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6-aryl substituted quinoline compounds and applications thereof

A compound and quinoline technology, applied in the field of 6-aryl substituted quinazolines and quinoline compounds, can solve the problems of underdeveloped value, narrow indications, and high toxicity of idelalisib

Active Publication Date: 2016-01-13
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the value of PI3Kδ inhibitors has not been fully developed, and the indications are relatively narrow, and the approved PI3Kδ inhibitor idelalisib is highly toxic, with a black box mark

Method used

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  • 6-aryl substituted quinoline compounds and applications thereof
  • 6-aryl substituted quinoline compounds and applications thereof
  • 6-aryl substituted quinoline compounds and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093]

[0094] 4-(4-(4-methylpiperazine-1-carbonyl)phenyl)amino-6-bromoquinazoline (intermediate 1-c) weighs 4-chloro-6-bromoquinazoline (1- a, 0.16g, 0.58mmol) was placed in isopropanol (5mL), 4-(4-methylpiperazine-1-carbonyl)aniline (0.14g, 0.64mmol) was added, and the temperature was raised to reflux for 5h under nitrogen protection, Cool to room temperature and filter to obtain white solid 1-c (0.18g, 73%). MS(ESI)m / z:[M+H] + =426.1,428.1.

[0095] 2-methoxy-5-(4-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)quinazolin-6-yl)benzamide (compound 1) weighed 2 -Methoxy-5-bromobenzamide (50mg, 0.22mmol) was placed in a 50mL bottle, dioxane (5mL) was added, and biboronic acid pinacol ester (60mg, 0.24mmol), potassium acetate ( 54mg, 0.55mmol), Pd(dppf)Cl 2 (12mg, 0.0165mmol), reflux reaction in a nitrogen atmosphere for 4h, the filtrate was concentrated to dryness, and the crude product 1-e was obtained; then intermediate 1-c (75mg, 0.22mmol), sodium carbonate (58mg, 0...

Embodiment 2

[0097]

[0098]4-(3-(4-methylpiperazine-1-carbonyl)phenyl)amino-6-bromoquinazoline (intermediate 2-c) can be prepared by a method similar to compound 1-c to obtain compound 2 -c (0.43g, 62%). M.p.256-258℃, MS(ESI)m / z:[M+H] + =426.1,428.1.

[0099] 2-methoxy-5-(4-((3-(4-methylpiperazine-1-carbonyl)phenyl)amino)quinazolin-6-yl)benzamide (compound 2) was prepared using Compound 2, a white solid (168 mg, 68%), could be prepared in a similar manner to 1. M.p.205-207℃, MS (ESI) m / z: [M+H] + =497.2. 1 H-NMR (400M, DMSO-d 6 )δ10.16(s,1H),8.85(s,1H),8.62(d,1H),8.30(d,1H),8.19(s,1H),7.99(d,3H),7.89(d,1H ),7.77(s,1H),7.68(s,1H),7.51(d,1H),7.36-7.29(m,1H),7.19(s,1H),3.98(s,3H),3.80-3.53( m,4H),2.75-2.45(m,4H),2.38(s,3H)ppm.

Embodiment 3

[0101]

[0102] 4-(3-(4-methylpiperazine-1-carbonyl) phenyl) amino-6-(2-methoxypyridin-5-yl) quinazoline (compound 3) preparation compound 1 similar method Compound 3 (50 mg, 11%) could be obtained. M.p.252-256℃, MS(ESI)m / z:[M+H] + =455.2. 1 H-NMR (400M, DMSO-d 6 )δ10.14(s,1H),8.95(s,1H),8.76(s,1H),8.68(s,1H),8.40-8.26(m,1H),8.22(d,1H),8.08-7.94 (m,2H),7.83(d,1H),7.49(t,1H),7.16(d,1H),7.02(d,1H),3.94(s,3H),3.54-3.34(m,4H), 2.48-2.28(m,4H),2.23(s,3H)ppm.

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Abstract

The invention discloses 6-aryl substituted quinoline compounds and applications thereof, and belongs to the technical field of biomedicine. The invention discloses 6-aryl substituted quinoline and quinoline compounds and applications thereof. The novel compounds can be used as a PI3K[delta] inhibitor. Tests on PI3K[delta] kinase activity and PI3K[delta] kinase selective activity are carried out, and the test results show that the provided compounds have a prominent inhibiting effect on PI3K[delta] kinase activity and has a prominent selective effect on PI3K[delta] activity. Through testing the in-vitro cell proliferation of leukemia cell lines, people find that the disclosed compounds has different inhibiting effects on leukemia cells. The disclosed compounds, pharmaceutically-acceptable salts, deuterated substances, hydrates, solvates, chemically-protected prodrug, or compositions thereof can be used as the PI3K[delta] inhibitor, and can be used to treat and / or prevent inflammation or tumor.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a 6-aryl substituted quinazoline and quinoline compounds and applications thereof. Background technique [0002] Phosphatidylinositol-3-kinase (PI3K) is a member of the lipid kinase family and an important part of the PI3K / AKT / mTOR signaling pathway. PI3K can be divided into three categories according to the structure and function. The most widely studied class I PI3Ks are heterodimers consisting of a regulatory subunit and a catalytic subunit. The regulatory subunit contains SH2 and SH3 domains and interacts with target proteins that contain corresponding binding sites, and this subunit is commonly referred to as p85. There are four catalytic subunits, namely p110α, p110β, p110δ, and p110γ (where p110α, p110β, and p110δ belong to the RTK family, and p110γ belongs to the GPCR family). PI3K can be divided into PI3K, PI3Kβ, PI3Kδ and PI3Kγ according to their catal...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D401/04C07D215/46C07D401/14C07D403/12C07D405/14C07D403/14A61K31/517A61K31/496A61K31/5377A61P35/00A61P29/00A61P35/02
CPCC07D215/46C07D239/94C07D401/04C07D401/14C07D403/12C07D403/14C07D405/14
Inventor 辛敏行张三奇张浩谢肖肖黑媛媛左赛杰毛帅
Owner XI AN JIAOTONG UNIV
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