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Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof

A 5-a, pyrazolo technology, applied in the direction of organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problem of low oral bioavailability, large toxic and side effects, unsatisfactory clinical treatment effect and pharmacokinetic parameters, etc. question

Active Publication Date: 2020-07-24
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are mainly the following problems in the research of c-Met inhibitors: high toxicity and side effects in clinical application, unsatisfactory clinical treatment effect and pharmacokinetic parameters, low oral bioavailability, etc.
The present invention relates to a novel substituted pyrazolo[1,5-a]pyrimidine compound as a c-Met inhibitor, which has not been reported in the literature

Method used

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  • Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
  • Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
  • Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: N-{3-fluoro-4-[6-methoxy-7-(3-morpholine propoxy)quinoline-4-oxyl]phenyl}-7-phenylpyrazolo Synthesis of [1,5-a]pyrimidine-5-carboxamide (Compound 1)

[0093]

[0094] Step 1: Synthesis of ethyl 4-phenyl-2,4-dioxobutanoate

[0095]

[0096] Metal sodium particles (11.5 g, 0.50 mol) were added in batches to 400 mL of cooled ethanol, and the reaction was stirred until the sodium particles disappeared, and then warmed to room temperature. Diethyl oxalate (36.5 g, 0.25 mol) and acetophenone (30.0 g, 0.25 mol) were added to the above solution, and the temperature was raised to 70° C., stirred for 5 h, most of the ethanol was removed by evaporation under reduced pressure, and the residue was added to 500 mL of water. . Ethyl acetate was extracted twice, 200 mL each time, and the ethyl acetate phase was discarded. The aqueous phase was adjusted to pH 4 with concentrated hydrochloric acid, extracted three times with ethyl acetate, 150 mL each time, combined t...

Embodiment 2

[0131] Example 2: N-{3-fluoro-4-[6-methoxy-7-(3-morpholine propoxy)quinoline-4-oxyl]phenyl}-7-(4-fluorobenzene base) pyrazolo[1,5-a]pyrimidine-5-carboxamide (compound 2)

[0132]

[0133] 1 H NMR (400MHz, CDCl 3 )δ9.94(s, 1H), 8.50(d, J=5.2Hz, 1H), 8.31(d, J=2.2Hz, 1H), 8.21(dd, J=8.6, 5.3Hz, 2H), 8.02( dd,J=11.9,2.0Hz,1H),7.90(s,1H),7.64–7.50(m,2H),7.44(s,1H),7.34–7.27(m,3H),6.94(d,J= 2.2Hz, 1H), 6.44(d, J=5.1Hz, 1H), 4.28(t, J=6.6Hz, 2H), 4.04(s, 3H), 3.78–3.66(m, 4H), 2.58(t, J=7.1Hz, 2H), 2.48(s, 4H), 2.25–2.01(m, 2H); MS(ESI) m / z(%): 667.2[M+H] + .

Embodiment 3

[0134] Example 3: N-{3-fluoro-4-[6-methoxy-7-(3-morpholine propoxy)quinoline-4-oxyl]phenyl}-7-(2-fluorobenzene base) pyrazolo[1,5-a]pyrimidine-5-carboxamide (compound 3)

[0135]

[0136] 1 H NMR (400MHz, CDCl 3 )δ9.91(s, 1H), 8.48(d, J=5.3Hz, 1H), 8.27(d, J=2.4Hz, 1H), 8.00(dd, J=11.9, 2.4Hz, 1H), 7.88( s,1H),7.83–7.75(m,1H),7.66–7.47(m,3H),7.42(s,1H),7.40–7.25(m,3H),6.93(d,J=2.4Hz,1H) ,6.43(d,J=4.9Hz,1H),4.26(t,J=6.7Hz,2H),4.02(s,3H),3.78–3.61(m,4H),2.60–2.40(m,6H), 2.19–2.05(m,2H); MS(ESI)m / z(%):667.7[M+H] + .

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Abstract

The invention provides a novel substituted pyrazolo [1, 5-a]pyrimidine compound and a preparation method and application thereof, and particularly relates to a pyrazolo [1, 5-a]pyrimidine-containing quinoline derivative shown as a general formula (I) and pharmaceutically acceptable salts thereof, and substituent groups X, Ar and A have meanings given in the specification. The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also relates to application of the compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and / or preventing cancers.

Description

technical field [0001] The present invention relates to novel 4-phenoxy substituted quinoline compounds containing pyrazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof, their preparation methods and pharmaceutical compositions containing the compounds . The present invention also relates to the use of the compounds and their pharmaceutically acceptable salts in the preparation of medicines for the treatment of diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of medicines for the treatment and / or prevention of cancer . [0002] technical background [0003] Cancer, also known as malignant tumor, is a common and frequently-occurring disease that seriously threatens human life and health. Dysregulation of protein tyrosine kinases (PTK) will activate multiple downstream signaling pathways, induce a series of physiological activities of tumor cells such as proliferation, differentiation, invasion, growth, etc., and e...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/519A61K31/5377
CPCC07D487/04A61P35/00A61P35/02
Inventor 刘举陈烨丁实杨亚星雷婷杨文婷刘雨冬贺一明陈阳李春艳郝雪晨
Owner LIAONING UNIVERSITY
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