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Tricyclic dual PI3K and mTOR inhibitors

A cycloalkyl and heterocyclyl technology, applied in the field of tricyclic PI3K and mTOR dual inhibitors

Inactive Publication Date: 2012-04-04
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there is no PI3K / mTOR dual inhibitor drug on the market. Therefore, it is necessary to develop more structural types of PI3K / mTOR dual inhibitors in order to select compounds with better efficacy and safety for the treatment of cancer.

Method used

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  • Tricyclic dual PI3K and mTOR inhibitors
  • Tricyclic dual PI3K and mTOR inhibitors
  • Tricyclic dual PI3K and mTOR inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1 9(6-methoxypyridine 3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[5,4-c][1, 5] Naphthyridine Preparation of -2(1H)-one (compound 1)

[0149]

[0150] (1) Preparation of 4-chloro-6-(6-methoxypyridine 3-yl)-1,5-naphthyridine 3-carboxylate

[0151]

[0152] Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.472g, 1.74mmol), 6-(methoxy)pyridin-3ylboronic acid (0.535g, 3.5mmol), Pd (PPh 3 ) 2 Cl 2 (0.119g, 0.17mmol) and K 2 CO 3 (0.718g, 5.2mmol) was added to dioxane (10mL) and water (5mL) in sequence, the nitrogen was replaced, the tube was sealed at 90°C for 4h, quenched with water, extracted with dichloromethane, dried, and column chromatography, 0.373 g of the product was obtained, and the yield was 62.4%.

[0153] (2) 4-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]-6-(6-methoxypyridin-3-yl)-1,5-naphthyridine-3-carboxylic acid ethyl Preparation of esters

[0154]

[0155] 4-Aminopiperidine-1-carboxylic acid tert-butyl ester (2.0 g...

Embodiment 2

[0169] Example 2 (R)-1-[1-(2-hydroxypropionyl)piperidin-4-yl]-9-(6-methoxypyridin-3-yl)-3-methyl-3,4 -dihydropyrimide Preparation of pyrido[5,4-c][1,5]naphthyridin-2(1H)-one (compound 2)

[0170]

[0171] Dissolve R-lactic acid (133 mg, 1.2 mmol) in 7 mL of DMF, add 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphoric acid at room temperature Ester (HATU) (456 mg, 1.2 mmol), 9-(6-methoxypyridin-3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimidino [5,4-c][1,5]Naphthyridin-2(1H)-one (compound 1) (405mg, 1.0mmol), stirred overnight at room temperature, poured into 5mL water, precipitated solid, filtered, dried to obtain the product 223 mg, yield 46.8%.

[0172] Molecular formula: C 25 h 28 N 6 o 4 Molecular weight: 476.53 Mass spectrum (M+H): 477

Embodiment 3

[0173] Example 3 9-(6-methoxypyridin-3-yl)-3-methyl-1-[4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl]-3 , 4-dihydropyrimide Preparation of pyrido[5,4-c][1,5]naphthyridin-2(1H)-one (compound 3)

[0174]

[0175] (1) 4-[4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-(trifluoromethyl)phenylamino]-6-(6-methoxypyridine-3- base)-1,5-naphthyridine-3-carboxylate ethyl ester

[0176]

[0177] Refer to (2) in Example 1 for specific operations, throw 4-[4-amino-2-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (3.799g, 11mmol), 4- Ethyl chloro-6-(6-methoxypyridin-3-yl)-1,5-naphthyridine-3-carboxylate (2.5g, 7.27mmol) was used to obtain 3.31g of the product with a yield of 69.8%.

[0178] (2) 4-[4-[3-Formyl-6-(6-methoxypyridin-3-yl)-1,5-naphthyridin-4-ylamino]-2-(trifluoromethyl) Preparation of tert-butyl phenyl]piperazine-1-carboxylate

[0179]

[0180] The specific operation refers to (3) in Example 1, cast 4-[4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-...

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Abstract

The invention which belongs to the technical field of medicines concretely relates to tricyclic dual PI3K and mTOR inhibitors with a general formula represented by formula (I), pharmaceutically acceptable salts thereof, or stereoisomers thereof. In the formula (I), R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, X, A, and B are defined in the specification. The invention also relates to a preparation method of above compounds, a medicinal preparation containing the compounds, and an application of the compounds in the preparation of medicines for treating and / or preventing proliferative diseases responding to the inhibition of the activity of lipase and / or PI3-kinase-related protein kinase, especially the PI3 kinase and / or mTOR.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and specifically relates to a tricyclic PI3K and mTOR dual inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a preparation method of these compounds, a pharmaceutical preparation containing these compounds, and these compounds Use in the preparation of a medicament for the treatment and / or prevention of proliferative diseases responsive to inhibition of lipase and / or PI3-kinase-related protein kinases, especially PI3 kinase and / or mTOR activity. 2. Background technology [0002] Tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in the genetic material of cells, resulting in abnormal gene expression and abnormal proliferation of cells. Tumor cells lose their normal growth regulation function and have the ability to grow independently or relatively independently. When the tumorigenic factors are stopped, they can c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14C07D519/00A61K31/519A61P35/00A61P35/02A61P29/00A61P37/08A61P37/06A61P17/06A61P13/08A61P43/00
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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