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A substituted pyrazolo[1,5-a]pyrimidine compound and its preparation method and application

A compound, 5-a technology, used in drug combinations, organic chemistry, pharmaceutical formulations, etc.

Active Publication Date: 2022-06-14
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the following problems mainly exist in the research of c-Met inhibitors: the clinical application has relatively high toxicity and side effects, the clinical treatment effect and pharmacokinetic parameters are not ideal, and the oral biological Utilization is not high
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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  • A substituted pyrazolo[1,5-a]pyrimidine compound and its preparation method and application
  • A substituted pyrazolo[1,5-a]pyrimidine compound and its preparation method and application
  • A substituted pyrazolo[1,5-a]pyrimidine compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092]

[0093] Step 1: Synthesis of ethyl 4-phenyl-2,4-dioxobutanoate

[0094]

[0095] 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 the ethyl acetate phases, washed with water three times, 200 mL each time, and the organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressu...

Embodiment 2

[0131]

[0132] 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] + .

[0133] 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)

Embodiment 3

[0134]

[0135] 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] + .

[0136] Example 4: N-{3-fluoro-4-[6-methoxy-7-(3-morpholine propoxy)quinoline-4-oxyl]phenyl}-7-(4-trifluoro Synthesis of Methylphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (Compound 4)

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Abstract

The present invention provides a novel substituted pyrazolo[1,5‑a]pyrimidine compound and its preparation method and application. Specifically, the present invention relates to a pyrazolo[1,5 ‑a] quinoline derivatives of pyrimidine and pharmaceutically acceptable salts thereof, wherein the substituents X, Ar, and A have the meanings given in the description. The present invention also relates to compounds of general formula (I) having a strong inhibitory effect on c-Met kinase, and also relates to the use of such compounds and pharmaceutically acceptable salts thereof in the preparation of treatment and / or prevention of c-Met kinase due to abnormally high c-Met kinase Use in medicines expressing the diseases caused, especially in the preparation of medicines for treating and / or preventing cancer.

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 . technical background [0002] 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 eventuall...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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