Novel fused pyridine derivatives useful as c-Met tyrosine kinase inhibitors

A kind of compound and chelate technology, applied in the field of novel fused pyridine derivatives

Active Publication Date: 2015-04-08
BETTA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although c-Met and HGF are expressed in various tissue types, they are usually restricted to cells of epithelial and mesenchymal origin

Method used

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  • Novel fused pyridine derivatives useful as c-Met tyrosine kinase inhibitors
  • Novel fused pyridine derivatives useful as c-Met tyrosine kinase inhibitors
  • Novel fused pyridine derivatives useful as c-Met tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0382] N-(4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-oxyl)-3-fluorophenyl)-5-(4-fluorophenyl)- 4-oxo-1,4-dihydropyridine-3-carboxamide (product 1);

[0383]

[0384] Step 0. Preparation of Acid 1

[0385]

[0386] 1. Preparation of A11

[0387] To dichloromethane (450ml) was added Maxwell's acid (50.32g) followed by pyridine (70.35g). The temperature was lowered to 0° C., A10 (62.28 g) was added dropwise, and the reaction was maintained at this temperature for 2.5 hours (TLC showed that the reaction was complete). Add dichloromethane (300ml), mix and then disperse into 1N HCl (750ml), stir, place to separate, dry and concentrate the organic phase, and dry in vacuo to obtain a solid, ie A11 (66.70g).

[0388] 2. Preparation of A12

[0389] Add A11 (66.7g) into ethanol (400ml), heat to 87°C and stir overnight. The reaction mixture was cooled and the solvent was removed to give an oily substance (55 g). The obtained oily substance was dissolved in DMF / DMA (200ml), hea...

Embodiment 2

[0407] N-(3-fluoro-4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-8-oxyl)phenyl)- 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (product 2);

[0408]

[0409] Step 1. Preparation of Compound 21

[0410] Compound 20 (184 mg, 1.0 mmol), 2-fluoro-4-amino-phenol (190 mg, 1.5 mmol) and cesium carbonate (652 mg, 2.0 mmol) were dissolved in N-methylpyrrolidone (3 ml). in N 2The reaction mixture was heated to 180° C. overnight. The reaction mixture was poured into water (50ml), extracted with ethyl acetate (100ml), washed with brine, dried, concentrated and purified by column chromatography to give compound 21 (105mg).

[0411] Step 2. Preparation of product 2

[0412] HATU (76 mg, 0.2 mmol), DIPEA (26 mg, 0.2 mmol), and acid 1 (25.6 mg, 0.11 mmol) were dissolved in DCM (3 ml). After stirring at 0°C for 15 minutes, compound 21 (27 mg, 0.1 mmol) was added and reacted at room temperature for 4 hours. After the reaction was completed, the reaction mixture was con...

Embodiment 3

[0414] N-(4-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-8-oxyl)-3-fluorophenyl)-5-(4-fluoro Phenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (product 3);

[0415]

[0416] Step 1. Preparation of compound 31

[0417] Compound 30 (1.52g, 10mmol), 3,4-difluoronitrobenzene (1.75g, 11mmol) and cesium carbonate (3.60g, 11mmol) were dissolved in DMF (15ml). The reaction was stirred overnight at room temperature. After the reaction was completed (TLC detection), water (400ml) was added, extracted with ethyl acetate (800ml), washed with brine, dried and purified to obtain compound 31 (2.20g).

[0418] Step 2. Preparation of compound 32

[0419] Compound 31 (2.20 g) was dissolved in methanol (100 ml), and 5% Pd / C (0.8 g) was added. Access to H 2 , and the reaction was stirred to completion. Pd / C in the reaction mixture was removed by filtration, and the filtrate was concentrated to obtain compound 32 (1.60 g).

[0420] Preparation of step 3 product 3

[0421] The target product ...

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PUM

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Abstract

This invention relates to novel fused quinazoline derivatives of Formula I as c-Met inhibitors, their synthesis and uses for treating c-Met mediated disorders.

Description

technical field [0001] The invention relates to a series of novel condensed pyridine derivatives as c-Met inhibitors, their preparation method and their application in treating c-Met regulation disorder. Background technique [0002] Novel molecular reagents targeting specific signaling pathways associated with disease are of potential therapeutic benefit, and therefore, the study of signaling pathways in normal and pathological states is of great value. [0003] Receptor tyrosine kinases (RTKs) are key enzymes in signaling pathways, which catalyze the autophosphorylation of tyrosine residues in the cytoplasmic C-terminal domain of proteins. Creating binding sites recruits downstream proteins and initiates a cascade of signaling involved in cell growth, proliferation and survival. More generally, deregulation of kinase signaling is implicated in the interplay of diverse pathological states including immunology, inflammatory disease, cardiovascular disease, and neurodegenera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/12C07D487/02A61K31/4353A61P35/00
CPCC07D471/04C07D498/04C07D513/04
Inventor 胡邵京王飞许志国王燕萍王印祥
Owner BETTA PHARM CO LTD
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