tert-butyl (2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate | 1448190-12-2

• 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: tert-butyl (2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate
• 英文别名: (2S,4R)-tert-butyl 4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate；tert-butyl (2S,4R)-4-hydroxy-2-[[2-hydroxy-4-(4-methylthiazol-5-yl)phenyl]methyl carbamoyl]pyrrolidine-1-carboxylate；(2S,4R)-tert-Butyl 4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl) carbamoyl)pyrrolidine-1-carboxylate；tert-butyl (2S,4R)-4-hydroxy-2-[[2-hydroxy-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate
• CAS: 1448190-12-2
• 化学式: C₂₁H₂₇N₃O₅S
• 分子量: 433.528
• InChiKey: KZQIVBRGXRGVIE-CVEARBPZSA-N

物化性质

• 沸点：
  682.1±55.0 °C(Predicted)
• 密度：
  1.324±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  140
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl (2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate 在 盐酸 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.33h， 生成 (2S,4R)-N-(2-(2-((1-(5-chloro-4-((1-methyl-3-(2- (methylamino)-2-oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  [EN] BIFUNCTIONAL MOLECULES CONTAINING AN E3 UBIQUITINE LIGASE BINDING MOIETY LINKED TO A BCL6 TARGETING MOIETY
  [FR] MOLÉCULES BIFONCTIONNELLES CONTENANT UNE FRACTION DE LIAISON À L'UBIQUITINE LIGASE E3 LIÉE À UNE FRACTION CIBLANT BCL6

  摘要：

  本发明描述了双功能化合物，其作为B细胞淋巴瘤6蛋白（BCL6；靶蛋白）的调节剂。特别是，本发明中的双功能化合物一端含有与相应的E3泛素连接酶结合的Von Hippel-Lindau、cereblon、凋亡蛋白抑制剂或小鼠双分钟同源蛋白2的配体，另一端含有与靶蛋白结合的部分，使得靶蛋白被置于泛素连接酶附近，以促进靶蛋白的降解（和抑制）。本发明中的双功能化合物展示了与靶蛋白降解/抑制相关的广泛药理活性。可以通过本发明中的化合物和组合物治疗或预防由靶蛋白聚集或积累引起的疾病或失调。

  公开号：

  WO2021077010A1
• 作为产物：
  描述：

  4-溴-2-氰基苯酚 在 lithium aluminium tetrahydride 、 potassium acetate 、 palladium diacetate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 tert-butyl (2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  [EN] BIFUNCTIONAL COMPOUNDS
  [FR] COMPOSÉS BIFONCTIONNELS

  摘要：

  这项发明提供了式(I)的双功能化合物，或其药学上可接受的盐，其中所述的靶向配体、连接剂和Degron如本文所述。

  公开号：

  WO2021086785A1

文献信息

• [EN] SMALL MOLECULES<br/>[FR] PETITES MOLÉCULES
  申请人：UNIV DUNDEE

  公开号：WO2018189554A1

  公开（公告）日：2018-10-18

  Compounds having the general structure A - L - B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1 B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.

  提供具有一般结构 A - L - B 的化合物，其中 A 和 B 分别是式 1A 或 1B 的 E3 泛素连接酶蛋白结合配体化合物。还提供包含这些化合物的药物组合物和使用方法。
• [EN] COMPOUNDS AND METHODS FOR TARGETED DEGRADATION OF KRAS<br/>[FR] COMPOSÉS ET PROCÉDÉS DE DÉGRADATION CIBLÉE DE KRAS
  申请人：ARVINAS OPERATIONS INC

  公开号：WO2021207172A1

  公开（公告）日：2021-10-14

  Bifunctional compounds, which find utility as modulators of Kirsten ras sarcoma protein (KRas or KRAS), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase and on the other end a moiety which binds KRas, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本发明描述了双功能化合物，其可用作Kirsten ras肉瘤蛋白（KRas或KRAS）的调节剂。特别是，本公开的杂双功能化合物在一端包含一个与Von Hippel-Lindau E3泛素连接酶结合的部分，在另一端包含一个与KRas结合的部分，使得目标蛋白被置于泛素连接酶附近，以实现目标蛋白的降解（和抑制）。本发明公开的杂双功能化合物展示了与目标蛋白降解/抑制相关的广泛药理活性。可通过本发明公开的化合物和组合物治疗或预防由目标蛋白异常调节引起的疾病或失调。
• Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  申请人：YALE UNIVERSITY

  公开号：US20140356322A1

  公开（公告）日：2014-12-04

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是作为本发明的双功能化合物对各种被降解和/或受到抑制的多肽和其他蛋白质的抑制剂。具体而言，本发明涉及含有一端结合泛素连接酶的VHL配体，另一端结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。本发明展示了与本发明化合物相关的广泛的药理活性范围，与靶向多肽的降解/抑制一致。
• [EN] BIFUNCTIONAL COMPOUNDS<br/>[FR] COMPOSÉS BIFONCTIONNELS
  申请人：HOFFMANN LA ROCHE

  公开号：WO2021086785A1

  公开（公告）日：2021-05-06

  The invention provides a bifunctional compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said Targeting Ligand, Linker and Degron are as described herein.

  这项发明提供了式(I)的双功能化合物，或其药学上可接受的盐，其中所述的靶向配体、连接剂和Degron如本文所述。
• ESTROGEN-RELATED RECEPTOR ALPHA BASED PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Yale University

  公开号：US20160045607A1

  公开（公告）日：2016-02-18

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是根据本发明抑制各种多肽和其他蛋白质的抑制剂。具体而言，本发明涉及一种在一端含有结合泛素连接酶的VHL配体，另一端含有结合靶蛋白的基团的化合物，使得靶蛋白位于靠近泛素连接酶以实现对该蛋白的降解（和抑制）。本发明展示了与根据本发明的化合物相关的广泛的药理活性范围，与靶向多肽的降解/抑制一致。