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Pyrazolo[1,5-a]pyridine derivatives as well as preparation method and application thereof

A compound, selected technology, applied in the field of medicine

Inactive Publication Date: 2020-09-08
CLUES THERAPEUTICS SHANGHAI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still problems in the effectiveness, safety or selectivity of the compounds and experimental drugs disclosed in these prior art. In addition, the current understanding of the role of RET in tumors is also deepening, and it is still necessary to study And develop new small molecule selective RET kinase inhibitors to fill and meet clinical treatment needs for RET abnormal diseases

Method used

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  • Pyrazolo[1,5-a]pyridine derivatives as well as preparation method and application thereof
  • Pyrazolo[1,5-a]pyridine derivatives as well as preparation method and application thereof
  • Pyrazolo[1,5-a]pyridine derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] 4-(1'-((6-methoxypyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-5-yl)-6-( 1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0159] 4-(1'-((6-methoxypyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-dipyridine]-5- Base)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 1

[0160]

[0161] first step

[0162] tert-butyl 5-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0163] tert-butyl 5-bromo-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate 1c

[0164] tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-methanol Ester 1a (5g, 16.18mmol, prepared by the method disclosed in the patent application "WO2003092686") was added to a 250mL three-necked flask, and 5-bromo-2-iodopyridine 1b (4.58g, 16.18mmol), dioxygen Hexacyclic (162 mL), water (20 mL), sodium carbonate (5.15 g, 48.54 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.18 g, 1.62 mmol) , the...

Embodiment 2

[0189] 6-(2-hydroxy-2-methylpropoxy)-4-(1'-((6-methoxypyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[2,4' -bipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0190] 6-(2-Hydroxy-2-methylpropoxy)-4-(1'-((6-methoxypyridin-3-yl)methyl)-1',2',3',6' -tetrahydro-[2,4'-dipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2

[0191]

[0192] first step

[0193] 4-(6-chloropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0194] 4-(6-Chloropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 2c

[0195] 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile 2a (1.6g, 5.12mmol, using patent application "WO2018071447" Prepared by the disclosed method) into a 100mL three-neck flask, followed by adding 35mL N,N-dimethylformamide, 2-chloropyridine-5-boronic acid pinacol ester 2b (1.6g, 6.7mmol), potassium phosphate (5.7g, 27.1mmol) and tetrakis(triphenylphosphine)palladium (0.295g, 0.26mmol), t...

Embodiment 3

[0215]6-(2-hydroxy-2-methylpropoxy)-4-(1'-((5-methoxypyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4' -bipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0216] 6-(2-Hydroxy-2-methylpropoxy)-4-(1'-((5-methoxypyridin-2-yl)methyl)-1',2',3',6' -tetrahydro-[2,4'-dipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0217]

[0218] first step

[0219] 6-(2-hydroxy-2-methylpropoxy)-4-(1'-((5-methoxypyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4' -bipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0220] 6-(2-Hydroxy-2-methylpropoxy)-4-(1'-((5-methoxypyridin-2-yl)methyl)-1',2',3',6' -tetrahydro-[2,4'-dipyridin]-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 3

[0221] 6-(2-hydroxy-2-methylpropoxy)-4-(1',2',3',6'-tetrahydro-[2,4'-dipyridinyl)-5-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile hydrochloride 2f (78mg, 0.175mmol) was added to a 10mL three-necked flask, followed by adding 3mL of acetonitrile, triethylamine (202mg, 2mmol), (5-methyl Oxypyridin-2-yl)...

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Abstract

The invention relates to pyrazolo[1,5-a]pyridine derivatives as well as a preparation method and medical application thereof. Specifically, the invention relates to the pyrazolo[1,5-a]pyridine derivatives represented by a general formula (I), and the preparation method and pharmaceutically acceptable salts thereof, and the application of the pyrazolo[1,5-a]pyridine derivatives as therapeutic agents, especially RET inhibitors, wherein the definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a pyrazolo[1,5-a]pyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its therapeutic agent, especially as a RET protein kinase inhibitor use. Background technique [0002] RET protein (Rerranged during Transfection, rearranged during transfection) belongs to the receptor tyrosine kinase family, as a receptor for nerve growth factor, its function involves the normal growth and development of the nervous system, cell proliferation and survival. Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL) regulate downstream signaling by binding to RET, and the GFL family also includes neurturin (NTRN), artemin (ARTN) and persephin ( PSPN) (Arighi et al., Cytokine Growth Factor rev., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET activation requires ligands, GDNF family receptor α proteins and RET proteins t...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61P35/00A61K31/444
CPCC07D471/04C07D519/00A61P35/00
Inventor 郑苏欣王中利张建平刘俊安泉林赵雯雯
Owner CLUES THERAPEUTICS SHANGHAI LTD
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