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Pyridine compounds containing triazole keto-amide and orazamide structures and application of pyridine compounds

A technology of triazolone amide and imidazole amide, which is applied in the field of pyridine compounds and their pharmaceutically acceptable salts, can solve the problem of unsatisfactory clinical treatment effect and pharmacokinetic parameters, large toxic and side effects, and poor oral bioavailability. higher question

Pending Publication Date: 2022-02-01
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are mainly the following problems in the research of c-Met inhibitors: the clinical application has relatively high toxicity and side effects, the clinical treatment effect and pharmacokinetic parameters are not ideal, and the oral bioavailability is not high.

Method used

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  • Pyridine compounds containing triazole keto-amide and orazamide structures and application of pyridine compounds
  • Pyridine compounds containing triazole keto-amide and orazamide structures and application of pyridine compounds
  • Pyridine compounds containing triazole keto-amide and orazamide structures and application of pyridine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(2-fluorophenyl)-4-methyl Preparation of yl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (compound 1)

[0049]

[0050] Step 1 N-(4-chloropyridin-2-yl)cyclopropylformamide (a)

[0051] 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...

Embodiment 2

[0067] Example 2: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(2-bromophenyl)-4-methyl Dihydro-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (Compound 2)

[0068]

[0069] 1 H NMR (600MHz, DMSO-d 6 )δ11.05(s,1H),10.89(s,1H),8.22(d,J=5.5Hz,1H),7.95(d,J=12.8Hz,1H),7.88(d,J=7.9Hz, 1H), 7.73(d, J=8.6Hz, 1H), 7.70–7.56(m, 3H), 7.52(t, J=7.6Hz, 1H), 7.40(t, J=8.9Hz, 1H), 6.74( d,J=4.8Hz, 1H), 3.56(s,3H), 2.13–1.86(m,1H), 0.77(d,J=5.7Hz, 4H).

Embodiment 3

[0070] Example 3: 2: N-(4-{[2-(cyclopropanecarboxamido)pyridin-4-yl]oxy}-3-fluorophenyl)-1-(2-methoxyphenyl) -4-Methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide (compound 3)

[0071]

[0072] 1 H NMR (600MHz, DMSO-d 6 )δ10.97(s,1H),10.89(s,1H),8.22(d,J=5.5Hz,1H),7.94(d,J=12.5Hz,1H),7.72(d,J=8.5Hz, 1H), 7.64(s, 1H), 7.53(t, J=7.6Hz, 1H), 7.48–7.33(m, 2H), 7.25(d, J=8.2Hz, 1H), 7.10(t, J=7.4 Hz,1H),6.74(d,J=3.5Hz,1H),3.81(s,3H),3.53(s,3H),2.02–1.92(m,1H),0.77(d,J=5.7Hz,4H ); MS (ESI) m / z (%): 519.2 [M+H] + .

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Abstract

The invention relates to pyridine compounds containing triazole keto-amide and orazamide structures and application of the pyridine compounds. The pyridine compounds containing the triazole keto-amide and orazamide structures have structures as shown in a general formula (I). The compounds have a strong effect of inhibiting c-Met kinase. The invention further relates to application of the compounds and pharmaceutically acceptable salts thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase, especially to application of the compounds and the pharmaceutically acceptable salts in preparation of medicines for treating and / or preventing cancers.

Description

technical field [0001] The present invention relates to pyridine compounds containing triazolone amide and imidazolamide structures represented by general formula (I) and their pharmaceutically acceptable salts, their preparation methods and pharmaceutical compositions containing the compounds. The present invention also relates to the use of the compounds and their pharmaceutically acceptable salts in the preparation of medicines for treating diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of medicines for treating and / or preventing cancer. Background technique [0002] Cancer generally refers to all malignant tumors. Cancer has always been a huge threat to human health. Statistics from the World Health Organization show that in 2020, 10 million people will die of cancer worldwide. What is even more heartbreaking is that about 400,000 children are diagnosed with cancer every year. cancer. One in five people will develop cancer i...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P35/00A61K31/4439
CPCC07D401/12A61P35/00
Inventor 刘举陈烨丁实李春艳沈继伟刘放田璐温迪吴爽李振张荠芳赵乐妍
Owner LIAONING UNIVERSITY
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