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Nitrogen heterocyclic ring compound, preparation method, midbody, composition and application

A nitrogen heterocyclic compound and compound technology, applied in the field of nitrogen-containing heterocyclic compounds, can solve the problems of poor compound effect and the like

Active Publication Date: 2019-03-05
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The problem to be solved by the present invention is the disadvantages of existing compounds such as poor effect, and provides a nitrogen-containing heterocyclic compound, preparation method, intermediate, composition and application

Method used

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  • Nitrogen heterocyclic ring compound, preparation method, midbody, composition and application
  • Nitrogen heterocyclic ring compound, preparation method, midbody, composition and application
  • Nitrogen heterocyclic ring compound, preparation method, midbody, composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0408]

[0409] N-(3-(4-((4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)quinazole Synthesis of olin-6-yl)cyclohexyl-3-en-1-yl)acrylamide

[0410] Step A: Preparation of 2-chloro-6-hydrazinopyrimidine: 2,6-dichloropyrimidine (25g, 167.81mmol) was dissolved in 350mL isopropanol, and hydrazine hydrate (29.5g, 503.44 mmol, 85%), exothermic during the dropwise addition and a white solid precipitated, and stirred at room temperature for 1 hour after the addition. The solvent was removed under reduced pressure, the residue was stirred with water (50 mL) for 30 minutes, filtered, the filter cake was washed with water, and dried to obtain 22.4 g of a white solid with a yield of 92.3%.

[0411] Step B: Preparation of 7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine: 2-chloro-6-hydrazinopyrimidine (21 g, 145.27 mmol) was dispersed in 210 mL of trimethylorthoformate The ester was stirred overnight at 60°C, and the reaction liquid became clear. Add p-toluenesulfonic acid ...

Embodiment 2

[0420]

[0421] N-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)-3-methylphenyl)-6-(3-amino-1H-pyridine Synthesis of oxazol-5-yl)quinazolin-4-amine

[0422] Step A: Preparation of 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylic acid tert-butyl ester: 5-bromo-1H-pyrazol-3-amine (250 mg, 1.54mmol), triethylamine (627mg, 6.19mmol) and di-tert-butyl dicarbonate (846mg, 3.87mmol) were added to dichloromethane (10mL), and then 4-dimethylaminopyridine (38mg, 0.31mmol ), the resulting reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue which was separated by column chromatography to obtain 135 mg of a white solid with a yield of 24%.

[0423]Step B: (E)-(5-(3-cyano-4-(((dimethylamino)methylene)amino)phenyl)-1H-pyrazol-3-yl)carbamate tert-butyl ester Preparation: tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylate (1...

Embodiment 3

[0427]

[0428] (R)-N-(1-(4-((4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)-3-methylphenyl) Synthesis of amino)quinazolin-6-yl)piperidin-3-yl)acrylamide

[0429] Step A: Preparation of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: 2-amino -5-Bromo-benzonitrile (1000mg, 5.08mmol), bis-pinacol borate (1930mg, 7.60mmol), potassium acetate (1490mg, 15.18mmol) and [1,1'-bis(diphenyl Phosphine)ferrocene]dichloropalladium dichloromethane complex (21mg, 0.05eq.) was mixed in 1,4-dioxane (15mL), and the mixture was stirred at 80°C for 16 hours under the protection of argon . Celite was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (10 mL), and washed with saturated brine (10 mL). The organic phase was separated and dried with anhydrous sodium sulfate, filtered, concentrated and the residue obtained was separated and purified by silica gel column to obtain 1400 mg of white solid with a y...

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Abstract

The invention discloses a nitrogen heterocyclic ring compound, a preparation method, a midbody, a composition and an application. The invention provides a nitrogen heterocyclic compound as shown in formula I, a pharmaceutically-acceptable salt, an enantiomer thereof, diastereoisomer, a tautomer, a solvent compound, a metabolism product or a drug precursor. The compound has high inhibition activityfor ErbB2 tyrosine kinase, and good inhibition actitivity for ErbB2 highly-expressed human breast cancer cell BT-474 and human gastric carcinoma cells NCI-N87, and has relatively weak inhibition activity for EGFR kinase. The nitrogen heterocyclic ring compound is an EGFR / ErbB2 double-target inhibitor capable of weakening the inhibition activity of EGFR kinase or a small-molecular inhibitor with selectivity for ErbB2 target. (Shown in the description).

Description

technical field [0001] The invention relates to a nitrogen-containing heterocyclic compound, a preparation method, an intermediate, a composition and an application. Background technique [0002] The epidermal growth factor receptor (EGFR, also known as ErbB or HER) family includes four receptor tyrosine kinases, namely EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). Several investigators have demonstrated the role of EGFR and ErbB2 in cancer progression, and squamous cell carcinomas of the head, neck and lung also express high levels of EGFR. Overexpression of ErbB2 occurs in 30% of all breast cancers and is also associated with other human cancers such as colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate cancers. ErbB2 overexpression is also associated with poor prognosis in other cancers, including metastasis and early recurrence. [0003] The epidermal growth factor receptor family has become an active field of anticancer research,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D403/12A61K31/519A61K31/517A61K31/5377A61P35/00C07F9/6512C07F9/40C07D401/12C07D413/12C07D401/14C07D413/14C07F9/6533C07C257/12
CPCA61P35/00C07C257/12C07D401/12C07D401/14C07D403/12C07D413/12C07D413/14C07D471/04C07D487/04C07F9/40C07F9/6533A61K31/517A61K31/519A61K31/5377A61K31/541C07D519/00C07F9/6512Y02P20/55
Inventor 夏广新李迪张晶段灵峻左洪剑萧文博徐佳刘彦君
Owner SHANGAI PHARMA GRP CO LTD
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