tert-butyl 4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate | 1401222-25-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-[1-(4-methylphenyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperidine-1-carboxylate
• CAS: 1401222-25-0
• 化学式: C₂₇H₃₁N₇O₃
• 分子量: 501.588
• InChiKey: FTNUNZNHCJJJOO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 21.25h， 生成 N-(3-(1-isopropylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

  摘要：

  IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing NI pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.

  DOI：

  10.1021/acsmedchemlett.5b00106
• 作为产物：
  描述：

  1-Boc-4-(氰基乙酰基)哌啶 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 50.0h， 生成 tert-butyl 4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

  摘要：

  IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing NI pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.

  DOI：

  10.1021/acsmedchemlett.5b00106

文献信息

• [EN] AMIDOPYRAZOLE INHIBITORS OF INTERLEUKIN RECEPTOR-ASSOCIATED KINASES<br/>[FR] INHIBITEURS DE KINASES ASSOCIÉES AUX RÉCEPTEURS D'INTERLEUKINE À BASE D'AMIDOPYRAZOLE
  申请人：MERCK SHARP & DOHME

  公开号：WO2012129258A1

  公开（公告）日：2012-09-27

  This invention relates to amidopyrazole compounds that are inhibitors of Interleukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment of cellular proliferative diseases, for example, cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation.

  这项发明涉及抗干扰素受体相关激酶（特别是IRAK-4）的抑制剂——amidopyRAzole化合物，可用于治疗细胞增殖性疾病，例如癌症、增生、再狭窄、心肌肥大、免疫紊乱和炎症。
• AMIDOPYRAZOLE INHIBITORS OF INTERLEUKIN RECEPTOR-ASSOCIATED KINASES
  申请人：McElroy William T.

  公开号：US20140194404A1

  公开（公告）日：2014-07-10

  This invention relates to amidopyrazole compounds that are inhibitors of Interleukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment of cellular proliferative diseases, for example, cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation.

  该发明涉及一种阻断白细胞介素受体相关激酶（尤其是IRAK-4）的酰胺吡唑化合物，可用于治疗细胞增殖性疾病，例如癌症、增生、再狭窄、心脏肥大、免疫失调和炎症。
• US9169260B2
  申请人：——

  公开号：US9169260B2

  公开（公告）日：2015-10-27