tert-butyl N-(6,6-difluoro-4-methyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl)carbamate | 1428577-24-5

• 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: tert-butyl N-(6,6-difluoro-4-methyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl)carbamate
• 英文别名: tert-butyl N-[6,6-difluoro-4-methyl-1-(2-methyl-4-nitropyrazol-3-yl)azepan-4-yl]carbamate
• CAS: 1428577-24-5
• 化学式: C₁₆H₂₅F₂N₅O₄
• 分子量: 389.402
• InChiKey: ZPEDXRSHUNUFMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl N-(1-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl)-5-methoxy-5-methyl-azepan-4-yl]carbamate 、 tert-butyl N-(6,6-difluoro-4-methyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl)carbamate 以gave tert-butyl N-(4-((5-(5-(tert-butoxycarbonylamino)-3,3-difluoro-5-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate as a yellow solid (409 mg, 58% over two steps)的产率得到tert-butyl N-(4-((5-(5-(tert-butoxycarbonylamino)-3,3-difluoro-5-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate
  参考文献：
  名称：

  PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE

  摘要：

  公式I中的吡唑-4-基杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中X为噻唑基、吡嗪基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。本文揭示了使用公式I化合物进行哺乳动物细胞的体外、原位和体内诊断、预防或治疗此类疾病或相关病理条件的方法。

  公开号：

  US20140080801A1
• 作为产物：
  描述：

  tert-butyl 4-methyl-6-oxo-3,7-dihydro-2H-azepine-1-carboxylate 在 盐酸 、 potassium fluoride 、 sodium tetrahydroborate 、 叠氮基三甲基硅烷 、 戴斯-马丁氧化剂 、 三乙胺 、 三苯基膦 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙腈 为溶剂， 反应 82.0h， 生成 tert-butyl N-(6,6-difluoro-4-methyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl)carbamate
  参考文献：
  名称：

  Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System

  摘要：

  Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the a carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.

  DOI：

  10.1021/acsmedchemlett.5b00191

文献信息

• US8614206B2
  申请人：——

  公开号：US8614206B2

  公开（公告）日：2013-12-24
• US9505746B2
  申请人：——

  公开号：US9505746B2

  公开（公告）日：2016-11-29
• [EN] PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE TYPE PYRAZOL-4-YL-HÉTÉROCYCLYL-CARBOXAMIDE ET LEURS MÉTHODES D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013045461A1

  公开（公告）日：2013-04-04

  Pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula (I), including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is a thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula (I), for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
• PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：GENENTECH, INC.

  公开号：US20130079321A1

  公开（公告）日：2013-03-28

  Pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  Formula I中的吡唑-4-基杂环基-羧酰胺化合物，包括其立体异构体、几何异构体、互变异构体和药学上可接受的盐，其中X为噻唑基、吡啶基、吡啶基或嘧啶基，用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用Formula I化合物进行体外、原位和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System
  作者：Xiaojing Wang、Minghua Sun、Connie New、Spencer Nam、Wesley P. Blackaby、Alastair J. Hodges、David Nash、Mizio Matteucci、Joseph P. Lyssikatos、Peter W. Fan、Suzanne Tay、Jae H. Chang

  DOI：10.1021/acsmedchemlett.5b00191

  日期：2015.8.13

  Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the a carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.