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Pyrazolo[1, 5-a]pyridine compound, and preparation method and application thereof

A technology of compounds and hydrates, applied in the fields of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve problems such as difficulty in exerting curative effect and high risk of off-target toxicity

Pending Publication Date: 2021-06-11
SHENZHEN ZHONGGE BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, due to the large homology between RET and the kinase domain of VEGFR2, these compounds not only inhibit RET, but also have a certain inhibitory effect on multiple targets including VEGFR2, which leads to a high risk of off-target toxicity and it is difficult to exert the inhibitory effect. Satisfactory curative effect

Method used

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  • Pyrazolo[1, 5-a]pyridine compound, and preparation method and application thereof
  • Pyrazolo[1, 5-a]pyridine compound, and preparation method and application thereof
  • Pyrazolo[1, 5-a]pyridine compound, and preparation method and application thereof

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[0172] The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.

[0173] The present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.

[0174] The present invention has the following main advantages:

[0175] (1) The compound of the present invention has excellent inhibitory ability to RET kinase, and has excellent selectivity to RET kinase, and has low inhibitory activity to other kinases su...

Embodiment 1

[0259] The synthesis of embodiment 1 compound 1

[0260]

[0261] Step 1: Synthesis of ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)H-pyrazolo[1,5-a]pyridine-3-carboxylate

[0262] Ethyl 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carboxylate (400mg, 1.4mmol) was mixed with 1-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (351 mg, 1.7 mmol) was dissolved in dioxane:water=(3:1, 20 mL), Then add Pd(PPh 3 ) 4 (145mg, 0.14mmol) and sodium carbonate (450mg, 4.2mmol), under nitrogen protection, stirred overnight at 85°C, after the reaction was complete, water was added to quench the reaction, the organic phase was separated, washed with water, dried, and column chromatography (PE:EA= 1:1), to obtain ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)H-pyrazolo[1,5-a]pyridine-3-carboxylate 250mg, received rate of 62%. MS m / z(ESI): 287.4[M+H] + .

[0263] Step 2: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(trifluoromethylsulfonyloxy)H-pyrazolo[1,5-a]pyridine-3-carboxy ethy...

Embodiment 2

[0268] Embodiment 2: the synthesis of compound 2

[0269]

[0270] Step 1: 6-Bromo-4-methoxyH-pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0271] At room temperature, ethyl 6-bromo-4-methoxy H-pyrazolo[1,5-a]pyridine-3-carboxylate (1.56g, 5.26mmol) was dissolved in THF / MeOH=(1:1, 20 mL), then NaOH (4M, 10 mL) was added, stirred at 50°C for 1 h, the reaction was complete, the organic solvent was concentrated under reduced pressure, acidified with hydrochloric acid to pH=2-3, stirred at 0°C for 0.5 h, the solid was filtered, washed with water, concentrated, 1.3 g of 6-bromo-4-methoxy H-pyrazolo[1,5-a]pyridine-3-carboxylic acid was obtained with a yield of 92%, MS m / z (ESI): 268.9[M-H]+.

[0272] Step 2: 6-Bromo-4-methoxyH-pyrazolo[1,5-a]pyridine-3-carbonyl chloride

[0273] Under nitrogen protection, 6-bromo-4-methoxy H-pyrazolo[1,5-a]pyridine-3-carboxylic acid (400 mg, 1.48 mmol) was dissolved in 20 (mL) DCM and cooled to 0 °C, add oxalyl chloride (282 mg, 2.22 mmol) and 1...

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Abstract

The invention relates to a pyrazolo[1, 5-a]pyridine compound, a preparation method and application thereof, a pharmaceutical composition containing the compound as an active component, or a pharmaceutically acceptable salt of the compound. The invention further relates to application of the compound of formula (I) in the treatment and prophylaxis of diseases treatable with RET kinase inhibitors, including diseases or conditions mediated by RET kinases.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to pyrazolo[1,5-a]pyridine compounds and their preparation methods and applications. Background technique [0002] Rearranged transfection (RET) kinase is a single transmembrane receptor tyrosine kinase that plays an important role in the development of the kidney and enteric nervous system, and the maintenance of homeostasis in the nervous, endocrine, hematopoietic, and male reproductive systems. The structure of RET is divided into extracellular region, transmembrane region and intracellular kinase region. Its ligand neurotrophic factor (GDNF) family does not directly bind to RET, but first forms a complex GFL-GFRα with the GDNF family receptor α, and then catalyzes RET homodimerization, making RET autophosphorylated in the intracellular region, This in turn recruits adapter proteins and pathway proteins to activate multiple signaling pathways including MAPK, PI3K, JAK-STAT, ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61P35/00A61K31/496A61K31/4995A61K31/5386A61K31/55
CPCC07D471/04C07D519/00A61P35/00
Inventor 程辉敏方磊温晓明刘志强陈誉马松龄陈萍齐珍珍牛春意张佩宇赖力鹏马健温书豪
Owner SHENZHEN ZHONGGE BIOLOGICAL TECH CO LTD
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