9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 9-O-triflate | 912824-69-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 9-O-triflate
• 英文别名: 9-hydroxy-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one 9-O-triflate；2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl trifluoromethanesulfonate；9-triflate-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one；(2-Morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl) trifluoromethanesulfonate
• CAS: 912824-69-2
• 化学式: C₁₃H₁₂F₃N₃O₅S
• 分子量: 379.317
• InChiKey: LTYJBWPIXLAPQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  96.9
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 9-O-triflate 在 四(三苯基膦)钯 、 potassium carbonate 、 溶剂黄146 、 三乙胺 、 锌 作用下， 以 1,4-二氧六环 、 N,N-二甲基乙酰胺 为溶剂， 反应 4.5h， 生成
  参考文献：
  名称：

  DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

  摘要：

  Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]-pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1 H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n) NR1 R-2, where n = 1 or 2 and the moiety (RRN)-R-1-N-2 was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]-pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

  DOI：

  10.1021/jm100608j
• 作为产物：
  描述：

  9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 、 三氟甲磺酸酐 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.5h， 以90%的产率得到9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one 9-O-triflate
  参考文献：
  名称：

  Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

  摘要：

  以选定的芳基和杂芳基为取代基合成了 8-取代的 2-吗啉-4-基-喹啉-4-酮和 9-取代的 2-吗啉-4-基-吡啶并[1,2-a]嘧啶-4-酮，作为 DNA 依赖性蛋白激酶的潜在抑制剂。在制备 8-取代的 2-吗啉-4-基-喹啉-4-酮的过程中，采用了铃木交叉偶联法的多重平行方法。为此，需要 8-溴-2-吗啉-4-基-喹啉-4-酮作为中间体。这种化合物是通过调整文献路线获得的，在该路线中，(2-溴苯胺基)-吗啉-4-基-5-亚甲基-2,2-二甲基[1,3]二噁烷-4,6-二酮的热环缩合得到 8-溴-2-吗啉-4-基-喹啉-4-酮。以 9-羟基-2-吗啉-4-基-吡啶并[1,2-a]嘧啶-4-酮 O-三氟甲磺酸酯为中间体，利用铃木交叉偶联法制备了 9-取代的 2-吗啉-4-基-吡啶并[1,2-a]嘧啶-4-酮。8-取代的 2-吗啉-4-基-喹啉-4-酮和 9-取代的 2-吗啉-4-基-吡啶并[1,2-a]嘧啶-4-酮都是 DNA 依赖性蛋白激酶的抑制剂。当取代基为二苯并噻吩-4-基、二苯并呋喃-4-基或二苯并噻吩-3-基时，观察到的 IC50 值在纳摩尔范围内。有趣的是，吡啶嘧啶酮和喹啉酮与之前报道的相应的 8-取代 2-吗啉-4-基-苯并吡喃-4-酮基本等效（I. R. Hardcastle、X. Cockcroft、N. J. Curtin、M. Desage El-Murr、J. J. J. Leahy、M. Stockley、B. T. Golding、L. Rigoreau、C. Richardson、G. C. M. Smith 和 R. J. Griffin，J. Med.Chem.，2005，48，7829-7846）。

  DOI：

  10.1039/b705095j

文献信息

• [EN] DIBENZOTHIOPHENE DERIVATIVES AS DNA- PK INHIBITORS<br/>[FR] DÉRIVÉS DE DIBENZOTHIOPHÈNE EN TANT QU'INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2010136778A1

  公开（公告）日：2010-12-02

  Compound formula I: wherein: X1 and X2 may be either (a) C and O, (b) N and N, or (c) C and NH, where the dotted bonds represents a double bond in the appropriate location; R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; RN1 is selected from hydrogen and an optionally substituted C1-4 alkyl group; RC1 is selected from an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group; or RN1 and RC1 may together form an optionally substituted C2-4 alkylene group.

  化合物公式I：其中：X1和X2可以是（a）C和O，（b）N和N，或（c）C和NH，其中点线代表适当位置的双键；R1和R2分别从氢，可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中独立选择，或者可以与它们附着的氮原子一起形成具有4至8个环原子的可选择取代的杂环环；RN1从氢和可选择的取代的C1-4烷基基团中选择；RC1从可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中选择；或RN1和RC1可以一起形成一个可选择取代的C2-4烷基烃基团。
• DNA-PK inhibitors
  申请人：Smith Cameron Murray Graeme

  公开号：US20060264427A1

  公开（公告）日：2006-11-23

  Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N;and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(═O), CH 2 and NH are disclosed for use in inhibiting DNA-PK.

  式I的化合物： 其中A、B和D分别从以下组中选择：(i) CH、NH、C；(ii) CH、N、N；和(iii) CH、O、C；虚线表示适当位置上的两个双键；Z从S、O、C(═O)、CH2和NH中选择，用于抑制DNA-PK。
• WO2006/109081
  申请人：——

  公开号：——

  公开（公告）日：——
• US7696203B2
  申请人：——

  公开号：US7696203B2

  公开（公告）日：2010-04-13
• DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype
  作者：Céline Cano、Olivier R. Barbeau、Christine Bailey、Xiao-Ling Cockcroft、Nicola J. Curtin、Heather Duggan、Mark Frigerio、Bernard T. Golding、Ian R. Hardcastle、Marc G. Hummersone、Charlotte Knights、Keith A. Menear、David R. Newell、Caroline J. Richardson、Graeme C. M. Smith、Ben Spittle、Roger J. Griffin

  DOI：10.1021/jm100608j

  日期：2010.12.23

  Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]-pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1 H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n) NR1 R-2, where n = 1 or 2 and the moiety (RRN)-R-1-N-2 was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]-pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.