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Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof

A technology of heteroaromatic rings and compounds, which is applied in the field of benzazeteroaromatic ring compounds and their preparation, and can solve the problems of easy tolerance and low curative effect

Active Publication Date: 2018-02-09
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to address the deficiencies in the prior art, to provide a new benzazeteroaromatic compound, which is used as a dual inhibitor of tyrosine kinase and Nampt to solve the problem of existing tyrosine kinase Drug efficacy is not high, tolerance defects and other issues

Method used

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  • Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof
  • Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof
  • Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137]

[0138] Step 1, 4-chloro-7-methoxyquinazolin-6-ol acetate

[0139] Place 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (4g, 17.1mmol) in a 100mL conical flask, add 40mL dichlorohydrin at room temperature After sulfone and 1 drop of DMF, heat and reflux for 24 hours; distill off most of the thionyl chloride, add ice water, filter, and dry to obtain 4-chloro-7-methoxyquinazolin-6-alcohol acetate ( 4.07 g), yield 94%.

[0140] 1 H-NMR (400MHz, CDCl 3 ): δ8.95(s,1H),7.90(s,1H),7.44(s,1H),4.02(s,3H),2.39(s,3H).

[0141] Step 2, 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol acetate

[0142] 4-Chloro-7-methoxyquinazolin-6-ol acetate (4.07g, 16.1mmol) and 3-aminophenylacetylene (3.77g, 21.3mmol) were placed in 140mL of isopropanol, heated to reflux for 12 hours, cooled, and filtered to obtain 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol acetate (4.59 g), with a yield of 85%.

[0143] 1 H-NMR (400MHz, DMSO-d 6): δ11.48(s,1H),8.94(s,1H),8.80(s,1H),7....

Embodiment 2

[0154]

[0155] In step 4 of Example 1, 2-(tert-butoxycarbonylamino)ethyl iodide was replaced by 3-(tert-butoxycarbonylamino)propyl bromide, and the others were the same as in Example 1 to obtain compound 1-2, (E )-N-(3-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-oxyl)propyl)-3-(pyridine-3-substituted)acrylamide.

[0156] MS(EI,m / z):480(M + +1). 1 H-NMR (400MHz, CDCl 3 ): δ8.62(s,1H),8.59(s,2H),8.51(d,J=4.7Hz,1H),7.93(s,1H),7.83(d,J=8.0Hz,1H),7.61 (d,J=8.0Hz,1H),7.51(d,J=15.7Hz,1H),7.47(s,1H),7.34–7.18(m,4H),7.14(s,1H),6.52(d, J=15.7Hz, 1H), 4.09(t, J=6.1Hz, 2H), 3.91(s, 3H), 3.60(q, J=6.0Hz, 2H), 3.02(s, 1H), 2.11–2.05( m,6.0Hz,2H). 13 C NMR (125MHz, CDCl 3 ) Δ165.8,156.7,154.9,153.6,150.4,148.9,147.4,139.1,137.6,130.5,127.7, 125.5, 122.7, 122.7.3,7.3,13.2.3.2.7.3.7, 103.2.3.7,13.2.3.7.6,13.3.2. ,56.1,37.5,28.6.

Embodiment 3

[0158]

[0159] In step 4 of Example 1, 2-(tert-butoxycarbonylamino) ethyl iodide was replaced by 4-(tert-butoxycarbonylamino) butyl bromide, and the others were the same as in Example 1 to obtain compound 1-3, (E )-N-(4-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-oxyl)butyl)-3-(pyridine-3-substituted)acrylamide.

[0160] MS(EI,m / z):494(M + +1). 1 H-NMR (400MHz, CDCl 3 ): δ8.60(s,1H),8.56(s,2H),8.49(d,J=4.7Hz,1H),7.91(s,1H),7.81(d,J=8.0Hz,1H),7.60 (d,J=8.0Hz,1H),7.49(d,J=15.7Hz,1H),7.45(s,1H),7.31–7.15(m,4H),7.12(s,1H),6.50(d, J=15.7Hz, 1H), 4.06(t, J=6.1Hz, 2H), 3.88(s, 3H), 3.60(q, J=6.0Hz, 2H), 3.02(s, 1H), 2.13–2.07( m,4H). 13 C NMR (125MHz, CDCl 3 )δ165.3, 156.3, 154.6, 153.3, 150.1, 148.6, 148.0, 147.2, 139.0, 137.3, 134.2, 130.3, 128.7, 127.5, 125.3, 123.5, 122.7, 122.6, 109.2, 107.5, 103.2 ,37.6,29.7,28.7.

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Abstract

The invention belongs to the field of chemical medicine, and discloses a benzo nitrogen hetero-aromatic ring compound represented by formula I, or pharmaceutically acceptable salts, stereisomers, racemic compounds, prodrugs, or solvates thereof. The invention also discloses applications of the benzo nitrogen hetero-aromatic ring compound in preparation of drugs used for treating diseases caused byprotein kinase and / or nicotinamide phosphoribosyltransferase abnormal activity. The benzo nitrogen hetero-aromatic ring compound represented by formula I or the salts thereof possess tyrosine kinaseand Nampt double inhibition effects, can be taken as effective components in treatment or prevention of tumor, are excellent in curative effect, and low in toxic or side effect.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and relates to a benzoazepine aromatic ring compound, a preparation method and application thereof, a pharmaceutical composition containing the compound and the application thereof. Background technique [0002] Some malignant tumors, such as lung cancer, liver cancer, rectal cancer and leukemia, have become one of the most important factors that seriously endanger people's life happiness and affect residents' health index because of their difficult early detection, early diagnosis and early treatment. As far as the current status of cancer treatment is concerned, the overall treatment effect is poor. Therefore, the development of targeted therapeutic drugs is an urgent scientific research problem that researchers need to solve. In recent years, although some new targeted new drugs such as tyrosine protein kinase inhibitors have been developed and marketed, they are far from meeting the gro...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/517A61P35/00A61P35/02
CPCC07D401/12
Inventor 蒋晟涂正超郝海平姚毅武邱亚涛姚和权强磊陈东
Owner CHINA PHARM UNIV
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