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6-(Pyridine-4-yl)-4-substituted amino quinazoline or quinoline compound and application thereof

A compound, quinazoline technology, applied in organic chemistry, drug combination, bone diseases, etc., can solve the problem that the value of PI3K inhibitors has not been fully developed, and achieve good inhibitory effect and tumor volume reduction effect

Pending Publication Date: 2018-08-07
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 PI3K inhibitors has not been fully developed, and the indications are only in the treatment of individual blood tumors

Method used

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  • 6-(Pyridine-4-yl)-4-substituted amino quinazoline or quinoline compound and application thereof
  • 6-(Pyridine-4-yl)-4-substituted amino quinazoline or quinoline compound and application thereof
  • 6-(Pyridine-4-yl)-4-substituted amino quinazoline or quinoline compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] N-(2-methoxy-5-bromo-3-pyridyl)cyclopropylsulfonamide (intermediate 1-b)

[0049] Weigh 2-methoxy-3-amino-5-bromopyridine (1-a, 1.52g, 7.43mmol) into 20mL DCM, add 1.1mL pyridine, dissolve cyclopropylsulfonyl chloride (1.56g, 11.12mmol Into 10mL of DCM, add dropwise under ice bath, after dropping, react overnight at room temperature. Evaporate the solvent, extract with ethyl acetate, recrystallize to obtain 1.85g, yield 81.8%.

[0050] 4-(N-(1-piperidinylethyl))amino-6-bromoquinazoline (intermediate 1-d)

[0051] Weigh 4-chloro-6-bromoquinazoline (1-c, 2.01g, 8.01mmol) in isopropanol (15mL), add 1-(2-aminoethyl) piperidine (1.05g, 8.01mmol ), heated to reflux for 5 h under the protection of nitrogen, cooled to room temperature, and filtered to obtain white solid 1-d (2.74 g, 74.6%). mp:215.0-217.5℃. 1 H NMR (CDCl 3 )δ8.84(s,1H,NH),8.78(d,J=2.0Hz,1H,Ar-H),8.60(s,1H,Ar-H),7.81(dd,J=8.9,2.1Hz, 1H, Ar-H), 7.68(d, J=8.9Hz, 1H, Ar-H), 4.22-4.12(t, 2H, CH 2 )...

Embodiment 2

[0055]

[0056] 4-(N-(4-morpholinoethyl))amino-6-bromoquinazoline (intermediate 2-b)

[0057] The same preparation method as intermediate 1-d, white solid (2.07g, 72.1%). mp:204.0-205.6℃. 1 H NMR (CDCl 3 ) δ8.65(s,1H,Ar-H),8.27(s,1H,Ar-H),7.84(dd,J=8.9,2.0Hz,1H,Ar-H),7.73(d,J=8.9 Hz, 1H,Ar-H),4.00(s,4H,CH 2 ),3.94(s,2H,CH 2 ),3.07(s,2H,CH 2 ),2.93(s,4H,CH 2 ).ESI-MS m / z:338.1 / 340.1[M+H] + .

[0058] N 1 -(2-Methoxy-5-((4-(N 2 -(4-morpholine ethyl))amino)-6-quinazoline)-3-pyridyl)cyclopropylsulfonamide (compound 2)

[0059] The preparation method was the same as that of compound 1 to obtain compound 2 (80.2 mg, 55.7%). mp:64.2-66.8℃. 1 H NMR (DMSO-d 6 ) δ8.54(s,1H,NH),8.50–8.44(m,2H,Ar-H),8.42(s,1H,Ar-H),8.07(d,J=8.5Hz,2H,Ar-H ), 7.76(d, J=8.6Hz, 1H, Ar-H), 4.00(s, 3H, OCH 3 ), 3.69 (d, J=6.0Hz, 2H, CH 2 ),2.80–2.70(m, 1H,CH), 2.57(t,J=6.9Hz,2H,CH 2 ),2.43(s,4H,CH 2 ×2),1.49(d,J=4.9Hz,4H,CH 2 ×2), 1.38(d,J=4.2Hz,2H,CH 2 ),0.95(d,J=7.4Hz,2H,CH 2 ).ESI-MS ...

Embodiment 3

[0061]

[0062] N-(2-methoxy-5-bromo-3-pyridyl)methylsulfonamide (intermediate 3-b)

[0063] Weigh 2-methoxy-3-amino-5-bromopyridine (1-a, 0.94g, 4.63mmol) into 20mL DCM, add 1.1mL pyridine, dissolve methanesulfonyl chloride (0.43mL, 5.56mmol in In 10mL of DCM, add dropwise under ice-cooling, after dropping, react overnight at room temperature. Evaporate the solvent, extract with ethyl acetate, recrystallize to obtain 1.05g, yield 80.8%.

[0064] N 1 -(2-Methoxy-5-((4-(N 2 -(1-piperidinyl))amino)-6-quinazoline)-3-pyridyl)methylsulfonamide (compound 3)

[0065] The preparation method was the same as that of compound 1 to obtain compound 3 (58.6 mg, 55.7%). mp:120.6-123.5℃. 1 H NMR (DMSO-d 6 )δ8.53(d,J=1.5Hz,1H,NH),8.50–8.38(m,3H,Ar-H),8.11–8.01(m,2H,Ar-H),7.76(d,J=8.7 Hz,1H,Ar-H),3.99(s,3H,OCH 3 ), 3.69 (dd, J=12.9, 6.4Hz, 2H, CH 2 ),3.08(s,3H,CH 3 ), 2.58(t, J=7.0Hz, 2H, CH 2 ),2.44(s,4H,CH 2 ×2), 1.50(dt, J=10.7, 5.5Hz, 4H, CH 2 ×2), 1.38(d, J=4.8Hz, 2H, CH 2 ...

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Abstract

The invention relates to 6-(pyridine-4-yl)-4-substituted amino quinazoline and quinoline compounds having PI3K inhibitory activity, which are compounds of formula (I) structure (as shown in the description), or solvates, enantiomers, diastereoisomers, tautomers or any-ratio mixtures of their pharmaceutically acceptable salts, including racemic mixtures. The 6-(pyridine-4-yl)-4-substituted amino quinazoline and quinoline compounds have good inhibitory action against PI3K, show good antitumor effect, and has a good prospect in the preparation of drugs for treatment of diseases responsive to PI3Kalpha and / or PI3K delta. The invention also relates to pharmaceutical application of the compounds as PI3K inhibitors.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a 6-(pyridin-4-yl)-4-substituted amino quinazoline or quinoline compounds and applications thereof. Background technique [0002] With the understanding of the function and role of PI3K, it is found that PI3K plays a key role in the occurrence and development of autoimmune diseases, solid tumors and hematological tumors. Inhibitors targeting PI3K are expected to become new anti-tumor drugs and are expected to play an important role in clinical practice. [0003] PI3K (phosphatidylinositol-3-kinase) is a member of the lipid kinase family and an important part of the PI3K / AKT / mTOR signaling pathway. The most widely studied PI3K is class I PI3K, which can be divided into PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Mutations of PI3Kα are associated with malignant tumors; PI3Kβ can activate platelets, which is related to the development of thrombotic diseases, and in PTEN-deficie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D405/14A61K31/517A61K31/5377A61P37/00A61P37/02A61P35/00A61P19/02A61P37/06A61P35/02
CPCC07D401/04C07D401/14C07D405/14
Inventor 辛敏行张三奇黑媛媛张浩汪慧岩申颖
Owner XI AN JIAOTONG UNIV
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