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2-aminopyrimidine compound and application thereof

An aminopyrimidine and compound technology, which can be used in compounds, drug combinations, organic chemistry, etc.

Pending Publication Date: 2019-10-08
JINAN UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with EGFR with L858R sensitive mutation, EGFR with secondary mutation of L858R / T790M has a stronger affinity for ATP, and the first-generation drugs are ATP competitive inhibitors, thus leading to drug resistance
Although the second-generation EGFR irreversible inhibitors have achieved good results in preclinical studies, they are not effective against wild-type EGFR (EGFR WT ) lacks selectivity and has greater toxicity
Further mechanistic studies showed that the point mutation of (EGFR) C797S changed the cysteine ​​at position 797 to serine, which resulted in the inability of Osimertinib to form a covalent bond with the target protein, eventually causing drug resistance
At present, there is still a lack of effective EGFR inhibitors for the new mutation (C797S) alone

Method used

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  • 2-aminopyrimidine compound and application thereof
  • 2-aminopyrimidine compound and application thereof
  • 2-aminopyrimidine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0166] (2-((5-chloro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-trifluoromethylphenyl)amino)pyrimidine -4-yl) amino) phenyl) dimethyl phosphorus oxide (LS2-31)

[0167] The synthetic route is as follows:

[0168]

[0169] Step 1. Preparation of (2-aminophenyl) dimethyl phosphorus oxide (2)

[0170] O-iodoaniline (1,5.06g, 23mmol), dimethyl phosphorus oxide (2.20g, 27.2mmol), palladium acetate (0.26g, 1.2 mmol), 4,5-bisdiphenylphosphine-9,9- Dimethylxanthene (0.67g, 1.2mmol) and potassium phosphate (5.40g, 25.4mmol) were dissolved in 50ml of N,N-dimethylformamide solvent, and reacted overnight at 120°C under argon protection. After the reaction was complete, most of the solvent was spin-dried under reduced pressure, extracted three times with dichloromethane / water, the organic layers were combined, washed with saturated brine, dried with anhydrous sodium sulfate and spin-dried, and separated by column chromatography to obtain a solid 3.2 g, yield 82%.

[0171] 1...

Embodiment 2

[0190] (2-((5-chloro-2-((5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino) Pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (LS2-39)

[0191]

[0192] The synthetic method refers to Example 1, and the yield is 67%.

[0193] 1 H NMR (400MHz, CDCl 3 )δ8.45-8.35(m,1H),8.18(d,J=2.5Hz,1H),8.08(s,1H),7.84 (d,J=2.5Hz,1H),7.62(ddd,J 1 =14.1Hz,J 2 =7.7Hz,J 3 =1.4Hz, 1H), 7.54(t, J=7.9Hz, 1H), 7.32-7.20(m, 1H), 3.39(d, J=12.4Hz, 2H), 3.09-2.65(m, 9H), 2.64 -2.32(m,5H),2.22(s,3H), 2.08-1.93(m,2H),1.87(s,3H),1.83(s,3H),1.76-1.65(m,2H).

[0194] MS(ESI):m / z 569[M+H] + .

Embodiment 3

[0196] (2-((5-chloro-2-((3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine-4- Base) amino) phenyl) dimethyl phosphorus oxide (LS2-40)

[0197]

[0198] The synthetic method refers to Example 1, and the yield is 58%.

[0199] 1 H NMR (400MHz, CDCl 3 )δ10.94(s,1H),8.58(dd,J 1 =8.4Hz,J 2=4.4Hz, 1H), 8.08(s, 1H), 7.76(d, J=2.5Hz, 1H), 7.55(t, J=7.9Hz, 1H), 7.33-7.28(m, 1H), 7.21(dd ,J 1 =8.6Hz,J 2 = 2.5Hz,1H),7.16-7.08(m,1H),6.98(d,J=8.7Hz,1H),6.84(s,1H),3.40(d,J=11.7Hz,2H), 2.84-2.46 (m,9H),2.46-2.37(s,1H),2.33(s,3H),2.05-1.89(m,3H),1.84(d,J=13.1Hz,6H), 1.81-1.73(m,2H ).

[0200] MS(ESI):m / z 588[M+H] + .

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Abstract

The invention relates to a 2-aminopyrimidine compound and application thereof. The structure of the 2-aminopyrimidine compound is shown as I. The compound can effectively inhibit the activity of EGFRprotein kinase resistance mutants (such as EGFRT790M and EGFRT790M / C797S), and can overcome clinical drug resistance of tumor patients such as patients suffering from non-small cell lung cancer induced by an existing third-generation selective EGFRT790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rocketinib (CO-1686) and the like.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a 2-aminopyrimidine compound and its application. Background technique [0002] Tumor molecular targeted therapy is a treatment method based on the selective killing of tumor cells by chemical or biological means to key molecules closely related to tumor growth. The characteristics of targeted therapy are: high specificity, strong selectivity, and mild side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence. Imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003), erlotinib (OSI774) (Genentech and OSIP, 2004), sorafenib p-toluenesulfonate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and dasatinib (BMS-354825) (Bristol-Myers Squibb, 2006) represented by targeted drugs has created a new era for tumor chemotherapy. Tumor ...

Claims

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Application Information

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IPC IPC(8): C07F9/6506C07F9/6558C07F9/6561A61P35/00A61P35/02A61K31/675
CPCA61P35/00A61P35/02C07F9/65583C07F9/65586C07F9/6561
Inventor 丁克丁健李姗谢华陆小云耿美玉任小梅童林江
Owner JINAN UNIVERSITY
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