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Novel quinoline derivative inhibitor

A compound and alkyl technology, applied in the field of medicine, can solve the problems of drug failure, inability to bind kinases, acquired drug resistance, etc., and achieve the effect of inhibiting growth

Active Publication Date: 2020-03-03
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010]Although there are first-generation NTRK inhibitors for NTRK gene fusion, such as Larotrectinib, Entrectinib, etc., TKI (tyrosine kinase inhibitor, tyrosine Kinase inhibitors) therapy also faces the problem of acquired drug resistance
At present, some TRKs have been found to have mutations in the kinase site in some patients receiving TRK inhibitor therapy, such as NTRK1-LMNA-G667C, NTRK1-LMNA-V573M, etc., leading to secondary drug resistance in cancer cells, including colon cancer , MASC, etc. (Mariangela Russo, American Association for Cancer Research, 2015; A.Drilon, Annals of Oncology, 2016)
These emerging mutations prevent the first-generation NTRK inhibitors Entrectinib and Larotrectinib from binding to the kinase, rendering the drugs ineffective

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0755] Example 1: N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl Synthesis of 4-oxo-1,4-dihydropyridine-3-carboxamide (compound 14)

[0756]

[0757] step:

[0758]

[0759] Step 1: Synthesis of 2-(4-fluorophenyl)acetyl chloride

[0760]

[0761] 2-(4-Fluorophenyl)acetic acid (50.0 g, 324.380 mmol, 1.0 eq) and thionyl chloride (77.18 g, 648.761 mmol, 2.0 eq) were dissolved in dichloromethane (250.0 mL), N 2 Under protection, the temperature was raised to 60°C, and refluxed for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and an appropriate amount of dichloromethane was added, concentrated, and repeated twice to obtain a yellow oily product.

[0762] Step 2: Synthesis of 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0763]

[0764] 2,2-Dimethyl-1,3-dioxane-4,6-dione (56.10 g, 389.3 mmol, 1.2 eq) and triethylamine (78.78 g, 7798.5 mmol, 2.4...

Embodiment 2

[0782] Example 2: N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-4-oxo-5-pair Synthesis of Tolyl-1,4-Dihydropyridine-3-Carboxamide (Compound 1)

[0783]

[0784] Step 1: Synthesis of ethyl 1-isopropyl-4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylate

[0785]

[0786] 4-oxo-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester (2.00g, 7.77mmol, 1.0eq), isopropyl bromide (1.15g, 9.33mmol, 1.2eq ) and K 2 CO 3 (3.22g, 23.32mmol, 3.0eq) was added into DMF (20mL), and the reaction was stirred overnight at 50°C. The completion of the reaction was monitored by TLC, filtered, the filter cake was rinsed with ethyl acetate, the filtrate was concentrated under reduced pressure, the crude product was dissolved in ethyl acetate (20 mL), washed successively with distilled water (10 mL×4) and saturated brine (10 mL), and anhydrous Dry over sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure. The crude product is purified ...

Embodiment 3

[0795] Example 3: N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-1-isopropyl Synthesis of 4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 15)

[0796]

[0797] Step 1: Synthesis of 6,7-dimethoxy-4-((6-nitropyridin-3-yl)oxy)quinoline

[0798]

[0799] 6,7-dimethoxyquinolin-4-ol (15.00g, 73.10mmol, 1.0eq), 5-chloro-2-nitropyridine (11.60g, 73.10mmol, 1.0eq) and K 2 CO 3 (20.20g, 146.11mmol, 2.0eq) was added into DMF (120mL), stirred and reacted overnight at 80°C under nitrogen protection. The completion of the reaction was monitored by TLC, filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated under reduced pressure, dissolved in dichloromethane (50mL), washed with distilled water (20×4mL) and saturated brine (20mL) successively, washed with anhydrous sulfuric acid Dry over sodium, filter with suction, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chr...

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Abstract

The invention provides a novel quinoline derivative inhibitor, which has a structure represented by the following general formula (I). According to the invention, the compound provided by the invention can selectively inhibit tyrosine kinase TAM family / and CSF1R kinase, and can be used for treating and / or preventing diseases mediated by abnormal expression of TAM family kinase / and CSF1R kinase receptors and / or ligands of the TAM family kinase / and CSF1R kinase receptors, so that the compound can be used to treat and / or prevent related diseases caused by NTRK, more specifically to treat and / or prevent drug-resistant related diseases caused by NTRK mutation.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to TAM family kinases / and CSF1R kinase inhibitor compounds represented by the general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers and compounds containing them Pharmaceutical compositions, pharmaceutical preparations and uses. The compound of the present invention can selectively inhibit tyrosine kinase TAM family / and CSF1R kinase, and can be used for the treatment and / or prevention of diseases mediated by abnormal expression of TAM family kinase / CSF1R kinase receptor and / or its ligand. Furthermore, the compound of the present invention can be used to treat and / or prevent related diseases caused by NTRK, more specifically, can be used to treat and / or prevent related diseases caused by NTRK mutation. Background technique [0002] The TAM family includes three members, Axl, Mer, and Tyro-3, and this family includes an extracellular domain, a transmembrane ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D491/056A61K31/4709A61K31/501A61K31/506A61P35/00A61P35/02A61P35/04
CPCC07D401/14C07D491/056A61P35/00A61P35/02A61P35/04A61K31/4709A61K31/501A61K31/506A61P29/00A61P15/00A61P19/02A61P19/10A61P9/00A61P13/12A61P27/02A61P17/06C07D213/80C07D237/24A61K45/06
Inventor 吴永谦万中晖
Owner TRANSTHERA SCIENCES (NANJING) INC
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