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N-phenyl substituted 1H-indazole-3-amine compound and preparation and application of N-phenyl substituted 1H-indazole-3-amine compound in antitumor activity

An amine compound and antitumor drug technology, applied in the field of medicinal chemistry, can solve the problems of not widely clinical application, increase the nucleus structure of non-small cell lung cancer, and reduce the nucleus structure of non-small cell lung cancer, and achieve good inhibitory effect, Good anti-tumor effect

Active Publication Date: 2022-01-21
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Comprehensive research at home and abroad has found that seven types of small-molecule inhibitors of EGFR tyrosine kinases have been formed through the structural modification of the quinazoline core. Among them, only quinazolines and 2,4-disubstituted pyrimidines have a Small cell lung cancer has a good inhibitory effect, but the treatment of non-small cell lung cancer has the disadvantage of less mother nucleus structure and is not widely used in clinical practice
In this regard, we are the first to propose an EGFR inhibitor with indazole as the mother nucleus, aiming to increase the treatment of non-small cell lung cancer. There is a shortcoming that the mother nucleus structure is not widely used in clinical practice.

Method used

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  • N-phenyl substituted 1H-indazole-3-amine compound and preparation and application of N-phenyl substituted 1H-indazole-3-amine compound in antitumor activity
  • N-phenyl substituted 1H-indazole-3-amine compound and preparation and application of N-phenyl substituted 1H-indazole-3-amine compound in antitumor activity
  • N-phenyl substituted 1H-indazole-3-amine compound and preparation and application of N-phenyl substituted 1H-indazole-3-amine compound in antitumor activity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The synthesis of embodiment 1 compound

[0032] 1.1 The specific synthetic route of compound (alkali listed in route, solvent and acid-binding agent are only exemplary, not limitation of the present invention) as follows:

[0033]

[0034] The general synthetic method of reaction formula 1 compound DF1-DF16

[0035] Reagents and reaction conditions: (a) iodine, KOtBu, THF, 0℃, 2h; (b) (Boc) 2 O, DMAP, THF, rt, 2h; (c) Pd 2 (dba) 3 ,Xantphos,Cs 2 CO 3 ,N 2 , toluene, 6h.(d)Pd(pph 3 )4 ,NaOH,dioxane:H 2 O(4:1),N 2 , 90°C, react overnight.

[0036] 1.2 Examples of synthetic steps

[0037] (1) Synthesis of Intermediate 1: Step 1: Take a clean and dry 50mL round-bottomed flask and put it into a stirring bar. Dissolve 2g (10.15mmol) of 6-bromoindazole in 20mL of anhydrous THF, add 2.28g (20.30mmol) of KOtBu several times in small amounts under ice bath, and add 3.9g (15.37mmol) of iodine after 10 minutes of activation, The reaction was continued under an ice ba...

Embodiment 2

[0096] Embodiment 2 compound antitumor cell activity (kinase experiment)

[0097] 2.1 Experimental operation steps

[0098] (1) Prepare 1×Kinase buffer.

[0099] (2) Preparation of compound concentration gradients: the test compound concentration was 10 μM, repeated wells were detected, and a solution with a final concentration of 100 times was prepared in a 384-well plate. Then use Echo550 to transfer 250nl to 384 reaction plate for later use. Add 250 nl of 100% DMSO to negative control wells and positive control wells respectively.

[0100] (3) Prepare a kinase solution with a final concentration of 2.5 times with 1×Kinase buffer.

[0101] (4) Add 10 μL of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 μL of 1×Kinase buffer to negative control wells.

[0102] (5) Centrifuge at 1000 rpm for 30 seconds, shake and mix well, and incubate at room temperature for 10 minutes.

[0103] (6) Use 1×Kinase buffer to prepare a mixe...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an N-substituted (4-(4-ethyl piperazine-1-yl) phenyl)-6-phenyl-1H-indazole-3-amine compound taking EGFRL858R as a target spot. The compound can selectively inhibit phosphorylation of EGFR kinase so as to treat malignant tumors closely related to the kinase and reduce adverse reactions. The compound can be used for treating EGFR enzyme related tumors or diseases. The compound is represented by general formula (1), wherein R1 can be selected from various substituent groups. The N-substituted (4-(4-ethyl piperazine-1-yl) phenyl)-6-phenyl-1H-indazole-3-amine compound taking the EGFR as the target spot has a good inhibition effect on EGFRL858R kinase and has an anti-proliferation effect on EGFR dependent tumor cell strain cells; the compound can be used for anti-tumor drugs and has a good anti-tumor effect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to an N-substituted (4-(4-ethylpiperazin-1-yl)phenyl)-6-phenyl-1H-indazol-3-amine target To EGFR L858R small molecule inhibitors and their preparation and application of anti-tumor activity. Background technique [0002] Lung cancer is one of the cancers with the highest incidence rate. It is mainly divided into small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma and large cell lung cancer. With the development of the disease, about 80% of lung cancer patients will change for non-small cell lung cancer. With the development of molecular biology and other disciplines, targeted therapy of epidermal growth factor receptor (EGFR) has gradually become a research hotspot. EGFR is one of the most potential drug targets for the treatment of NSCLC. It is a member of the ErbB family and plays an important role in cell proliferation, survival, migration, adhesio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/496A61P35/00
CPCC07D401/04A61P35/00Y02P20/55
Inventor 叶发青陈波杜宗轩屠思军杨小娇孙艳亭刘志国
Owner WENZHOU MEDICAL UNIV
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