4-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine | 1158908-31-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine
• 英文别名: 4-[5-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-methylsulfonylpyrimidine
• CAS: 1158908-31-6
• 化学式: C₁₄H₁₁ClN₄O₂S
• 分子量: 334.786
• InChiKey: IJKRRVZLMLVJTO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  97
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine 、 trans-4-Aminocyclohexanol 以 1,4-二氧六环 为溶剂， 反应 0.5h， 以17%的产率得到trans-(4-(4-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)cyclohexanol
  参考文献：
  名称：

  Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

  摘要：

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

  DOI：

  10.1021/jm5013598
• 作为产物：
  描述：

  4-甲基-2-甲硫基嘧啶 在 间氯过氧苯甲酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 146.0h， 生成 4-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine
  参考文献：
  名称：

  Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

  摘要：

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

  DOI：

  10.1021/jm5013598

文献信息

• Chemically enabled synthesis of 2-amino-4-heteroarylpyrimidines
  作者：Paul S. Humphries、Quyen-Quyen T. Do、David M. Wilhite

  DOI：10.1016/j.tetlet.2009.03.073

  日期：2009.5

  2-Amino-4-heteroarylpyrimidines were initially synthesized by microwave-induced SNAr reactions of primary alkyl amines and 2-methylsulfonylpyrimidines or 2-chloropyrimidines. Following this methodology, pendant piperidine functionality was elaborated utilizing silica-bound reagents in microwave-assisted reductive amination and amide bond formation protocols. These methods proved to be versatile, efficient, and amenable to parallel synthesis. (C) 2009 Elsevier Ltd. All rights reserved.
• Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors
  作者：Paul S. Humphries、Jennifer A. Lafontaine、Charles S. Agree、David Alexander、Ping Chen、Quyen-Quyen T. Do、Lilian Y. Li、Elizabeth A. Lunney、Ranjan J. Rajapakse、Karen Siegel、Sergei L. Timofeevski、Tianlun Wang、David M. Wilhite

  DOI：10.1016/j.bmcl.2009.03.023

  日期：2009.4

  The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported. (C) 2009 Elsevier Ltd. All rights reserved.
• Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1<i>H</i>-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors
  作者：John Wityak、Kevin F. McGee、Michael P. Conlon、Ren Hua Song、Bryan C. Duffy、Brent Clayton、Michael Lynch、Gwen Wang、Emily Freeman、James Haber、Douglas B. Kitchen、David D. Manning、Jiffry Ismail、Yuri Khmelnitsky、Peter Michels、Jeff Webster、Macarena Irigoyen、Michele Luche、Monica Hultman、Mei Bai、IokTeng D. Kuok、Ryan Newell、Marieke Lamers、Philip Leonard、Dawn Yates、Kim Matthews、Lynette Ongeri、Steve Clifton、Tania Mead、Susan Deupree、Pat Wheelan、Kathy Lyons、Claire Wilson、Alex Kiselyov、Leticia Toledo-Sherman、Maria Beconi、Ignacio Muñoz-Sanjuan、Jonathan Bard、Celia Dominguez

  DOI：10.1021/jm5013598

  日期：2015.4.9

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.