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Diaryl urea mTOR kinase inhibitor as well as pharmaceutical composition and application thereof

The technology of a kinase inhibitor and diaryl urea, which is applied in the field of medicine, can solve the problems of non-target side effects and achieve the effects of low toxicity, cost reduction and high yield

Pending Publication Date: 2022-07-15
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since different isoforms of PI3K kinases have different tissue distribution and physiological functions, non-selective inhibition will inevitably lead to non-target related side effects

Method used

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  • Diaryl urea mTOR kinase inhibitor as well as pharmaceutical composition and application thereof
  • Diaryl urea mTOR kinase inhibitor as well as pharmaceutical composition and application thereof
  • Diaryl urea mTOR kinase inhibitor as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1: (S)-1-(4-(4-(3-Methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3 -(1-oxo-1,3-dihydroisobenzofuran-5-yl)urea, the structural formula is as follows:

[0107]

[0108] The synthetic method includes the following steps:

[0109] Step 1: Synthesis of 4-(4,6-Dichloro-1,3,5-triazin-2-yl)morpholine

[0110] The structural formula of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine:

[0111]Weigh the raw material cyanuric chloride (10.84mmol) and put it into a 100mL double-necked flask, add DCM to dissolve, then add DIPEA (10.84mmol), and cool down at a low temperature of -78°C for 10 minutes after vacuum nitrogen circulation for three times. Morpholine (10.84 mmol) was slowly added to the liquid funnel and the reaction was kept at low temperature for 1 h. TLC monitoring was completed. The reaction solution was directly concentrated in vacuo and mixed with silica gel, and the obtained product was purified by silica gel column chromatography (PE:EA=5:1). ...

Embodiment 2

[0120] Example 2: (R)-1-(4-(4-(2-(hydroxymethyl)morpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl )-3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)urea, the structural formula is as follows:

[0121]

[0122] Synthesis method: The substituted heterocyclic fragment in step 2 in Example 1 was changed to (R)-2-hydroxymethylmorpholine, and other steps and operations were the same as those in Example 1; white solid, yield: 17%. NMR data are 1 H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.17(s,1H),8.34-8.28(m,2H),7.90(s,1H),7.76(d,J=8.4Hz, 1H), 7.58(s, 2H), 7.52(d, J=9.3Hz, 1H), 5.36(s, 2H), 4.83(s, 2H), 4.77-4.43(m, 2H), 3.90(d, J = 51.7Hz, 5H), 3.67(s, 4H), 3.47(d, J=58.4Hz, 4H), 3.01(s, 1H), 2.76(s, 1H); 13 C NMR(151MHz,DMSO-d6)δ170.8,169.4,168.9,164.9,164.7,163.8,152.4,149.7,145.6,142.8,130.9,129.5,126.3,119.3,118.4,117.9,111.0,76.0,73.8. ,56.5,55.3.HRMS(ESI)calcd.for C 27 H 29 N 7 O 6 [M+H] + :548.2258,found:548.2253.

Embodiment 3

[0123] Example 3: 1-(4-(4-(4-(Dimethylamino)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl )-3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)urea, the structural formula is as follows:

[0124]

[0125] Synthetic method: The substituted heterocyclic fragment in step 2 in Example 1 was changed to 4-dimethylaminopiperidine, and other steps and operations were the same as those in Example 1. White solid, yield: 27%. NMR data are 1 H NMR(600MHz,DMSO-d6)δ9.35(s,1H),9.19(s,1H),8.28(d,J=7.2Hz,2H),7.90(s,1H),7.75(s,1H) ,7.57(s,2H),7.51(s,1H),5.35(s,2H),4.76(d,J=126.1Hz,2H),3.79(s,4H),3.65(s,4H),2.91( s, 2H), 2.37(ddq, J=11.5, 7.8, 3.7Hz, 1H), 2.18(s, 6H), 1.81(s, 2H), 1.30(d, J=11.3Hz, 2H); 13C NMR( 151MHz,DMSO-d6)δ170.8,169.4,165.2,164.6,152.4,149.7,145.6,142.8,131.1,129.5,126.3,119.3,118.4,118.0,111.0,70.0,66.5,62.02,43.7,42. HRMS(ESI)calcd.for C 29 H 34 N 8 O 4 [M+H] + :559.2781,found:559.2776.

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Abstract

The invention relates to the technical field of medicine, in particular to a benzolactone-substituted diarylurea mTOR inhibitor and a pharmaceutical composition and application thereof, and the benzolactone-substituted diarylurea mTOR inhibitor comprises a substituted triazine compound with a general formula (I), a stereoisomer, a hydrate or a pharmaceutically acceptable salt of the substituted triazine compound, or a pharmaceutically acceptable salt of the substituted triazine compound with a general formula (II), or a pharmaceutically acceptable salt of the substituted triazine compound with a general formula (II), or a pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the substituted triazine compound with a general formula (II), the structure of the general formula (I) is shown in the specification. The terminal benzo lactone substituted diaryl urea mTOR inhibitor and the pharmaceutical composition containing the same provided by the invention can be used for inhibiting mTOR kinase; an inhibitor with better effectiveness and selectivity can be provided for proliferative diseases, metabolic diseases, nervous system diseases and nodular sclerosis caused by mTOR kinase overactivity.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a diarylurea mTOR kinase inhibitor and a pharmaceutical composition and application thereof. Background technique [0002] Malignant tumor is one of the most common and serious diseases that directly endanger human life in the world. It is a new organism formed by the loss of gene regulation of local tissue cells under the action of various carcinogenic factors, resulting in clonal abnormal proliferation. . Due to the lack of specificity, traditional chemotherapy and radiotherapy often bring greater toxic and side effects to patients while achieving curative effects (Nature 2019, 575(7782), 299-309). It is an important development direction of current anti-tumor drugs to select a tumor cell-specific target and apply the drugs targeting the target for treatment, so as to avoid damage to normal cells and achieve a high-efficiency and low-toxicity treatment mode. [0003] The PI3...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D405/14C07D491/08C07D498/08C07D519/00C07D487/08C07D405/12A61P35/00A61P35/02A61P3/00A61P3/10A61P25/00A61K31/5386A61K31/541A61K31/5377
CPCC07D413/14C07D405/14C07D491/08C07D498/08C07D519/00C07D487/08C07D405/12A61P35/00A61P35/02A61P3/00A61P3/10A61P25/00
Inventor 张吉泉张娜娜吴春风王领汤磊
Owner GUIZHOU MEDICAL UNIV
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