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Fused pyridones as kinase inhibitors

A compound, selected technology, applied in the direction of drug combination, organic chemistry, medical preparations containing active ingredients, etc.

Active Publication Date: 2022-05-03
SHANGHAI JEMINCARE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no specific targeted drug that acts on this target

Method used

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  • Fused pyridones as kinase inhibitors
  • Fused pyridones as kinase inhibitors
  • Fused pyridones as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Embodiment 1: the preparation of compound 1

[0136] Step 1: Preparation of Compound 1-2

[0137]

[0138] The raw materials chloral hydrate (22g, 133.01mmol, 17.32mL) and sodium sulfate (168.20g, 1.18mol, 120.14mL) were dissolved in water (360mL), the system was heated to 35°C, and the raw materials 1-1( 25g, 131.57mmol) in aqueous solution (120mL), hydrochloric acid (12M, 14.80mL) and hydroxylamine hydrochloride (29.26g, 421.02mmol). After the addition was complete, the system was heated to 90°C for 16 hours. A yellow precipitate appeared in the system, the system was cooled to room temperature, filtered to obtain a filter cake, washed with water, dissolved in ethyl acetate (300mL), filtered, and the filtrate was concentrated to obtain compound 1-2, which was directly used in the next reaction without further purification .

[0139] MS(ESI)m / z(M+H) + =262.9.

[0140] Step 2: Preparation of Compound 1-3

[0141]

[0142] At 60°C, compound 1-2 (30.8g, 117.99...

Embodiment 2

[0228] Embodiment 2: the preparation of compound 2

[0229] Step 1: Preparation of compound 2-2

[0230]

[0231] Dissolve compound 1-13 (500mg, 0.96mmol), 2-1 (323.0mg, 1.252mmol), N,N-diisopropylethylamine (246.0mg, 1.926mmol) in acetonitrile (4mL), and add , the system was heated to 110°C and stirred for 10 h. After cooling the system, the system was concentrated to obtain a crude product. The crude product was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-25%) to obtain compound 2-2.

[0232] MS(ESI)m / z:(M+H) + =743.2

[0233] Step 2: Preparation of compound 2-3

[0234]

[0235] Compound 2-2 (115 mg, 0.155 mmol) and iron powder (30.0 mg, 0.5414 mmol) were dissolved in acetic acid (3.0 mL), and the system was heated to 80° C. and stirred for 2 h. After the system was cooled, the reaction was quenched with water, extracted with ethyl acetate (10mL x 2), the organic phases were combined, dried over anhydrous sodium sul...

Embodiment 3

[0266] Embodiment 3: the preparation of compound 3

[0267] Step 1: Preparation of compound 3-1

[0268]

[0269] Compound 2-6 (50mg, 0.087mmol), ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (42.0 mg, 0.0957 mmol) and 1,8-diazabicycloundec-7-ene (55.0 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), The system was heated to 100°C and stirred for 1 h. After the system was cooled, it was quenched with water, extracted with ethyl acetate (5mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by a medium-pressure preparative column (methanol / dichloromethane (v / v)=0~10%), the target compound 3-1 was obtained.

[0270] MS(ESI)m / z:(M+H) + =692.2

[0271] Step 2: Preparation of compound 3-2

[0272]

[0273] Compound 1-19A (45mg, 0.39mmol) and sodium hydride (15.6mg, 0.39mmol, 60% purity) were di...

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PUM

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Abstract

The present invention discloses fused pyridone compounds as kinase inhibitors. Specifically, the present invention discloses compounds represented by formula (I), their optical isomers and pharmaceutically acceptable salts thereof, and the compounds as Use of KRAS inhibitors.

Description

technical field [0001] The present invention relates to the compound represented by formula (I), its optical isomer and its pharmaceutically acceptable salt, and the application of the compound as KRAS inhibitor. Background technique [0002] Cancer has ranked first among the top ten causes of death in China for 31 years in a row. Lung cancer is one of the tumors with the highest incidence rate. Non-small cell lung cancer accounts for more than 80%. At the same time, the incidence of lung cancer is high and there are many types of mutations. In order to enrich the company's R&D pipeline and focus on unmet medical needs, the research and development of innovative drugs for cancer treatment is very necessary for the company's long-term development and has important economic and social significance. [0003] About 30% of cancer patients have RAS gene mutations. In the study of cancer genes, scientists have discovered as early as 20 years ago that the RAS gene is a key gene in ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14C07D519/00A61K31/4985A61K31/5377A61K31/506A61P35/00
CPCC07D471/14C07D519/00A61P35/00
Inventor 郭淑春范珺刘洋包方彭建彪郭海兵
Owner SHANGHAI JEMINCARE PHARMA CO LTD