(S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate | 1615254-54-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
• 英文别名: tert-butyl N-[(1S)-1-(5-bromo-4-oxo-3-phenylquinazolin-2-yl)ethyl]carbamate
• CAS: 1615254-54-0
• 化学式: C₂₁H₂₂BrN₃O₃
• 分子量: 444.328
• InChiKey: XCCOLRRDEGBIQV-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  71
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate 在 XPhos Pd G2 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 反应 11.5h， 生成 (S)-tert-butyl (1-(4-oxo-3-phenyl-5(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
  参考文献：
  名称：

  [EN] PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
  [FR] INHIBITEURS DE PHOSPHATIDYLINOSITOL 3-KINASE

  摘要：

  本公开提供了公式（J）中的磷脂酰肌醇3-激酶（PI3K）抑制剂，或其药用盐，其中A、n、m、R1、R2、R3、R4、R5、R6和R7如本文所定义。这些化合物对于治疗由一个或多个PI3K异构体介导的疾病是有用的。本公开还提供包含公式（J）中的化合物或其药用盐的药物组合物，以及使用这些化合物和组合物治疗由一个或多个PI3K异构体介导的疾病的方法。

  公开号：

  WO2015200352A1

文献信息

• [EN] INHIBITORS OF PHOSPHOINOSITIDE 3-KINASE AND HISTONE DEACETYLASE FOR TREATMENT OF CANCER<br/>[FR] INHIBITEURS DE LA PHOSPHOINOSITIDE 3-KINASE ET DE L'HISTONE DÉSACÉTYLASE POUR LE TRAITEMENT DU CANCER
  申请人：US HEALTH

  公开号：WO2018237007A1

  公开（公告）日：2018-12-27

  The present invention is directed to a dual inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC), including a core containing a quinazoline moiety or a quinazolin-4(3H)-one moiety, a kinase hinge binding moiety, and a histone deacetylase pharmacophore, a pharmaceutically acceptable salt thereof, a prodrug thereof, or solvate thereof. The present invention is also directed to a histone deacetylase inhibitor, including a core containing a quinazolin-4(3H)-one moiety and a histone deacetylase pharmacophore.

  本发明涉及一种磷脂酰肌醇3-激酶（PI3K）和组蛋白去乙酰化酶（HDAC）的双重抑制剂，包括一个含有喹唑啉基团或喹唑啉-4(3H)-酮基团的核心，一个激酶铰链结合基团，和一个组蛋白去乙酰化酶药效团，以及其药用盐、前药或溶剂化物。本发明还涉及一种组蛋白去乙酰化酶抑制剂，包括一个含有喹唑啉-4(3H)-酮基团和一个组蛋白去乙酰化酶药效团的核心。
• Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors
  作者：Ashish Thakur、Gregory J. Tawa、Mark J. Henderson、Carina Danchik、Suiyang Liu、Pranav Shah、Amy Q. Wang、Garrett Dunn、Md Kabir、Elias C. Padilha、Xin Xu、Anton Simeonov、Surender Kharbanda、Richard Stone、Gurmit Grewal

  DOI：10.1021/acs.jmedchem.0c00193

  日期：2020.4.23

  quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines

  通过经由优化的接头将HDAC药效团掺入PI3K抑制剂（Idelalisib）中，合理设计和合成了一系列基于喹唑啉-4-酮的异羟肟酸，作为新型的双重PI3K / HDAC抑制剂。这些双重抑制剂中的几种非常有效（IC50 <10 nM），对PI3Kγ，δ和HDAC6酶具有选择性，并且对多种癌细胞具有良好的抗增殖活性。铅化合物48c在AML患者的几种突变型和FLT3抗性AML细胞系和原代细胞中诱导坏死，而对正常PBMC，NIH3T3和HEK293细胞无细胞毒性。使用细胞热位移分析（CETSA）在MV411细胞中证明了48c的PI3Kδ和HDAC6的靶标结合。
• PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
  申请人：GILEAD CALISTOGA LLC

  公开号：US20140179673A1

  公开（公告）日：2014-06-26

  The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , n, R 3 , R 4 , R 5 and R 6 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

  本公开提供了式(I)的磷脂酰肌醇3-激酶（PI3K）抑制剂，或其药用盐，其中R1、R2、n、R3、R4、R5和R6如本文所定义。这些化合物可用于治疗由一个或多个PI3K亚型介导的疾病，如PI3Kδ。本公开还提供了包括式(I)化合物或其药用盐的药物组合物，以及使用这些化合物和组合物治疗由一个或多个PI3K亚型介导的疾病的方法，如PI3Kδ。
• Phosphatidylinositol 3-kinase inhibitors
  申请人：Gilead Calistoga LLC

  公开号：US09018221B2

  公开（公告）日：2015-04-28

  The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), or pharmaceutically acceptable salts thereof, in which R1, R2, n, R3, R4, R5 and R6 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

  本公开提供式(I)的磷脂酰肌醇3-激酶（PI3K）抑制剂，或其药学上可接受的盐，其中R1、R2、n、R3、R4、R5和R6如本文所定义。这些化合物可用于治疗由一个或多个PI3K亚型介导的疾病，如PI3Kδ。本公开进一步提供包括式(I)的化合物或其药学上可接受的盐的制药组合物，以及使用这些化合物和组合物治疗由一个或多个PI3K亚型介导的疾病，如PI3Kδ的方法。
• ISOQUINOLINONE OR QUINAZOLINONE PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
  申请人：Gilead Calistoga LLC

  公开号：EP2935246B1

  公开（公告）日：2018-07-25