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A class of 3-amino-benzo five-membered heterocyclic compound and its preparation method and use

A five-membered heterocycle and compound technology, applied in the field of 3-amino-benzo five-membered heterocycle compounds, can solve the problems of weakening the direct relationship and the like

Inactive Publication Date: 2017-09-26
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although, many of the reported small molecule inhibitors exhibit high c-Met activity, and have shown good anti-tumor activity in vivo and in vitro; however, most of the small molecule inhibitors of c-Met in clinical research Also has significant inhibitory activity against other tyrosine kinases, this multiple pharmacological profile weakens the direct relationship between the evaluation of the antitumor effect of these inhibitors and c-Met activity

Method used

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  • A class of 3-amino-benzo five-membered heterocyclic compound and its preparation method and use
  • A class of 3-amino-benzo five-membered heterocyclic compound and its preparation method and use
  • A class of 3-amino-benzo five-membered heterocyclic compound and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0055] General formula for the preparation of compounds IA-1 to IA-19

[0056]

[0057] Compound 1 (its synthesis reference Ji ZQ et al, J Med Chem2008, 51:1231-1241) (1equiv) and various acids 2 (its synthesis reference WO:2005 / 030140A2) (1equiv) were mixed, and an appropriate amount Dissolve in dichloromethane (DCM) or dimethyl sulfoxide (DMF), stir at 0°C, add HATU (1.8equiv), stir for 5min, then add triethylamine (TEA) (1equiv), stir for 5min, then warm to room temperature Stir overnight. After the reaction was monitored by TLC, the reaction solution was diluted with dichloromethane or ethyl acetate, the organic layer was washed 3 times with water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (0-10% Methanol: dichloromethane) to obtain the target product IA. Table 1. The corresponding structural formulas of the raw materials 2a–2s for the synthesis of compound IA

[0058]

preparation Embodiment 1

[0059] Preparation Example 1: Preparation of compound IA-1

[0060]

[0061] Mix compound 1 (40mg, 0.178mmol) with acid 2a (40mg, 0.178mmol), dissolve with 3mL of dichloromethane, stir at 0°C, add HATU (122mg, 0.32mmol), stir for 5min, then add triethylamine ( 25μL, 0.178mmol), after stirring for 5min, warm to room temperature and stir overnight. After the reaction was monitored by TLC, the reaction solution was diluted by adding 40 mL of dichloromethane, the organic layer was washed with water (3×20 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography ( 0-30% methanol: dichloromethane) to obtain the target product IA-1 as a white solid (55 mg, 72%).

[0062] 1 H NMR(300MHz, CDC1 3 )δ9.63(s,1H), 8.77(s,1H), 7.69(d,J=8.5Hz,2H), 7.58–7.44(m,5H), 7.40(d,J=8.4Hz,1H), 7.16–6.98(m,3H), 4.18(s,2H), 1.77–1.62(m,4H).

preparation Embodiment 2

[0063] Preparation Example 2: Preparation of Compound IA-2

[0064] Except for using the corresponding acid 2b, IA-2 was synthesized using the same method as IA-1, a white solid (74%).

[0065] 1 H-NMR (300MHz, CDC1 3 )δ10.11(s,1H),8.08(s,1H),7.71(d,J=8.7Hz,2H),7.55-7.34(m,6H),7.11(d,J=7.2Hz,1H), 6.89(d,J=8.9Hz,2H),4.15(s,2H),3.80(s,3H),1.79(dd,J=7.6,4.8Hz,2H),1.62–1.58(dd,J=7.6, 4.8Hz, 2H).

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Abstract

The present invention provides a 3-amino-benzo five-membered heterocyclic compound having a structure shown in general formula (I), and a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a preparation method thereof, And in the preparation of the medicine for inhibiting the activity of tyrosine kinase c-Met; in the preparation of the abnormal proliferation and morphological changes of cells related to the hepatocyte growth factor receptor (c-Met) in the living body As well as the use in medicines for diseases related to hyperkinesia and diseases related to angiogenesis or cancer metastasis, especially in the preparation of medicines for treating or preventing tumor growth and metastasis. The present invention realizes the separation of c-Met and VEGFR2 activities of target compounds, and they retain better c-Met inhibitory activity.

Description

Technical field [0001] The present invention relates to a class of 3-amino-benzo five-membered heterocyclic compounds, and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, and pharmaceutical compositions containing the compounds, and preparation methods thereof. The present invention also relates to the preparation of such compounds for inhibiting the activity of tyrosine kinase c-Met, preventing or treating abnormal cell proliferation, morphological changes and motor functions related to hepatocyte growth factor receptor (c-Met) in organisms The use in drugs for diseases related to hyperplasia and diseases related to angiogenesis or cancer metastasis, especially for the preparation of drugs for treating or preventing tumor growth and metastasis. Background technique [0002] The receptor tyrosine kinase c-Met belongs to a unique subfamily of the receptor tyrosine kinase family. It is the exclusive receptor of hepatocyte growth factor (HGF) or sc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/20C07D413/12C07D413/14C07D231/56C07D401/12A61K31/423A61K31/454A61K31/496A61K31/416A61K31/4439A61P35/00A61P35/04
Inventor 张翱耿美玉蒋晓龙艾菁彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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