2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one | 688745-47-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one
• 英文别名: 2-morpholino-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one；2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-4-yl)-4a,8a-dihydro-chromen-4-one；2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)chromen-4-one；2-Morpholin-4-yl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-chromen-4-one；2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromen-4-one
• CAS: 688745-47-3
• 化学式: C₁₉H₂₄BNO₅
• 分子量: 357.214
• InChiKey: HOAQUINQAVIOKI-UHFFFAOYSA-N

物化性质

• 熔点：
  165-166 °C
• 沸点：
  500.6±50.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.93
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one 在 四(三苯基膦)钯 、 sodium hydride 、 sodium carbonate 、 溶剂黄146 、 三乙胺 、 锌 作用下， 以 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.08h， 生成 N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide
  参考文献：
  名称：

  DNA-dependent protein kinase (DNA-PK) inhibitors: Structure–activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

  摘要：

  Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110 alpha), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM). (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.12.047
• 作为产物：
  描述：

  3-甲氧基水杨酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 三氯化铝 、 三氟甲磺酸酐 、 硫酸 、 potassium acetate 、 N,N-二异丙基乙胺 、 sodium iodide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 101.0h， 生成 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one
  参考文献：
  名称：

  磷脂酰肌醇3-激酶抑制剂LY294002及相关类似物的合成研究

  摘要：

  已经开发了用于直接和高产制备磷脂酰肌醇 3-激酶抑制剂 LY294002 的合成方法。这些方法很容易适用于有效生成类似物，这将有助于对这一重要的酶家族进行详细研究。

  DOI：

  10.1071/ch03113

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。
• [EN] DNA PK INHIBITORS<br/>[FR] INHIBITEURS DE L'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2009010761A1

  公开（公告）日：2009-01-22

  A compound of formula (I): wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocydyl group, or 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; X is CH or N; n is 1 or 2; RC1 and RC2 are independently selected from H and methyl; when X is N, Rx is selected from the group consisting of H, and optionally substituted C1-7 alkyl, C3-20 heterocydyl, C5-20 aryl, acyl, ester, amido and sulfonyl; and when X is CH, Rx is selected from the group consisting of H, and optionally substituted C1-7 alkyl, C3-2O heterocyclyl, C5-20 aryl, acyl, ester, amido, sulfonyl, amino and ether. The compounds according to formula (I) are DNA-PK inhibitors, useful in the treatment of tumours and retroviral mediated diseases.

  公式(I)的化合物：其中：R1和R2独立地选自氢、一个可选地取代的C1-7烷基团、C3-20杂环烷基团或C5-20芳基团，或者可以共同形成，连同它们所连接的氮原子，一个从4到8个环原子组成的可选地取代的杂环；X是CH或N；n是1或2；RC1和RC2独立地选自H和甲基；当X是N时，Rx选自由H、和可选地取代的C1-7烷基、C3-20杂环烷基、C5-20芳基、酰基、酯、酰胺和磺酰基组成的组；当X是CH时，Rx选自由H、和可选地取代的C1-7烷基、C3-20杂环烷基、C5-20芳基、酰基、酯、酰胺、磺酰基、氨基和醚组成的组。根据公式(I)的化合物是DNA-PK抑制剂，在治疗肿瘤和逆转录病毒介导的疾病中有效。
• [EN] DNA-PK INHIBITORS<br/>[FR] INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2006032869A1

  公开（公告）日：2006-03-30

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocyclyl group, or 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; Q is -NH-C(=O)- or -O-; Y is an optionally substituted C1-5 alkylene group; X is selected from SR3 or NR4R5, wherein, R3, or R4 and R5 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R4 and R5 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; if Q is -O-, X is additionally selected from -C(=O)-NR6R7, wherein R6 and R7 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R6 and R7 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; and if Q is -NH-C(=O)-, -Y-X may additionally be selected from C1-7 alkyl.

  化合物I的分子式为：及其异构体、盐、溶剂和化学保护形式、以及其前药，其中：R1和R2独立选择氢、可选取代的C1-7烷基、C3-20杂环基或C5-20芳基，或者与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；Q为-NH-C（=O）-或-O-；Y为可选取代的C1-5烷基；X选自SR3或NR4R5，其中R3，或R4和R5独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R4和R5可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-O-，X还被选自-C（=O）-NR6R7，其中R6和R7独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R6和R7可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-NH-C（=O）-，-Y-X还可以被选自C1-7烷基。
• Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure
  作者：Sonsoles Rodriguez-Aristegui、Kate M. Clapham、Lauren Barrett、Céline Cano、Marine Desage-El Murr、Roger J. Griffin、Ian R. Hardcastle、Sara L. Payne、Tommy Rennison、Caroline Richardson、Bernard T. Golding

  DOI：10.1039/c1ob05282a

  日期：——

  5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity

  通过2,6-二溴苯胺与苯基硼酸（被Me，NO 2，OH，OMe或Cl取代）的Suzuki交叉偶联，获得氨基取代的联苯，优选在微波辐射的辅助下进行。氨基转化为硫醇之前，先进行碱诱导的分子内取代，然后通过微波加热促进其生成目标二苯并噻吩的第二个C–S键。将所获得的1-，2-，3-或4-取代的6-卤代二苯并噻吩与2-吗啉-4--4-基-8-（4,4,5,5-四甲基-1,3）进行钯介导的偶联，2-二氧杂硼烷-2-基）-4 H-chromen-4-one给出各自的6-，7-，8-或9-取代的二苯并噻吩-4-基色农酮。这些化合物被评估为DNA依赖性蛋白激酶（DNA-PK）的抑制剂，并与母体8-（dibenzo [ b，d ] thiophen-4-yl）-2-morpholin-4-yl-4 H -chromen进行了比较。 -4-一 值得注意的是，在C-8或C-9上带有羟基或甲氧基取代基的衍生物保留
• Atropisomeric 8-arylchromen-4-ones exhibit enantioselective inhibition of the DNA-dependent protein kinase (DNA-PK)
  作者：Céline Cano、Bernard T. Golding、Karen Haggerty、Ian R. Hardcastle、Marcus Peacock、Roger J. Griffin

  DOI：10.1039/b926245h

  日期：——

  Substitution at the 3-position of the dibenzothiophen-4-yl ring of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with propyl, allyl or methyl enabled the separation by chiral HPLC of atropisomers. This is a consequence of restricted rotation about the dibenzothiophene–chromenone bond. Biological evaluation against DNA-PK of the pairs of atropisomers showed a marked difference in potency, with only one enantiomer being biologically active.

  在 8-(二苯并[b,d]噻吩-4-基)-2-吗啉基-4H-色烯-4-酮 NU7441（一种强效的选择性 DNA 依赖性蛋白激酶（DNA-PK）抑制剂）的二苯并噻吩-4-基环的 3 位上用丙基、烯丙基或甲基取代，可通过手性 HPLC 分离出对映体。这是二苯并噻吩-色酮键旋转受限的结果。针对 DNA-PK 的生物评估显示，这对对映体的效力存在明显差异，只有一种对映体具有生物活性。