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Pyrazolopyridine compound or salt thereof as well as preparation method and application of pyrazolopyridine compound or salt thereof

A compound, C1-C6 technology, applied in the field of chemical medicine, can solve the problem of limited treatment options for patients

Pending Publication Date: 2022-03-15
SHANGHAI LITEDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And once drug resistance develops, treatment options for patients will become very limited

Method used

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  • Pyrazolopyridine compound or salt thereof as well as preparation method and application of pyrazolopyridine compound or salt thereof
  • Pyrazolopyridine compound or salt thereof as well as preparation method and application of pyrazolopyridine compound or salt thereof
  • Pyrazolopyridine compound or salt thereof as well as preparation method and application of pyrazolopyridine compound or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] Example 1: 3- (3-cyano-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-a] pyridine-4-yl) -N- (((6- (4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) methyl) -1-methyl-1H-pyrazole-5-formamide (compound 1) synthesis

[0225]

[0226] Step 1: 3-cyano-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-A] pyridine-4-ylifluoromethanesulfonate synthesis

[0227] 4-hydroxy-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-A] pyridine-3-methitrile (500 mg, 2.09 mmol) and TEA (0.581 ml, 4.18 mmol Add to DCM (10.0ml). Under nitrogen protection, trifluoromethanesulfonic anhydride (0.520 mL, 3.14 mmol) was added dropwise to the reaction liquid under an ice bath. After the dropwise addition, the reaction mixture continued to be stirred under an ice bath for 1.5 hours. The organic solvent was concentrated under reduced pressure to give a target compound (600 mg, crude, black oil). LC-MS (ESI) M / Z 370.0 [M-H] - .

[0228]Step 2: 3- (3-cyano-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-a] pyridine-4-yl) -1-...

Embodiment 2

[0234] Example 2: 3- (3-cyano-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-a] pyridine-4-yl) -N- ((6- (4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) methyl) -1H-pyrazole-5-formamide (compound 2) synthesis

[0235]

[0236] Step 1: Synthesis of 3-hydroxy-1- (4-methoxybenzyl) -1H-pyrazole-5-formate

[0237] (4-methoxyzyl) hydrazine hydrochloride (2.46 g, 14.1 mmol) and TEA (4.40 mL, 31.7 mmol) were added to a mixed solvent of water (10.0 mL) and methanol (20.0 mL). The reaction mixture was stirred at 0 ° C for 15 minutes, dimethyl butarcidate (2.00 g, 14.1 mmol) was added. The reaction mixture was stirred at 80 ° C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was added to water (30.0 mL), filtered, and the filter cake washed with water (10.0 mL). The filter cake was dried under vacuum (2.70 g, yield 73.2%, yellow solid). LC-MS (ESI) M / Z 263.0 [M + H] + .

[0238] Step 2: 1- (4-methoxy) -3 - (((trifluoromethyl...

Embodiment 3

[0250] Example 3: 4- (3-cyano-6- (1-methyl-1H-pyrazole-4-yl) pyrazole [1,5-a] pyridine-4-yl) -N- ((6- (4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) methyl) piperazine-1-formamide (compound 3) and hydrochloride thereof (compound) 3-1) synthesis

[0251]

[0252] Step 1: 4- (5-bromipate-3-yl) synthesis of tert-butylpirazine-1-formate

[0253] Potassium carbonate (7.85) is added to 3-bromine-5-fluoropyridine (5.00 g, 28.4 mmol) and tert-methylpyrrolidone (50.0 ml) solution (7.94 g, 42.6 mmol) solution (7.85) G, 56.8 mmol). The reaction mixture was stirred at 100 ° C for 16 hours, and the reaction was continued at 120 ° C for 5 hours. The reaction mixture was poured into water (100 mL), extracted with EA (250 mL). The organic phase was washed with saturated brine (50.0 ml × 3), dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain a crude product. Purification was separated from column chromatography (PE: EA = 20: 1-10: 1) obtained the tar...

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Abstract

The invention relates to pyrazolopyridine compounds or salts thereof as well as a preparation method and application of the pyrazolopyridine compounds or the salts thereof, in particular to compounds shown in a formula (I) or stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts or solvates of the compounds, wherein R1, R2, R3, R4, R5, rings A, B, m and n of the compounds are as defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of drugs for treating or preventing RET-related diseases.

Description

Technical field [0001] The present invention belongs to the field of chemical medicine, and more particularly to a pyrazole pair compound having RET inhibitory activity and a preparation method thereof and a pharmaceutical composition containing the compound, and also relates to the pyrazolopyridine compound in preparing prevention or treatment. Use of RET related diseases. Background technique [0002] RET (REARRANGED DURING TRANSFECTION) protein is a receptor tyrosine kinase (RTK), but also a micro-membrane, expressed by a raw carcinogen gene RET on chromosome, in chromosome, in the kidneys and intestines in embryos The development of the nervous system plays an important role in various tissues, such as neurons, neuroendocrine, hematopoietic tissue, and male germ cells. Unlike other receptor tyrosine kinases, RET is not directly incorporated into ligand molecules: such as neurodeemin, colloidal cellular neurotropic factor (GDNF), nerve growth factor (NGF), these It is a GNDF f...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/444A61K31/496A61K31/4545A61K31/5377A61P35/00A61P35/02
CPCC07D471/04C07D519/00A61P35/00A61P35/02A61K31/444A61K31/4545A61K31/496A61K31/5377A61P29/00A61K31/437
Inventor 程耀邦王永辉董志强周娟
Owner SHANGHAI LITEDD CO LTD
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