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Spiro aryl phosphorus oxide or sulfide

A compound and alkyl technology, applied in the field of spirocyclic aryl phosphorus oxides or sulfides as ALK inhibitors, can solve problems such as unsatisfactory curative effect and drug loss of effectiveness

Active Publication Date: 2016-02-17
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, although more than half of NSCLC patients respond well to Crizotinib, drug resistance always develops over time and the drug loses its effectiveness
Although in recent years, ALK inhibitors for the treatment of non-small cell lung cancer have been vigorously developed at home and abroad, but their efficacy is not satisfactory.

Method used

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  • Spiro aryl phosphorus oxide or sulfide
  • Spiro aryl phosphorus oxide or sulfide
  • Spiro aryl phosphorus oxide or sulfide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] (2-((5-chloro-2-((2-methoxy-5-(6-methyl-6-azaspiro[3.4]oct-2-yl)phenyl)amino)pyrimidine-4- base) amino) phenyl) dimethyl phosphine oxide

[0150]

Embodiment 1A

[0152] 1-methoxy-4-vinylbenzene

[0153]

[0154] 1-Bromo-4-methoxybenzene (8.15 g, 43.6 mmol), potassium vinyltrifluoroborate (7.08 g, 52.8 mmol), Pd(dppf)Cl 2 (1.6 g, 2.20 mmol) and cesium carbonate (28.7 g, 88.1 mmol) in 1,4-dioxane (120 mL) and water (25 mL) was heated to 110°C and stirred for 16 hours. TLC showed that the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product; the crude product was separated and purified by column chromatography (PE) to obtain the title compound (yellow oil, 3.45 g, yield 59%).

Embodiment 1B

[0156] 2,2-Dichloro-3-(4-methoxyphenyl)cyclobutanone

[0157]

[0158] A mixture of Example 1A (3.45 g, 9.33 mmol) and copper-zinc reagent (3.18 g, 64.3 mmol) in anhydrous THF (25.0 mL) was heated to reflux, and phosphorus oxychloride (7.78 g, 50.7 mmol) and 2,2,2-trichloroacetyl chloride (8.75 g, 48.1 mmol) in anhydrous THF (25.0 mL) were added dropwise for 1 hour. The reaction mixture was stirred at reflux for 12 hours. TLC (PE) showed that the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily compound (6.0 g, crude product), which was directly used in the next reaction.

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PUM

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Abstract

The invention discloses a spiro aryl phosphorus oxide or sulfide as ALK inhibitor, and in particular discloses a compound shown in a formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof.

Description

field of invention [0001] The present invention relates to a spirocyclic aryl phosphorus oxide or sulfide as an ALK inhibitor. In particular, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof as ALK inhibitors. Background of the invention [0002] Protein kinases play a dominant regulatory role in almost all types of cellular biological activities. They include proliferation, apoptosis, cytoskeletal rearrangements, differentiation, development, immune response, nervous system function and conduction. In addition, many diseases and / or disorders are associated with abnormal, abnormal or dysregulated activity of one or more kinases. [0003] Anaplastic lymphoma kinase (ALK) is part of the receptor protein family of tyrosine kinases (RTKs). The ALK gene provides instructions for the receptor tyrosine kinase protein to transmit signals from the cell surface to the cell through a process called signal transduction. This proc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07F9/6561A61K31/675A61P35/00
Inventor 丁照中张明会陈曙辉刘希乐朱屹东范传文赵保平张龙陈栋杨莹莹郑庆梅郑善松万海文胡金清
Owner QILU PHARMA CO LTD
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