Triazine double aromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof

A technology of epidermal growth factor and aromatic ring, which is applied in the direction of active ingredients of heterocyclic compounds, drug combinations, and pharmaceutical formulas, and can solve problems such as cancer recurrence in patients

Active Publication Date: 2019-10-22
YA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients who develop secondary drug mutations to these drugs suffer from cancer recurrence within a few months

Method used

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  • Triazine double aromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof
  • Triazine double aromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof
  • Triazine double aromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: 2-{1'-N,N-dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro- 6'-quinoxaline}-4-(1"-methyl-1H-3"-indole) triazine (compound 601)

[0034]

[0035] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)triazine:

[0036]

[0037] 2,4-dichlorotriazine (0.60g, 4mmol) was dissolved in ethylene glycol dimethyl ether (20mL), stirred under ice bath, ferric chloride (0.77g, 4.59mmol) was added in batches, and then The reaction was stirred at room temperature for 15 minutes. Then N-methylindole (0.68 g, 5.2 mmol) was added dropwise, followed by heating to 60° C. and stirring the reaction for 24 hours. Stop the reaction, lower to 0°C, add 3.5mL of methanol and 9mL of water, and then stir the reaction at room temperature for 3 hours. A large amount of solid precipitated, filtered, washed the filter cake with methanol, and dried to obtain 0.70 g of yellow solid, yield: 72%. LC / MS (ESI): m / z 245 (M+H) + .

[0038] Preparation of tert-butyl 4-fluoro-2...

Embodiment 2

[0062] Example 2: 2-{1'-N,N-dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro- Preparation of 6'-quinoxaline}-4-(1"-methyl-7"-aza-1H-3"-indole)triazine (compound 602):

[0063]

[0064] Preparation of 2-chloro-4-(1'-methyl-7'-aza-1H-3'-indole)triazine:

[0065]

[0066]1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-B]pyridine ( 0.74g, 2.87mmol) and 2,4-dichlorotriazine (0.51g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL), then dichlorodi-tert-butyl-(4-dimethyl Aminophenyl)phosphine palladium(II) (0.31g, 0.19mmol), 2M sodium carbonate solvent (3.2mL, 6.3mmol). Under nitrogen protection, stirred and heated to 80°C for 4 hours. The reaction was complete as detected by TLC. The reaction was stopped and diluted with water (1 mL). Ethyl acetate (25mL) extracted twice, anhydrous MgSO 4 After drying and concentration, the crude product was separated by flash column to obtain 457 mg of yellow solid, yield: 65%. ...

Embodiment 3

[0073] Example 3: 2-{1'-N,N-Dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro-6 '-quinoxaline}-4-(3"-pyrazol[1,5-a]pyridine)triazine (compound 603)

[0074]

[0075] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)triazine:

[0076]

[0077] Pyrazolopyridine (1,5,-A)-3-boronate (0.70 g, 2.87 mmol) and 2,4-dichlorotriazine (0.51 g, 3.44 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL), then dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (0.13 g, 0.19 mmol), 2M sodium carbonate solvent (32 mL, 6.3 mmol) was added with stirring. Under nitrogen protection, stir and heat to 80° C. for 4 hours. The reaction was complete as detected by TLC. The reaction was quenched and diluted with water (2 mL). Ethyl acetate (25mL) extracted twice, anhydrous MgSO 4 After drying and concentration, the crude product was separated by flash column to obtain 378 mg of yellow solid, yield: 57%. LC / MS (ESI): m / z 232 (M+H) + .

[0078] 2...

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Abstract

The invention discloses a selective inhibitor of a clinical mutant of EGFR protein tyrosine kinase, the selective inhibitor is a triazine-containing double aromatic ring template compound and has a structure as shown in a formula (I), and the invention also discloses a preparation method of the compound and application of the compound as the selective inhibitor of the clinical mutant of the EGFR protein tyrosine kinase, in particular the inhibition effect on T790M variant epidermal growth factor receptor EGFR and the treatment of diseases such as renal cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and glioblastoma related to overexpression of the epidermal growth factor receptor EGFR.

Description

technical field [0001] The present invention relates to triazine bisaromatic ring derivatives. Background technique [0002] Epithelial growth factor EGFR (epithelial growth factor receptor) is a 170kDa transmembrane glycoprotein receptor tyrosine kinase, which is activated by epidermal growth factor and affects cell growth and differentiation. Binding of EGF or TGFα to EGFR activates the receptor's tyrosine kinase activity. The tyrosine residues Tyr1068, Tyr1148, and Tyr1173 at the carboxy-terminus of EGFR are the main sites for autophosphorylation following EGF binding. Once activated, phosphorylated tyrosine residues at positions 1068 and 1173 of EGFR mediate the binding of Grb2 to EGFR. In addition, the phosphorylated tyrosine residue at position 1173 is the main binding site of SHC on EGFR. EGFR is widely distributed in many normal and malignant epithelial cells, and its overexpression and self-activation may be related to the occurrence and development of many tumor...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D471/04C07D403/12A61K31/53A61K31/5377A61P35/00
CPCC07D403/14C07D471/04C07D403/12A61P35/00
Inventor 梁永宏曾兆森凌苑
Owner YA THERAPEUTICS INC
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