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Fused ring compound and preparation method, application and intermediate compound thereof

A compound and composition technology, applied in the field of condensed ring compounds and phosphatidylinositol 3-kinase inhibitors

Active Publication Date: 2016-08-17
苏州泽润新药研发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The first reported PI3K synthesis inhibitor is LY294002, which has a micromolar inhibitory activity against class I PI3K and an IC of PI3Kα. 50 The value reached 0.63μM, and it also showed certain anti-tumor effects in animal experiments, but due to safety, stability and other reasons, it failed to enter clinical trials

Method used

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  • Fused ring compound and preparation method, application and intermediate compound thereof
  • Fused ring compound and preparation method, application and intermediate compound thereof
  • Fused ring compound and preparation method, application and intermediate compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: N-(5-(3-cyano-4-thiomorpholinoquinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (compound 3)

[0080]

[0081] Step 1: N-(5-(4-Chloro-3-cyanoquinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide

[0082]

[0083] 6-Bromo-4-chloroquinoline-3-carbonitrile (140mg, 0.6mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (203mg, 0.618mmol, 1.03eq) and 2N aqueous potassium carbonate (0.9mL, 1.8mmol, 3.0eq) in dioxane The mixture in the ring (6 mL) was degassed and bis(triphenylphosphine)palladium dichloride (21 mg, 0.03 mmol, 0.05 eq) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), then stirred at 100° C. under argon atmosphere for 7 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate,...

Embodiment 2

[0090] N-(5-(3-cyano-4-morpholinoquinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (Compound 6)

[0091]

[0092] Step 1: 6-Bromo-4-morpholinoquinoline-3-carbonitrile

[0093]

[0094] 6-Bromo-4-chloro-quinoline-3-carbonitrile (535 mg, 2.0 mmol) and morpholine (523 mg, 6.0 mmol, 3 eq) were stirred in dioxane (7.5 mL) at 100°C. After the reaction was completed, it was concentrated in vacuo, and the concentrate was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed successively with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate=3:1, v / v) to obtain Yellow solid (556 mg, 87.4% yield).

[0095] 1 H NMR (400MHz, DMSO-d 6 )δ8.81(s,1H),8.20(d,J=2.0Hz,1H),7.99(dd,J=8.8,2.0Hz,1H),7.93(d,J=8.8Hz,1H),3.87( t,J=4.4Hz,4H),3.68(t,J=4.4Hz,4H).

[0096] Step 2: N-(5-(3-cyano-4-morph...

Embodiment 3

[0100] Example 3: N-(5-(3-cyano-4-(2,6-dimethylmorpholinyl)quinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonate Amide (compound 2)

[0101]

[0102] The preparation method is as in Example 1, in step 2), N-(5-(4-chloro-3-cyanoquinolin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide and React at room temperature.

[0103] 1 H NMR (400MHz, DMSO) δ9.42(s,1H),8.76(s,1H),8.45(d,J=2.0Hz,1H),8.26–8.14(m,2H),8.12–8.01(m, 2H), 4.00(s, 3H), 3.99–3.90(m, 2H), 3.85(d, J=12.4Hz, 2H), 3.29–3.18(m, 2H), 3.13(s, 3H), 1.17(d ,J=6.1Hz,6H).

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Abstract

The invention relates to a fused ring compound and a preparation method, application and intermediate compound thereof. The fused ring compound can be used as an inhibitor of phosphatidylinositol 3-kinase.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a condensed ring compound, a preparation method thereof and an application thereof as a phosphatidylinositol 3-kinase inhibitor. The present invention also relates to intermediate compounds of the compound. Background technique [0002] Malignant tumors are a class of major diseases that seriously threaten human health. Most small-molecule anti-tumor drugs used clinically either affect the structure and function of DNA, or interfere with the synthesis and repair of nucleic acid, or inhibit the synthesis and function of a certain housekeeping protein (such as tubulin). However, there are disadvantages such as high toxicity and side effects and easy drug resistance in clinical application. [0003] The emergence of molecularly targeted drugs is a milestone event in the history of anticancer drug development. This type of drug acts on specific molecular targets of t...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D413/14C07D417/14C07D401/14A61K31/496A61K31/5377A61K31/541A61P35/00A61P35/02A61P29/00A61P37/06A61P11/00A61P11/06A61P19/02A61P17/06
CPCC07D401/04C07D401/14C07D413/14C07D417/14A61K31/496A61K31/537A61K31/541
Inventor 龙凯廖立东王万
Owner 苏州泽润新药研发有限公司
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