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Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound

A compound and mixture technology, applied in the field of new nitrogen heterocyclic compounds, can solve problems such as the listing of inhibitors, and achieve good inhibitory effect and good pharmacokinetic effect.

Pending Publication Date: 2020-08-04
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no inhibitors with RET as the main target are currently on the market.

Method used

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  • Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound
  • Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound
  • Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0410] Example 1: 2-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-N-(1-(4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)acetamide (compound 1)

[0411]

[0412] The first step: 2-(6-iodopyridin-3-yl) methyl acetate (1b)

[0413] Compound 1a (2g, 10.78mmol), acetyl chloride (1.28g, 16.16mmol), and sodium iodide (20.04g, 107.75mmol) were added to acetonitrile (50mL), heated to 80°C for 16h, and cooled to room temperature after the reaction . The reaction solution was concentrated to dryness to obtain compound 1b (2.8 g).

[0414] MS (ESI, m / z): 278.0 [M+H] + .

[0415] The second step: methyl 2-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)acetate (1d)

[0416] Compound 1b (0.4g, 1.44mmol), 4-fluoropyrazole (186.39mg, 2.17mmol), salicylaldoxime 1c (39.60mg, 288.75μmol), cuprous oxide (20.6mg, 144μmol) and cesium carbonate (941.32mg , 2.89mmol) was placed in a reaction flask, acetonitrile (10mL) was added, and the reaction was carried out at 80°C for ...

Embodiment 2

[0434] Example 2: 2-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-N-(1-(4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)propionamide (Compound 2)

[0435]

[0436] The first step: methyl 2-(6-chloropyridin-3-yl)propionate (2a)

[0437] Compound 1a (2.04g, 10.78mmol) was dissolved in THF (30mL), cooled to -78°C, and 4.74mL of 2.5Mn-BuLi in THF was slowly added under nitrogen protection and stirred for 30min, then MeI (15.61g, 107.75mmol), and then reacted for 12h. After the reaction was completed, it was raised to room temperature, and 100 mL of saturated NH 4 Cl solution, extracted with EA (100 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and then separated and purified by silica gel column chromatography (PE:EA=10:1-1:1) to obtain compound 2a (1.1 g).

[0438] MS m / z(ESI): 200.1[M+H] + .

[0439] The second step: methyl 2-(6-iodopyridin-3-yl)propionate (2b)

[0440] Compound 2...

Embodiment 3

[0452] Example 3: 2-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)-N-(1-(4-methyl-6-((5-methyl Base-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)propionamide (compound 3)

[0453]

[0454] The first step: methyl 2-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)propionate (3b)

[0455] Compound 2a (200 mg, 901.65 μmol) was dissolved in dioxane (10 mL), and compound 3a (246.29 mg, 1.08 mmol), K 2 CO 3 (253.93 mg, 1.80 mmol) and water (2 mL), and finally Pd(dppf)Cl 2 · DCM (150.15 mg, 180.33 μmol), heated to 90° C. for 4 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature, diluted with 50 mL of water, and extracted with EA (40 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain compound 3b (185 mg).

[0456] MSm / z(ESI): 261.1[M+H] + .

[0457] The second step: 2-(6-(3,5-dimethylisoxazol-...

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PUM

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Abstract

Disclosed are a nitrogen heterocyclic compound represented by a formula (I), a pharmaceutical composition comprising the same, and a preparation method and use of the nitrogen heterocyclic compound, and in particular, relates to the use of the nitrogen heterocyclic compound for prevention or treatment of diseases or conditions associated with RET activity.

Description

technical field [0001] The present invention relates to novel nitrogen heterocyclic compounds, pharmaceutical compositions containing them, processes for their preparation and their use in the prevention or treatment of diseases or conditions associated with RET activity. Background technique [0002] Protein kinase is an enzyme that catalyzes the phosphorylation of proteins. By mediating the process of cell signal transduction, protein phosphorylation regulates the physiological activities of cells, such as cell survival, proliferation, differentiation, apoptosis and metabolism. Dysregulation of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes. [0003] RET (Rearranged during transfection) is a proto-oncogene, and its encoded RET protein is a transmembrane receptor-type tyrosine protein kinase, composed of a cysteine-rich cadherin-like e...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14C07D417/14A61P35/00A61K31/506A61K31/5377
CPCC07D401/14C07D413/14C07D417/14A61P35/00Y02P20/55
Inventor 李桂英韩润丰陈忠辉孙启正韩晓军冉茂盛田强宋宏梅薛彤彤王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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