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2,4-diarylaminopyrimidine derivative as well as preparation method and application thereof

A technology of arylaminopyrimidine and its derivatives, applied in the field of medicine, can solve problems such as ROS1 protein imbalance

Inactive Publication Date: 2018-05-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Fusion, overexpression and mutation of ROS1 gene can lead to dysregulation of ROS1 protein

Method used

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  • 2,4-diarylaminopyrimidine derivative as well as preparation method and application thereof
  • 2,4-diarylaminopyrimidine derivative as well as preparation method and application thereof
  • 2,4-diarylaminopyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Step A Isopropyl(2-nitrophenyl)sulfide (Ⅱ)

[0200] Add 509.1g (3.61mol) of o-fluoronitrobenzene and 698.0g (5.06mol) of anhydrous potassium carbonate to 2500mL of dry N,N-dimethylformamide (DMF), slowly drop into 301.8g (3.97mol ) isopropyl mercaptan, after dropping, the temperature was raised to 110° C. for 10 h. After cooling to room temperature, the reaction solution was poured into a large amount of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 604.6 g of a yellow liquid with a yield of 85.0%.

[0201] Step B 1-Isopropylsulfonyl-2-nitrobenzene (Ⅲ)

[0202] Add 197.1g (1.00mol) of isopropyl (2-nitrophenyl) sulfide to 1500mL of glacial acetic acid, slowly drop into 583.0g (6.00mol) of 35% hydrogen peroxide, raise the temperature to 80°C, and react for 9h. After cooling to room temperature, the reaction solution was poured into a large amount of water, stirred at room temperature for 30 min, filtered wi...

Embodiment 2

[0217] Example 2 3-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)- N,N-Dimethyl-2-oxoimidazoline-1-amide

[0218] m.p.: 134-136°C; ESI-MS [M+Na] (m / z): 610.3; 1 H NMR (400MHz, CDCl3) δ9.77(s, 1H), 8.52(d, J=8.4Hz, 1H), 8.12(s, 1H), 8.09(d, J=8.7Hz, 1H), 7.92(dd ,J=8.0,1.5Hz,1H),7.64(t,J=7.2Hz,1H),7.53(d,J=2.3Hz,1H),7.30(d,J=8.0Hz,1H),6.72(dd ,J=8.8,2.3Hz,1H),3.91(s,3H),3.89(s,4H),3.23(dt,J=13.6,6.8Hz,1H),3.08(d,J=5.5Hz,6H) ,1.32(s,3H),1.31(s,3H).

Embodiment 3

[0219] Example 3 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)- 3-(tetrahydro-2H-pyran-4-carbonyl)imidazolidin-2-one

[0220] m.p.: 234-235°C; ESI-MS [M+Na] (m / z): 651.3; 1 H NMR (400MHz, CDCl 3 )δ10.44(s,1H),8.73(s,1H),8.02–7.83(m,2H),7.83(d,J=7.3Hz,1H),7.73(d,J=7.8Hz,1H), 7.39–7.30(m,2H),7.23(t,J=7.6Hz,1H),6.85(dd,J=18.9,4.0Hz,1H),4.07–4.01(m,2H),3.94(d,J= 8.6Hz, 2H), 3.75(s, 3H), 3.69(t, J=7.6Hz, 2H), 3.22(d, J=11.0Hz, 2H), 2.92(t, J=10.8Hz, 1H), 1.97 (d,J=8.9Hz,2H),1.79–1.67(m,2H),1.29(s,3H),1.25(s,3H),0.87(dd,J=16.6,9.8Hz,1H).

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Abstract

The invention relates to a 2,4-diarylaminopyrimidine derivative shown as a general formula I and optical isomers thereof, pharmaceutically acceptable salts, solvates or prodrugs, as well as preparation methods thereof and a pharmaceutical composition taking the compound of the general formula I as an active ingredient. In the formula, substituent groups R1, R2, R3, R4, R5, R6 and X have meanings given in the description. The invention further relates to a compound of the general formula I with strong ALK and ROS1 kinase inhibition effects, and further relates to application of the compounds and optical isomers and pharmaceutically acceptable salts thereof in preparation of medicines for treating and / or preventing diseases caused by abnormal expressions of ALK and ROS1, particularly application in preparation of medicines for treating and / or preventing cancers. The structural formula is as shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to 2,4-diarylaminopyrimidine derivatives and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs, their preparation methods and pharmaceutical combinations containing the compounds things. The present invention also relates to the strong ALK and ROS1 kinase inhibitory effect of the compound and its application in the preparation of medicines for treating and / or preventing diseases caused by abnormal expression of ALK and ROS1, especially in the preparation of therapeutic and / or Use in medicines for the prevention of cancer. Background technique [0002] The research on kinase target drugs has become an important direction in the research and development of anticancer drugs. Among the currently discovered kinase target drugs, protein kinases are known to be the most studied class. Due to mutation or rearrangement of protein kinases, the signal transductio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D405/14C07D401/12C07D403/12C07D239/48C07D239/50C07D405/12A61K31/506A61K31/541A61K31/5377A61P35/00
CPCC07D239/48C07D239/50C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14
Inventor 翟鑫左代英宫平王娇郭明王小强类红瑞
Owner SHENYANG PHARMA UNIVERSITY
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