1,6-dihydro-5H-pyrrolo<3,2-g>quinazolin-5-one | 171179-70-7

• 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: 1,6-dihydro-5H-pyrrolo<3,2-g>quinazolin-5-one
• 英文别名: pyrrolo<3,2-g>quinazolone；1H-pyrrolo<3,2-g>quinazolin-5(6H)-one；3,8-Dihydro-4H-pyrrolo[3,2-g]quinazolin-4-one；3,8-dihydropyrrolo[3,2-g]quinazolin-4-one
• CAS: 171179-70-7
• 化学式: C₁₀H₇N₃O
• 分子量: 185.185
• InChiKey: PZEMHRJOPGIHBM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  57.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1,6-dihydro-5H-pyrrolo<3,2-g>quinazolin-5-one 在 sodium hydroxide 、 tetraphosphorus decasulfide 、 sodium hydride 作用下， 以 吡啶 、 甲醇 、 水 为溶剂， 反应 20.58h， 生成 1-methyl-5-(methylthio)pyrrolo[3,2-g]quinazoline
  参考文献：
  名称：

  Tyrosine Kinase Inhibitors. 11. Soluble Analogues of Pyrrolo- and Pyrazoloquinazolines as Epidermal Growth Factor Receptor Inhibitors:  Synthesis, Biological Evaluation, and Modeling of the Mode of Binding

  摘要：

  A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-S-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.

  DOI：

  10.1021/jm960789h
• 作为产物：
  描述：

  N-<(dimethylamino)methylene>-(E)-5-<2-(dimethylamino)ethenyl>-2,4-dinitrobenzamide 在 氢气 、 镍 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 25.0 ℃ 、10.34 MPa 条件下， 反应 22.0h， 以57%的产率得到1,6-dihydro-5H-pyrrolo<3,2-g>quinazolin-5-one
  参考文献：
  名称：

  Concise Syntheses of the Novel 1H-Pyrrolo[3,2-g]quinazoline Ring System and its [2,3-f] Angular Isomer

  摘要：

  DOI：

  10.1021/jo951790b

文献信息

• [EN] QUINAZOLINE-DERIVED HCK INHIBITORS FOR USE IN THE TREATMENT OF MYD88 MUTATED DISEASES<br/>[FR] INHIBITEURS DE HCK DÉRIVÉS DE QUINAZOLINE DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DE MALADIES À MUTATION MYD88
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2021247845A1

  公开（公告）日：2021-12-09

  The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., HCK, BTK, LYN) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating diseases (e.g., proliferative diseases) in a subject in need thereof). (I)

  本公开提供了式（I）的化合物，以及其在药用上可接受的盐、溶剂结晶体、水合物、多晶形态、共晶体、互变异构体、立体异构体、同位素标记衍生物和前药。所提供的化合物可能是激酶（例如HCK、BTK、LYN）抑制剂。还提供了包括所提供的化合物的药物组合物和工具包。进一步提供了使用所提供的化合物、药物组合物和工具包的方法（例如，用于治疗需要的患者的疾病（例如增殖性疾病））。 （I）
• Tyrosine Kinase Inhibitors. 9. Synthesis and Evaluation of Fused Tricyclic Quinazoline Analogues as ATP Site Inhibitors of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor
  作者：Gordon W. Rewcastle、Brian D. Palmer、Alexander J. Bridges、H. D. Hollis Showalter、Li Sun、James Nelson、Amy McMichael、Alan J. Kraker、David W. Fry、William A. Denny

  DOI：10.1021/jm950692f

  日期：1996.1.1

  4-[(3-bromophenyl)amino]-6,7-dimethoxyquinazoline (4; PD 153035) as an extremely potent (IC(50) 0.025 nM) inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), several fused tricyclic quinazoline analogues have been prepared and evaluated for their ability to inhibit the enzyme. The most potent compound was the linear imidazo[4,5-g]quinazoline (8), which exhibited an IC(50) of 0

  发现4-[（（3-溴苯基）氨基] -6,7-二甲氧基喹唑啉（4; PD 153035）作为表皮生长因子受体酪氨酸激酶活性的极强抑制剂（IC（50）0.025 nM） （EGFR），已经制备了几种稠合的三环喹唑啉类似物，并对其抑制酶的能力进行了评估。最有效的化合物是线性咪唑并[4,5-g]喹唑啉（8），其IC（50）为0.008 nM，可抑制磷脂酶C-gamma-1片段作为底物的磷酸化。虽然8的N-甲基类似物显示出相似的效价，但类似的N- [2-（二甲基氨基）乙基]衍生物效果较差。接下来最有效的化合物是线性吡唑并喹唑啉（19和20）（IC（50）s为0.34和0.44 nM）和吡咯并喹唑啉（21）（IC（50）为0.44nM），而其他几个几何形状类似于8的线性三环系统（三唑并，噻唑并和吡嗪并喹唑啉）的效果则较差。在咪唑并[4,5-g]喹唑啉和吡咯并喹唑啉系列中，相应的角型异构体的效力也远低于
• PHENYLAMINO-SUBSTITUTED TRICYCLIC DERIVATIVES FOR TREATMENT OF HYPERPROLIFERATIVE DISEASES
  申请人：PFIZER INC.

  公开号：EP0907642B1

  公开（公告）日：2005-11-02
• US6335344B1
  申请人：——

  公开号：US6335344B1

  公开（公告）日：2002-01-01
• [EN] KINESIN INHIBITORS<br/>[FR] INHIBITEURS DE LA KINÉSINE
  申请人：TAIGEN BIOTECHNOLOGY CO LTD

  公开号：WO2008147852A1

  公开（公告）日：2008-12-04

  [EN] This invention relates to the compounds of formula shown in the specification. These compounds can be used to treat a kinesin Eg5 protein-mediated disorder.
  [FR] La présente invention concerne des composés représentés par la formule qui figure dans la description. Ces composés peuvent être utilisés pour traiter un trouble médié par la protéine Eg5 kinésine.