘要：

  The Medicinal chemistry community has directed considerable efforts toward the discovery Of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK) given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure-and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiprolifetative effects, Which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

  DOI：

  10.1021/jm501998m

文献信息

• Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo
  作者：Jason D. Burch、Kathy Barrett、Yuan Chen、Jason DeVoss、Charles Eigenbrot、Richard Goldsmith、M. Hicham A. Ismaili、Kevin Lau、Zhonghua Lin、Daniel F. Ortwine、Ali A. Zarrin、Paul A. McEwan、John J. Barker、Claire Ellebrandt、Daniel Kordt、Daniel B. Stein、Xiaolu Wang、Yong Chen、Baihua Hu、Xiaofeng Xu、Po-Wai Yuen、Yamin Zhang、Zhonghua Pei

  DOI：10.1021/jm501998m

  日期：2015.5.14

  The Medicinal chemistry community has directed considerable efforts toward the discovery Of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK) given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure-and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiprolifetative effects, Which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.