isobutyl ((2R,6S,13aS,14aR,16aS,Z)-9'-methoxy-14a-(1-methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-6-yl)carbamate | 1565770-83-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: isobutyl ((2R,6S,13aS,14aR,16aS,Z)-9'-methoxy-14a-(1-methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-6-yl)carbamate
• 英文别名: isobutyl ((2R,6S,13aS,14aR,16aS,Z)-9'-methoxy-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1Hspiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinolin]-6-yl)carbamate；MK-8831；2-methylpropyl N-[(1'S,3R,4'R,6'S,7'Z,14'S)-9-methoxy-4'-[(1-methylcyclopropyl)sulfonylcarbamoyl]-2',15'-dioxo-5-(trifluoromethyl)spiro[1,2-dihydropyrano[2,3-c]quinoline-3,18'-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene]-14'-yl]carbamate
• CAS: 1565770-83-3
• 化学式: C₄₀H₅₀F₃N₅O₉S
• 分子量: 833.926
• InChiKey: GBJKXZJNFVRHCK-XPTVTBSVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  58
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  191
• 氢给体数：
  3
• 氢受体数：
  13

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	tert-butyl (2R,6S,13aS,14aR,16aS,Z)-9'-methoxy-14a-(1-methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-6-ylcarbamate	1565770-81-1	C40H50F3N5O9S	833.926
  ——	(2R,6S,12Z,13aS,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-9'-methoxy-5,16-dioxo-5'-(trifluoromethyl)-1,1',2',6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrospiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-14a(5H)-carboxylic acid	1565776-79-5	C36H43F3N4O8	716.755
  ——	(2S,6S,13aS,14aR,16aS,Z)-ethyl 6-((tert-butoxycarbonyl) amino)-9'-methoxy-1',5,16-trioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15, 16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-14a-carboxylate	1565776-32-0	C38H45F3N4O9	758.792
  ——	ethyl (1'S,3S,4'R,6'S,7'Z,14'S)-1-chloro-9-methoxy-14'-[(2-methylpropan-2-yl)oxycarbonylamino]-2',15'-dioxo-5-(trifluoromethyl)spiro[1,2-dihydropyrano[2,3-c]quinoline-3,18'-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene]-4'-carboxylate	1565778-60-0	C38H46ClF3N4O8	779.253
  ——	1-[6-Methoxy-3-phenylmethoxy-2-(trifluoromethyl)quinolin-4-yl]ethanone	1565778-55-3	C20H16F3NO3	375.347
  ——	1-(3-Hydroxy-6-methoxy-2-(trifluoromethyl)quinolin-4-yl)ethanone	1565778-56-4	C13H10F3NO3	285.223

反应信息

• 作为产物：
  描述：

  3-hydroxy-6-methoxy-quinoline-4-carboxylic acid 在 四氢吡咯 、 盐酸 、 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 copper(l) iodide 、 四(三苯基膦)钯 、 nickel(II) chloride hexahydrate 、 lithium hydroxide monohydrate 、 palladium on activated charcoal 、 氢气 、 caesium carbonate 、 甲基磺酰氯 、 三乙胺 、 苯甲酸 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 34.75h， 生成 isobutyl ((2R,6S,13aS,14aR,16aS,Z)-9'-methoxy-14a-(1-methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo-5'-(trifluoromethyl)-1',2',3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3'-pyrano[2,3-c]quinoline]-6-yl)carbamate
  参考文献：
  名称：

  [EN] HCV NS3 PROTEASE INHIBITORS
  [FR] INHIBITEURS DE LA PROTÉASE NS3 DU VHC

  摘要：

  这项发明涉及含有螺环结构基团的丙型肝炎病毒（HCV）NS3蛋白酶抑制剂，以及这类化合物的用途和合成。

  公开号：

  WO2014025736A1

文献信息

• Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor
  作者：Santhosh F. Neelamkavil、Sony Agrawal、Thomas Bara、Chad Bennett、Sathesh Bhat、Dipshikha Biswas、Linda Brockunier、Nicole Buist、Duane Burnette、Mark Cartwright、Samuel Chackalamannil、Robert Chase、Mariappan Chelliah、Austin Chen、Martin Clasby、Vincent J. Colandrea、Ian W. Davies、Keith Eagen、Zhuyan Guo、Yongxin Han、John Howe、Charles Jayne、Hubert Josien、Stacia Kargman、Karen Marcantonio、Shouwu Miao、Randy Miller、Andrew Nolting、Patrick Pinto、Murali Rajagopalan、Rebecca T. Ruck、Unmesh Shah、Aileen Soriano、Donald Sperbeck、Francisco Velazquez、Jin Wu、Yan Xia、Srikanth Venkatraman

  DOI：10.1021/acsmedchemlett.5b00425

  日期：2016.1.14

  different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling

  我们一直专注于鉴定与MK-5172（我们的Ns3 / 4a蛋白酶抑制剂，目前正在监管审查中）在结构上不同的下一代抑制剂，该抑制剂将实现具有可接受的安全性和药代动力学特征的优异的泛型活性。这些努力导致发现了一种新型的HCV NS3 / 4a蛋白酶抑制剂，该抑制剂具有独特的螺环-脯氨酸结构基序。设计策略包括基于分子建模的方法，以及对该系列的优化工作，以获得具有良好口服剂量暴露的泛基因型覆盖率。这项工作的关键要素之一是P2喹啉基团的螺环化，它刚性化并限制了结合构象，从而提供了一个新的核心。该小组的第二个重点还在于提高针对基因型3a和基因型1b关键突变体的活性。结构化学与分子建模的合理应用指导了结构与活性关系的设计和优化，从而鉴定出具有优良泛基因型活性和安全性的临床候选药物MK-8831。
• Chimeric antigen receptor (CAR) modulation
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US11059864B2

  公开（公告）日：2021-07-13

  The technology described herein is directed to CAR polypeptides and systems comprising repressible proteases. In combination with a specific protease inhibitor, the activity of said CAR polypeptides and systems and cells comprising them can be modulated. Also described herein are methods of using said CAR polypeptides and systems, for example to treat various diseases and disorders.

  本文所述技术针对的是包含可抑制蛋白酶的 CAR 多肽和系统。结合特定的蛋白酶抑制剂，可以调节所述 CAR 多肽和系统以及包含它们的细胞的活性。本文还描述了使用所述 CAR 多肽和系统的方法，例如用于治疗各种疾病和失调。
• Regulated synthetic gene expression systems
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US11530246B2

  公开（公告）日：2022-12-20

  The technology described herein is directed to regulated synthetic gene expression systems. In one aspect described herein are synthetic transcription factors (synTFs) comprising a DNA binding domain, a transcriptional effector domain, and a regulator protein. In other aspects described herein are gene expression systems comprising said synTFs and methods of treating diseases and disorders using said synTFs.

  本文所述技术针对的是受调控的合成基因表达系统。一方面，本文所述的合成转录因子（synTFs）包括 DNA 结合结构域、转录效应结构域和调节蛋白。在其他方面，本文所述的基因表达系统包括所述的合成转录因子和使用所述合成转录因子治疗疾病和失调的方法。
• CHIMERIC ANTIGEN RECEPTOR (CAR) MODULATION
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US20200308234A1

  公开（公告）日：2020-10-01

  The technology described herein is directed to CAR polypeptides and systems comprising repressible proteases. In combination with a specific protease inhibitor, the activity of said CAR polypeptides and systems and cells comprising them can be modulated. Also described herein are methods of using said CAR polypeptides and systems, for example to treat various diseases and disorders.
• REGULATED SYNTHETIC GENE EXPRESSION SYSTEMS
  申请人：TRUSTEES OF BOSTON UNIVERSITY

  公开号：US20200377564A1

  公开（公告）日：2020-12-03

  The technology described herein is directed to regulated synthetic gene expression systems. In one aspect described herein are synthetic transcription factors (synTFs) comprising a DNA binding domain, a transcriptional effector domain, and a regulator protein. In other aspects described herein are gene expression systems comprising said synTFs and methods of treating diseases and disorders using said synTFs.