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DNA-PK inhibitor

A technology based on alkylation and selection, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve problems such as cell death and apoptosis

Active Publication Date: 2021-03-30
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DNA double-strand breaks, if not promptly and completely repaired, can lead to cell death through apoptosis and / or mitotic disturbance

Method used

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Examples

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Effect test

preparation example Construction

[0161] 1 Preparation examples of compounds of the present invention

[0162] In the preparation examples, the meanings represented by the abbreviations are as follows:

[0163] KOH: potassium hydroxide EA: ethyl acetate DCM: dichloromethane

[0164] DMAP: 4-Dimethylaminopyridine Na 2 SO 4 : Sodium sulfate TFA: Trifluoroacetic acid

[0165] DMF: N,N-Dimethylformamide THF: Tetrahydrofuran Pd / C: Palladium / Carbon catalyst

[0166] MeOH: Methanol EtOH: Ethanol Tf 2 O: Trifluoromethanesulfonic anhydride

[0167] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DIEA: N,N-Diisopropylethylamine

[0168] Lawson's reagent: 2,4-bis(p-methoxyphenyl)-1,3-dithio-diphosphetane-2,4 sulfide

[0169] HATU: 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

preparation example 1

[0170] Preparation 1: N-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-sulfur Preparation of formamide (compound 1)

[0171] 1, Preparation of 8-(3-((tert-butoxycarbonyl)amino)prop-1-en-2-yl)quinoline-4-carboxylic acid

[0172]

[0173] Dissolve tert-butyl (2-(4-cyanoquinolin-8-yl)allyl)carbamate (1.2g, 3.9mmol), KOH (0.87g, 15.5mmol) in ethanol (30mL), water (10 mL), react at 110° C. for 10 h. After the reaction was completed, adjust the pH to 5-6 with dilute hydrochloric acid, add water (20mL), extract three times with EA (3×30mL), combine the organic phases, wash over anhydrous Na 2 SO 4 Dried, filtered, and spin-dried to obtain 770 mg of the product, with a yield of 60.3%.

[0174] 2. Preparation of (2-(4-(methylcarbamoyl)quinolin-8-yl)allyl)carbamate tert-butyl ester

[0175]

[0176] 8-(3-((tert-butoxycarbonyl)amino)prop-1-en-2-yl)quinoline-4-carboxylic acid (770mg), methylamine hydrochloride (317mg, 4.70mmol), EDCI (893mg, 4.70...

preparation example 2

[0191] Preparation 2: (R)-N-methyl-8-(1-(((2'-methyl-[4,5'-pyrimidin]]-6-yl)amino)propan-2-yl)quinone Preparation of phenoline-4-thiocarboxamide (compound 1-1)

[0192] 1. Preparation of tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl) allyl) carbamate

[0193]

[0194] At 0°C, add N-tert-butoxycarbonylaminopropyne (150.0g, 967.7mmol), B 2 (Pin) 2 (300.0 g, 1181.1 mmol), CuCl (10.0 g, 100.8 mmol), t-BuONa (15.0 g, 156.1 mmol), and P(t-Bu) 3 (25.0 g, 123.6 mmol) was slowly added dropwise to MeOH (75.0 mL, 1875.0 mmol) in 3.0 L of toluene suspension. After the dropwise addition, the system was warmed up to 20° C. and stirred for 16 h. After silica gel column chromatography (petroleum ether: ethyl acetate = 5:1), the crude compound (330.0 g) was obtained, which was directly used in the next step.

[0195] 2. Preparation of (2-(4-hydroxyquinolin-8-yl) allyl) tert-butyl carbamate

[0196]

[0197] Will contain 4-hydroxy-8-bromoquinoline (150.0g, 669.6mmol), te...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a class of compounds capable of being used as an inhibitor of DNA-dependent protein kinase (DNA-PK), a pharmaceutically acceptable salt, a deuterated substance and a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt, the deuteratedsubstance and the stereoisomer thereof, and uses of the compound, the pharmaceutically acceptable salt, the deuterated compound and the stereoisomer thereof.

Description

technical field [0001] The invention belongs to the technical field of medicine. In particular, the present invention relates to a class of compounds that can be used as inhibitors of DNA-dependent protein kinase (DNA-PK), pharmaceutically acceptable salts thereof, deuterated products and stereoisomers thereof, comprising said compounds, their Pharmaceutical compositions and preparations of pharmaceutically acceptable salts, their deuterated products and their stereoisomers, and uses of the compounds, their pharmaceutically acceptable salts, their deuterated products and their stereoisomers. Background technique [0002] Cancer is a malignant disease that is difficult to treat all over the world. It is difficult to treat and has a high mortality rate, which brings a heavy burden to patients and families. It is the main disease affecting the health of Chinese residents. In recent years, the incidence of cancer in my country has increased significantly, and its mortality rate...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14A61P35/00Y02P20/55
Inventor 刘斌陈博
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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