[5-tert-butyl-2-(3-nitrophenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester | 611168-84-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [5-tert-butyl-2-(3-nitrophenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester
• 英文别名: phenyl (3-(tert-butyl)-1-(3-nitrophenyl)-1H-pyrazol-5-yl)carbamate；phenyl N-[5-tert-butyl-2-(3-nitrophenyl)pyrazol-3-yl]carbamate
• CAS: 611168-84-4
• 化学式: C₂₀H₂₀N₄O₄
• 分子量: 380.403
• InChiKey: OFEUMGABGWCHQI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [5-tert-butyl-2-(3-nitrophenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester 在 palladium on activated charcoal 吡啶 、 ammonium formate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二甲基亚砜 为溶剂， 反应 49.5h， 生成 N-[3-(3-tert-butyl-5-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-ureido}-pyrazol-1-yl)-phenyl]-acetamide
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k
• 作为产物：
  描述：

  氯甲酸苯酯 、 2-(3-nitrophenyl)-5-tert-butyl-2H-pyrazol-3-yl-amine 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 以67%的产率得到[5-tert-butyl-2-(3-nitrophenyl)-2H-pyrazol-3-yl]-carbamic acid phenyl ester
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k

文献信息

• Synthesis and anti-tumor activity of imidazopyrazines as TAK1 inhibitors
  作者：Seok Jong Kang、Jung Wuk Lee、Shin Hyuck Chung、Sun Young Jang、Jaeyul Choi、Kwee Hyun Suh、Young Hoon Kim、Young Jin Ham、Kyung Hoon Min

  DOI：10.1016/j.ejmech.2018.12.025

  日期：2019.2

  Transforming growth factor-β activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice

  转化生长因子-β激活的激酶1（TAK1）是癌症和炎症性疾病的潜在治疗靶标。我们合成了一系列新型的咪唑并吡嗪衍生物，发现它们对TAK1表现出有效的抑制作用。具有良好药代动力学特征的化合物22a在SW620（一种KRAS依赖性结肠癌细胞系）异种移植小鼠中表现出出色的体外激酶活性和显着的体内功效。
• Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-<i>tert</i>-Butyl-2-<i>p</i>-tolyl-2<i>H</i>-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)
  作者：John Regan、Alison Capolino、Pier F. Cirillo、Thomas Gilmore、Anne G. Graham、Eugene Hickey、Rachel R. Kroe、Jeffrey Madwed、Monica Moriak、Richard Nelson、Christopher A. Pargellis、Alan Swinamer、Carol Torcellini、Michele Tsang、Neil Moss

  DOI：10.1021/jm030121k

  日期：2003.10.1

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.