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Pyrimidine derivative and application thereof

A technology of drugs and compounds, applied in the field of pyrimidine derivatives and their preparation

Active Publication Date: 2017-05-24
HUBEI BIO PHARMA IND TECHCAL INST +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, current ALK inhibitors still need to be improved

Method used

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  • Pyrimidine derivative and application thereof
  • Pyrimidine derivative and application thereof
  • Pyrimidine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] The preparation process of compound shown in embodiment 1 formula I-17

[0126]

[0127] 1. Preparation of compounds shown in formula 3A-1

[0128] The compound shown in formula 1A-1 (0.5g, 2.92mmol), the compound shown in formula 2A-1 (0.5g, 2.52mmol) and potassium carbonate (807mg, 5.84mmol) were dissolved in anhydrous DMF (10mL), heated Raise the temperature to 80°C, stir the reaction for 5 hours, monitor the completion of the reaction by TLC, add 100 ml of ethyl acetate for extraction, wash with saturated brine three times, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain formula 3A The crude compound (0.8 g, yield 78.4%) shown in -1 was directly used in the next reaction without purification.

[0129] 2. Preparation of compounds shown in formula 4A-1

[0130] The compound shown in Formula 3A-1 (0.8g, 2.28mmol) was dissolved in THF / MeOH (v / v=1:1, 20ml in total) and 10ml of satura...

Embodiment 2

[0136] The preparation process of the compound shown in embodiment 2 formula I-12

[0137]

[0138] Dissolve the compound shown in Formula 4A-1 (41.85 mg, 0.131 mmol), the compound shown in Formula 5A-2 (45.48 mg, 0.131 mmol) in n-butanol (2 mL), and add p-toluenesulfonic acid (23 mg, 0.132mmol), heated to 100°C and stirred for 5 hours, TLC detection showed that the reaction was complete, concentrated under reduced pressure, and the resulting crude product was purified and separated by column chromatography to obtain an off-white solid product (35mg, yield 42.4%), which is the formula Compound shown in I-12.

[0139] 1 H NMR (400MHz, cd 3 od)δ9.11(d, J=8.6Hz, 1H), 8.34(dd, J=4.4, 1.3Hz, 1H), 8.10(s, 1H), 7.49(dd, J=12.8, 6.5Hz, 2H) ,6.68(d,J=2.4Hz,1H),6.56(dd,J=8.7,2.5Hz,1H),3.86–3.79(m,3H),3.79–3.72(m,2H),3.72–3.62(m ,2H),3.46(d,J=7.2Hz,1H),2.94(d,J=11.0Hz,2H),2.72(t,J=11.5Hz,2H),2.37(d,J=11.4Hz,2H ), 2.04(d, J=12.2Hz, 2H), 1.94(t, J=10.9Hz, 2H), 1.66(ddd, J=24.2, 12....

Embodiment 3

[0141] The preparation process of the compound shown in embodiment 3 formula I-4

[0142]

[0143] 1. Preparation of compounds shown in formula 3A-2

[0144] The compound shown in formula 1A-1 (0.5g, 2.92mmol), the compound shown in formula 2A-2 (254.5mg, 2.92.mmol) and potassium carbonate (1.21g, 8.77mmol) were dissolved in anhydrous DMF (10mL) , heated to 80°C, stirred and reacted for 5 hours, TLC monitored the completion of the reaction, added 100 ml of ethyl acetate for extraction, washed three times with saturated brine, separated liquids, dried the organic phase with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The crude compound represented by formula 3A-2 (566 mg, yield 81.3%) was directly used in the next reaction without purification.

[0145] 2. Preparation of compounds shown in formula 4A-1

[0146] The compound shown in Formula 3A-2 (0.54g, 2.28mmol) was dissolved in THF / MeOH (v / v=1:1, 20ml in total) and 10ml of satura...

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PUM

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Abstract

The invention provides a pyrimidine derivative and application thereof. The pyrimidine derivative is a compound as shown in formula I or pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite or a prodrug of the compound as shown in formula I, wherein R1, R2, R3, R4 and R5 are as defined in the specification. The compound can be used as an ALK (Anaplastic Lymphoma Kinase) inhibitor for preparing an anti-tumor treatment medicine for inhibiting ALK.

Description

technical field [0001] The present invention belongs to the field of biomedicine. Specifically, the present invention relates to pyrimidine derivatives and uses thereof. More specifically, the present invention relates to pyrimidine derivatives, a preparation method thereof, and uses thereof in preparing medicines. Background technique [0002] Non-small-cell lung cancer (NSCLC) is synonymous with "non-small-cell carcinoma". Non-small cell lung cancer, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, has slower growth and division of cancer cells than small cell carcinoma, and relatively late spread and metastasis. Non-small cell lung cancer accounts for about 80-85% of all lung cancers. Statistics show that the current incidence of lung cancer in my country is increasing by 26.9% every year. From 2000 to 2005, the number of lung cancer patients in China is estimated to increase by 120,000 people. Among them, male lung cancer patients increased ...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D401/12C07D401/14C07D409/14C07D413/14C07D239/48A61K31/5377A61K31/506A61P35/00
CPCC07D401/14C07D413/14A61K31/5377C07D401/12C07D239/48C07D409/12C07D409/14A61K31/506A61P35/00A61K45/06A61K9/0019A61K9/08A61K9/12A61K9/14A61K9/20A61K9/48A61K2300/00
Inventor 王学海许勇盛锡军张晓林夏汉贵杨仲文乐洋黄璐肖强
Owner HUBEI BIO PHARMA IND TECHCAL INST
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