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4-phenoxy pyridine derivative containing 3-pyridazinone structure, 4-pyridazinone structure and 1,2,4-triazinone structure, and applications thereof.

A phenoxypyridine and pyridazinone technology, which is applied in the directions of medical preparations containing active ingredients, drug combinations, active ingredients of heterocyclic compounds, etc., can solve the problem of low oral bioavailability, large toxic and side effects, and clinical treatment Problems such as unsatisfactory effects and pharmacokinetic parameters

Inactive Publication Date: 2020-01-14
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are mainly the following problems in the research of c-Met inhibitors: high toxicity and side effects in clinical application, unsatisfactory clinical treatment effect and pharmacokinetic parameters, low oral bioavailability, etc.

Method used

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  • 4-phenoxy pyridine derivative containing 3-pyridazinone structure, 4-pyridazinone structure and 1,2,4-triazinone structure, and applications thereof.
  • 4-phenoxy pyridine derivative containing 3-pyridazinone structure, 4-pyridazinone structure and 1,2,4-triazinone structure, and applications thereof.
  • 4-phenoxy pyridine derivative containing 3-pyridazinone structure, 4-pyridazinone structure and 1,2,4-triazinone structure, and applications thereof.

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-4-methyl-6-oxo-1-benzene Preparation of 1,6-dihydropyridazine-3-carboxamide (Compound 1)

[0063]

[0064] Step 1 N-(4-chloropyridin-2-yl)cyclopropylformamide (a)

[0065] 8.80g of 2-amino4-chloropyridine and 20.80g of triethylamine were dissolved in 80mL of dichloromethane, and 30mL of dichloromethane solution containing 9.30g of cyclopropylformyl chloride was added dropwise to the solution under ice-bath conditions. Warm up to room temperature after the addition is complete. Stirred for 12h, after the completion of the reaction, the mixture was washed with 20% K 2 CO 3 solution and saturated brine were washed 3 times respectively, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain a crude product, which was separated by column chromatography to obtain a white solid N-(4-chloropyridin-2-yl) Cyclopropylfor...

Embodiment 2

[0079] Example 2: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-4-methyl-6-oxo-1-( 4-fluorophenyl)-1,6-dihydropyridazine-3-carboxamide (Compound 2)

[0080]

[0081] 1 H NMR (600MHz, CDCl 3 )δ8.92(s,1H),8.64(s,1H),8.12(d,J=5.7Hz,1H),7.82–7.68(m,2H),7.60(dd,J=8.8,4.7Hz,2H ),7.26–7.18(m,3H),7.14(t,J=8.6Hz,1H),6.91(s,1H),6.64(dd,J=5.7,2.2Hz,1H),2.66(s,3H) ,1.57–1.45(m,1H),1.11–0.97(m,2H),0.93–0.79(m,2H); MS(ESI)m / z(%):518.1[M+H] + ,540.1[M+Na] + .

Embodiment 3

[0082] Example 3: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-4-methyl-6-oxo-1-( 4-Chlorophenyl)-1,6-dihydropyridazine-3-carboxamide (Compound 3)

[0083]

[0084] 1 H NMR (600MHz, CDCl 3 )δ8.89(s,1H),8.44(s,1H),8.12(d,J=5.8Hz,1H),7.82–7.66(m,2H),7.59(d,J=8.8Hz,2H), 7.50(d, J=8.8Hz, 2H), 7.24(s, 1H), 7.15(t, J=8.6Hz, 1H), 6.92(t, J=7.4Hz, 1H), 6.63(m, 1H), 2.66(s,3H),1.55–1.43(m,1H),1.07–1.00(m,2H),0.89–0.81(m,2H); MS(ESI)m / z(%):534.1[M+H ] + ,556.1[M+Na] + .

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PUM

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Abstract

The invention relates to a 4-phenoxy pyridine derivative containing a 3-pyridazinone structure, a 4-pyridazinone structure and a 1,2,4-triazinone structure, and applications thereof. According to theinvention, the 4-phenoxy pyridine derivative has a structure represented by a general formula (I), and the compound has strong inhibiting effect on c-Met kinase. The invention further relates to applications of the compound, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase, especially in preparation of drugs for treating and / or preventing cancers.

Description

technical field [0001] The present invention relates to 4-phenoxypyridine derivatives containing 3-pyridazinone, 4-pyridazinone and 1,2,4-triazone structures represented by general formula (I) and their pharmaceutically acceptable Salts, hydrates, solvates or prodrugs, processes for their preparation and pharmaceutical compositions containing said compounds. The present invention also relates to the use of such compounds and their pharmaceutically acceptable salts, hydrates, solvates or their prodrugs in the preparation of medicines for the treatment of diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of medicines for the treatment of and / or use in preventive cancer drugs. Background technique [0002] Cancer generally refers to all malignant tumors. It is a major and intractable disease that threatens human life and health. Its mortality rate even exceeds that of cardiovascular and cerebrovascular diseases, ranking first among al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/501A61K31/53A61P35/00
CPCC07D401/12A61P35/00
Inventor 刘举陈烨李春艳丁实宫益林史建涛郝雪晨王震杨亚星
Owner LIAONING UNIVERSITY
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