2,4-diarylaminopyrimidine derivatives containing aromatic heterocycles and their preparation and application

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

Active Publication Date: 2021-11-23
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 derivatives containing aromatic heterocycles and their preparation and application
  • 2,4-diarylaminopyrimidine derivatives containing aromatic heterocycles and their preparation and application
  • 2,4-diarylaminopyrimidine derivatives containing aromatic heterocycles and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0240] Step A N- (2,5-dichloronidin-4) -1,2-diphenylamine (III)

[0241] 30.00 g (0.16 mol) orthodontisylamine (II) and 17.70 g (0.16 mol) 2,4,5-triclactane were added to 300 ml of dried isopropanol (I-prOH), and 42.30 g slowly added ( 0.33 mol) N, N-diisopropylethylamine, warmed to 80 ° C for 1.5 h. The filtration was filtered, and the white powder solid was 37.35 g, and the yield was 89.7%.

[0242] Step B N- (2 - (((2,5-dichloroprid-4-yl) amino) phenyl) methanesulfonamide (M 1 -1)

[0243] Under ice bath conditions, 10 g (0.04 mol) intermediate III and 9.3 g (0.12 mol) pyridine (PY) were added to 50 ml of dried tetrahydrofuran, slowly added 5.4 g (0.05 mol) methylsulfonyl chloride. Tipping, at room temperature for 2.5 hours, filtration, tetrahydrofuran (10 mL × 3) washed, and the white powder solid was 11.7 g, and the yield was 89.3%.

[0244] Step C 2- (chloromethyl) -6-nitro-1H-benzo [D] imidazole (VI)

[0245] 10.0 g (0.07 mol) of 4-nitro-xylomide (V), 12.3 g (0.13 mol) chlo...

Embodiment 2

[0253] Example 2N- (2 - ((5- chloro-2 - ((2 - ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) lH-benzo [d] imidazole - 6-yl) amino) pyrimidine-4-yl) amino) phenyl) methanesulfonamide

[0254] According to the method of step d in Example 1, the N-hydrocarbonization reaction was prepared from N-hydroxyethylpiperazine by VI to obtain 2- (4 - (((6-nitro-1H-benzo [D] Imidazole-2-yl) methyl) piperazine-1-yl) ethyl-1-alcohol (VII-2). The yield was 83.0%.

[0255] According to the method of step e in Example 1, it is obtained by the reduction reaction to obtain 2- ((6-amino-1H-benzo [D] imidazole-2-yl) methyl) piperazine by the reduction reaction at VII-2. -1-yl) ethyl-1-alcohol (M 2 -2), the yield is 97.8%.

[0256] In accordance with the method of step f in Example 1, 1 -1 and M 2 -2 is raw material, prepared Example 2, and yields 80.5%.

[0257] M.p.:237.6-240.2 CAE (es) + (m / z): 572.46; 1 H NMR (400MHz, DMSO-D 6Δ12.05 (S, 1H), 9.27 (S, 1H), 8.63 (S, 1H), 8.18 (D, J = 7.8 Hz, 1H), 8.15...

Embodiment 3

[0258] Example 3 N- (2 - ((5-chloro-2 - ((2 - (dimethylamino) methyl) -1H-benzo [D] imidazole-6-yl) amino) pyrimidine-4- Base) amino) phenyl) methanesulfonamide

[0259] According to the method of step d in Example 1, N-hydrocarbonization reaction was prepared from dimethylamine (40% aqueous solution) at VI, N-hydrocarbonization reaction was prepared from N-hydrocarbonization reaction to N, N-dimethyl-1- (6-nitro-1H- Benzo [D] imidazole-2-yl) methylamine (VII-3). The yield was 96.2%.

[0260] According to the method of step e in Example 1, the reacting reaction was obtained by the reduction reaction by the reduction reaction to obtain 2 - ((dimethylamino) methyl) -1H-benzo [D] imidazole-6-amine (M) by the reduction reaction. 3 -2), the yield is 92.6%.

[0261] In accordance with the method of step f in Example 1, 1 -1 and M 3 -2 is raw material, preparation Example 3, yield 95.9%.

[0262] m.p.:212.3-215.1 CA es es -[[m +h] + (m / z): 487.28; 1 H NMR (400MHz, DMSO-D 6 Δ12.14 (S, 1...

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Abstract

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs, their preparation methods and general The compound shown in formula I is the pharmaceutical composition of the active ingredient, wherein the substituent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z have the meanings given in the specification. The present invention also relates to compounds of the general formula I having strong ALK and ROS1 kinase inhibitory effects, and also to such compounds and their optical isomers, pharmaceutically acceptable salts, used in the preparation for the treatment and / or prevention of ALK and the application in medicines for diseases caused by the abnormal expression of ROS1, especially in the preparation of medicines for treating and / or preventing cancer.

Description

Technical field [0001] The present invention belongs to the field of medical technology, and the 2,4-diarylaminopyrimidine derivatives containing aromatic ring and its optical isomers, pharmaceutically acceptable salts, solvate or prodrugs, their preparation methods, and The pharmaceutical composition of the compound. The invention also relates to the suppression of the compounds of the compounds, Alk and ROS1 kinases and their application in the preparation of the drug caused by the disease due to abnormal expression of ALK and ROS1, particularly in the preparation of treatment and / or Use of drugs to prevent cancer. Background technique [0002] The study of kinase target drugs has become an important direction in today's anti-tumor drug research and development, in which protein kinase is known to have the most research. Signal conduction process disorders or abnormalities caused by mutation or rearrangement of protein kinases can result in abnormal cell growth, differentiati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D401/14A61K31/506A61K31/5377A61K31/541A61P35/00
CPCA61P35/00C07D401/14C07D403/12
Inventor 翟鑫郭明左代英邢凌云曹猛赵天铭陈煜翔
Owner SHENYANG PHARMA UNIVERSITY
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