4-nitro-1-[phenyl(tetrahydro-2H-thiopyran-4-yl)methyl]-1H-pyrazole | 1557245-00-7

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: 4-nitro-1-[phenyl(tetrahydro-2H-thiopyran-4-yl)methyl]-1H-pyrazole
• 英文别名: 4-Nitro-1-[phenyl(thian-4-yl)methyl]pyrazole；4-nitro-1-[phenyl(thian-4-yl)methyl]pyrazole
• CAS: 1557245-00-7
• 化学式: C₁₅H₁₇N₃O₂S
• 分子量: 303.385
• InChiKey: GXRIQDINYNGGNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  88.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-nitro-1-[phenyl(tetrahydro-2H-thiopyran-4-yl)methyl]-1H-pyrazole 在 palladium 10% on activated carbon 、 氢气 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 5.0~20.0 ℃ 、101.33 kPa 条件下， 反应 12.5h， 生成 4-[(4-amino-1H-pyrazol-1-yl)(phenyl)methyl]-1λ⁶-thiane-1,1-dione
  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
• 作为产物：
  描述：

  四氢噻喃-4-甲醛 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 4-nitro-1-[phenyl(tetrahydro-2H-thiopyran-4-yl)methyl]-1H-pyrazole
  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

• [EN] PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE<br/>[FR] COMPOSÉS PYRAZOLE CARBOXAMIDES, COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014023258A1

  公开（公告）日：2014-02-13

  Provided herein are compounds of formula (AA): N N H HN O N N R R 6 A (R a ) p, (AA) stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a, p, R and R 6 are defined herein, compositions including the compounds and methods of manufacturing and using the compounds for the treatment of diseases.

  本文提供了以下式（AA）的化合物：N N H HN O N N R R 6 A（R a）p，（AA）立体异构体或其药学上可接受的盐，其中A、R a、p、R和R 6在此处有定义，包括这些化合物的组合物以及用于治疗疾病的制备和使用这些化合物的方法。
• PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20150158851A1

  公开（公告）日：2015-06-11

  Provided herein are compounds of formula (AA): stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a , p, R 5 and R 6 are defined herein, compositions including the compounds and methods of manufacturing and using the compounds for the treatment of diseases.

  本文提供了式（AA）的化合物：其立体异构体或其药学上可接受的盐，其中A、Ra、p、R5和R6在此定义，包括该化合物的组合物以及制造和使用该化合物治疗疾病的方法。
• 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.