Aryl kinase inhibitor

An alkyl and amino technology, applied in the field of aryl kinase inhibitors, can solve problems such as malignant transformation

Inactive Publication Date: 2013-05-08
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The analysis of these fusion genes shows that they all contain the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, and the gene fragments fused with ALK all contain prom...

Method used

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Examples

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preparation example Construction

[0130] The present invention also provides the preparation method of above-mentioned compound, but not limited to following method, and reaction equation is as follows:

[0131] when for hour,

[0132]

[0133] Reaction steps:

[0134] Step 1 Preparation of intermediate 1 and intermediate 2

[0135] Prepared with reference to US2008 / 300273A1 literature.

[0136] The preparation of step 2 intermediate 3

[0137] Dissolve intermediate 1 and an equivalent amount of intermediate 2 in an appropriate amount of N, N-dimethylformamide, and add catalyst Pd (PPh 3 ) 4 1. Organic solvent (such as ethanol and toluene, water), react at 80°C until the raw materials disappear, add water after cooling down, then extract, filter with suction, and use HPLC to separate and purify to obtain intermediate 3.

[0138] Step 3 Preparation of Compound I' of the present invention

[0139] Intermediate 3 was dissolved in dioxane of saturated hydrochloric acid, stirred for 1 hour, the solvent...

Embodiment 1N

[0168] Example 1N 3 -(1-(2,6-dichloro-3-fluorophenyl)ethyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-2,3 - diamine (Compound 1) Preparation of Hydrochloride

[0169] (1) tert-butyl 4-hydroxypiperidine-1-carboxylate

[0170]

[0171] Dissolve tert-butyl 4-oxopiperidine-1-formyl ester (19.9g, 99.9mmol) in methanol (1000mL), cool in an ice-water bath, add sodium borohydride (5.7g, 0.15mol), and Stir for 10 hours, remove methanol by rotary evaporation, add water (250 mL), extract with ethyl acetate, concentrate and dry under reduced pressure to obtain the product (20 g, yield 99%).

[0172] (2) tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate

[0173]

[0174] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (20.1 g, 0.1 mol) and N, N-diisopropylethylamine (15 mL) were dissolved in dichloromethane, and methanesulfonyl chloride ( 17.1 g, 0.15 mol), stirred at room temperature for 3 hours. After the reaction was completed, it was filtered, and ...

Embodiment 23

[0198] Example 23-(1-(2,6-dichloro-3-fluorophenyl)ethylthio)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine -2-amine ( Compound 2) Preparation

[0199] (1) 1-(2,6-dichloro-3-fluorophenyl)ethanol

[0200]

[0201] Dissolve 1-(2,6-dichloro-3-fluorophenyl)ethanone (20.7g, 0.1mol) in methanol (1000mL), cool in an ice-water bath, add sodium borohydride (5.7g, 0.15mol), Stir for 10 hours, remove the organic solvent by rotary evaporation, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and remove the organic solvent by rotary evaporation (20.9 g, yield 100%).

[0202] (2) (2-(1-bromoethyl)-1,3-dichloro-4-fluorobenzene

[0203]

[0204] 1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9g, 0.1mol) was dissolved in hydrobromic acid (100mL), refluxed for 3 hours, cooled to room temperature, extracted with ethyl acetate, and the combined The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to...

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PUM

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Abstract

The invention belongs to the technical field of medicines, in particular to an aryl kinase inhibitor represented by the general formula (I), pharmaceutically acceptable salts or stereisomers thereof, wherein R1, R2, R3, m, n, R5, Y, W, M, L or Q are defined in the specification. The invention further relates to a preparation method of the compounds, pharmaceutical preparations or pharmaceutical compositions comprising the compounds, and an application of the compounds for preparing medicines for treating and/or preventing ALK or c-Met mediated cancer related diseases.

Description

1. Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to aryl kinase inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations or pharmaceutical compositions containing these compounds, and the use of these compounds in Application in preparation of medicines for treating and / or preventing cancer-related diseases mediated by ALK or c-Met. 2. Background technology [0002] Anaplastic Lymphoma Kinase (ALK) is a member of the receptor tyrosine kinase family, which can recruit downstream proteins through autophosphorylation, and then express specific genes to regulate cell metabolism and growth. [0003] Anaplastic lymphoma kinase was first discovered in ALCL (Anaplastic large cell lymphoma), which is an independent type of non-Hodgkin's lymphoma (NHL). In the latest WHO classification, ALCL is classified as peripheral T-cell lymphoma ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D213/74C07D401/04A61K31/4545A61K31/496A61K31/4439A61P35/00A61P17/00A61P13/08
Inventor 刘兆贵
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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