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Indazole cyclotriazole compound as well as preparation method and application thereof

A technology of indazole-linked triazoles and compounds, which is applied in the field of inhibitor preparation and can solve problems such as adverse reactions and drug resistance

Active Publication Date: 2022-06-03
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but there are problems such as drug resistance and other clinical adverse reactions.

Method used

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  • Indazole cyclotriazole compound as well as preparation method and application thereof
  • Indazole cyclotriazole compound as well as preparation method and application thereof
  • Indazole cyclotriazole compound as well as preparation method and application thereof

Examples

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preparation example Construction

[0045] A preparation method of the above-mentioned indazole-linked triazole compound, comprising the following steps:

[0046] 1) 4-bromo-2-fluorobenzonitrile reacts with hydrazine monohydrate to prepare 6-bromo-1H-indazol-3-amine;

[0047] 2) Under nitrogen protection, 6-bromo-1H-indazol-3-amine reacts with trimethylsilyl acetylene to prepare 6-((trimethylsilyl)ethynyl)-1H-indazol-3-amine ;

[0048]3) Use tetrabutylammonium fluoride trihydrate to remove trimethylsilyl from 6-((trimethylsilyl)ethynyl)-1H-indazol-3-amine to obtain 6-ethynyl-1H- indazol-3-amine;

[0049] 4) substitution reaction of L-hydroxyproline and di-tert-butyl dicarbonate in ice-water bath to prepare L-hydroxyproline (Boc-L-hydroxyproline) protected by tert-butoxycarbonyl;

[0050] 5) Boc-L-hydroxyproline is condensed with a substituted aniline compound to form an ammoniated Boc-L-hydroxyproline compound; the substituted aniline compound is 5-amino-2-chlorotrifluoromethane benzene, 2,4-dichloroaniline,...

Embodiment 1

[0069] An indazole ring-linked triazole compound, R 1 4-Cl-3-CF 3 , R 2 For H, when R' is Boc or H, the preparation method is as follows:

[0070] 1) Synthesis of 6-bromo-1H-indazol-3-amine: Dissolve 4-bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) in n-butanol (20 mL), then add hydrazine monohydrate (1.0 mL, 50.3 mmol). The reaction mixture was heated to reflux for 4 h, cooled to room temperature, filtered, washed with n-hexane and dried to obtain 4.77 g of a white solid with a yield of 85%.

[0071] 2) Synthesis of 6-((trimethylsilyl)ethynyl)-1H-indazol-3-amine: 6-bromo-1H-indazol-3-amine (3.42g, 16.12mmol), CuI ( 10%, 0.31g, 1.61mmol), and Pd (PPh 3 ) 4 (10%, 1.86 g, 1.61 mmol) was added to a 100 mL two-necked round bottom flask with condenser and magnetic stirring. The vessel was then sealed with a rubber stopper, evacuated and backfilled with nitrogen (3 times). Using triethylamine (30 mL) as base and solvent, inject with syringe. After 5 min at room temperature, ...

Embodiment 2

[0080] An indazole ring-linked triazole compound, R 1 4-Cl-3-CF 3 , R 2 When being an acetyl group, the preparation method is as follows:

[0081] Steps 1) to 8) are the same as in Example 1, to obtain (2S,4S)-4-(4-(3-amino-1H-indazol-6-yl)-1H-1,2,3-triazole -1-yl)-2-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0082] 9) (2S,4S)-4-(4-(3-acetylamino-1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)-N-(4 - Preparation of chloro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide (IDZ3): compound (2S,4S)-4-(4-(3-amino-1H-indazole-6) -yl)-1H-1,2,3-triazol-1-yl)-2-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate Tert-butyl acid (0.30 g, 0.51 mmol) was dissolved in 30 mL of anhydrous dichloromethane and triethylamine (0.37 mL, 2.7 mmol) was added. The solution was stirred at 0° C. for 30 min, and acetyl chloride (43 μL, 0.61 mmol) in dichloromethane (2 mL) was added dropwise. The solution was reacted at room te...

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Abstract

The invention discloses an indazole cyclotriazole compound as well as a preparation method and application thereof, a drug design strategy based on fragments is adopted, and a halogenated substituent group is introduced to an end benzene ring while amino acylation is performed on an indazole ring, so that an indazole cyclotriazole compound library with kinase inhibition activity is constructed; the tyrosine kinase inhibitor with Bcr-Abl kinase inhibition activity is found through kinase activity screening, and the tyrosine kinase inhibitor can be used for preparing antitumor drugs, has certain activity of inhibiting Bcr-AblWT and Bcr-AblT315I kinase, and has certain cell proliferation inhibition activity on K562 cells. Meanwhile, an activity test shows that indazoletriazole has an important effect on the inhibition activity of a compound, can improve the affinity between a receptor and the compound, and can be used as a pharmacological fragment of a Bcr-Abl tyrosine kinase inhibitor.

Description

technical field [0001] The invention belongs to the technical field of inhibitor preparation, and relates to an indazole ring-linked triazole compound and a preparation method and application thereof. Background technique [0002] Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease that occurs in bone marrow hematopoietic stem cells, accounting for 15% to 20% of adult leukemia patients. It is characterized by the detection of Ph chromosome in CML patients. Ph chromosome is a cluster of breakpoint clusters formed by the mutual translocation of human normal chromosome 22 and chromosome 9-Albeson (Bcr-Abl) fusion gene, which encodes Bcr that produces continuous activation of tyrosine kinase activity -Abl fusion protein. At present, there are small molecule tyrosine kinase inhibitors targeting Bcr-Abl on the market, but they all have problems such as drug resistance and other clinical adverse reactions. Subsequently, research and development of novel Bcr...

Claims

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Application Information

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IPC IPC(8): C07D403/14A61P35/00A61P35/02
CPCC07D403/14A61P35/00A61P35/02Y02P20/55
Inventor 潘晓艳张杰卢闻柳南辛张晴晴司茹王瑾
Owner XI AN JIAOTONG UNIV
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