Pyrido[1,2-a]pyrimidone analogs as mTOR/PI3K inhibitors

A compound, selected technology, applied in the field of the compound represented by the formula or its pharmaceutically acceptable salt

Active Publication Date: 2016-04-06
SHANGHAI JIA TAN PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is currently no drug that can inhibit both PI3K and mTOR on the market. Therefore, it is necessa

Method used

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  • Pyrido[1,2-a]pyrimidone analogs as mTOR/PI3K inhibitors
  • Pyrido[1,2-a]pyrimidone analogs as mTOR/PI3K inhibitors
  • Pyrido[1,2-a]pyrimidone analogs as mTOR/PI3K inhibitors

Examples

Experimental program
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Effect test

Embodiment 1

[0107] 2,4-Difluoro-N-(2-methoxy-5-(4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)pyridin-3-yl)benzenesulfonamide

[0108]

[0109] a) (E)-5-(((5-bromopyridin-2-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6 - dione

[0110]Triethyl orthoformate (25.8g, 0.174mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.1g, 0.174mol) were placed in the three neck In a round bottom flask, the reaction was stirred at 60°C for 2 hours. A solution of 2-amino-5-bromopyridine (30 g, 0.174 mol) in ethanol (150 mL) was added dropwise to the above mixture. The reaction solution was stirred at 60°C for 2 hours. The mixture was cooled to 25°C, filtered, and the filter cake was rinsed with ethanol (200 mL*3) to obtain the title compound (40 g, 70%) as a white solid.

[0111] 1HNMR (400MHz, CDCl 3 )ppmδ1.77(s,6H),6.93-7.04(m,1H),8.44-8.53(m,1H),7.85-7.91(m,1H),9.31-9.42(m,1H),11.28-11.40( m,1H).

[0112] b) 7-Bromo-4H-pyrido[1,2-a]pyrimidin-4-one

[0113] (E)-5-(((5-bromopyridin-2-yl)imino)methyl)-2,2-d...

Embodiment 39

[0129] 24-Difluoro-N-(2-methoxy-5-(4-oxo-4H-pyrazino[12-a]pyrimidin-7-yl)pyridin-3-yl)benzenesulfonamide

[0130]

[0131] a) (E)-5-(((5-bromopyrimidin-2-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6 - dione

[0132] Triethyl orthoformate (9.9g, 0.0689mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (10.8g, 0.073mol) were placed in the three neck In a round bottom flask, the reaction was stirred at 60°C for 2 hours. A solution of 5-bromo-2-aminopyrazine (12 g, 0.0689 mol) in ethanol (50 mL) was added dropwise to the above mixture. The reaction solution was stirred at 60°C for 2 hours. The mixture was cooled to 25°C, filtered, and the filter cake was rinsed with ethanol (200 mL*3) to obtain the title compound (12.5 g, 55.3%) as a white solid.

[0133] 1HNMR (400MHz, DMSO-D 6 )ppmδ11.601(s,1H),9.039(s,1H),8.825(s,1H),8.712(s,1H),1.690(s,6H).

[0134] b) 7-bromo-4H-pyrazino[1,2-a]pyrimidin-4-one

[0135] (E)-5-(((5-bromopyrimidin-2-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4...

Embodiment 52

[0148] 2,4-Difluoro-N-(2-methoxy-5-(6-methyl-4-oxo-4hydro-pyrido[1,2-a]pyrimidin-7-yl)pyridine-3 -yl)benzenesulfonamide

[0149]

[0150] a) (E)-5-(((5-bromo-6-methylpyridin-2-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane Alkane-4,6-dione

[0151] Trimethyl orthoformate (4.39 g, 0.03 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.03 g, 0.028 mmol) were placed in an equipped Mechanically stirred three-neck round bottom flask. The resulting suspension was stirred at 60°C for 2 hours. To this mixture was added dropwise a solution of 5-bromopyrazin-2-amine (5 g, 0.027 mmol) dissolved in ethanol (50 mL). The reaction solution was then stirred at 60°C for 2 hours. The reaction solution was cooled to 25°C and filtered. The filter cake was washed with ethanol (200 mL*3) to obtain the title compound (6 g, 65.6%) as a white solid.

[0152] 1HNMR (400MHz, DMSO-D6)ppmδ11.344-11.378(d,1H),9.143-9.177(d,1H),8.066-8.087(d,1H),7.457-7.479(d,1H),2.578(s, 3H), 1.678(s, 6H).

[0153] b)...

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PUM

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Abstract

The present invention discloses a class of pyrido[1,2-a]pyrimidone analogs as mTOR/PI3K inhibitors, and particularly relates to a compound represented by a formula (I) or a pharmaceutically acceptable salt thereof. The formula (I) is defined in the specification.

Description

technical field [0001] The present invention relates to a class of pyrido[1,2-a]pyrimidinone analogs as mTOR / PI3K inhibitors, specifically, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Background technique [0002] The PI3K pathway is the most frequently mutated place in human cancer cells, which can lead to cell proliferation, activation, and signal amplification. PI3K and mTOR are the two most important kinases in the PI3K signaling pathway. [0003] PI3 kinases (phosphatidylinositol 3-kinases, PI3Ks) belong to the lipid kinase family and can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol. Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of regulatory subunit p85 or p101 and catalytic subunit p110, which catalyzes phosphatidylinositol 4,5-diphosphate (phosphatidylinositol4 , 5-bisphosphate, PIP2) is phosphorylated into phosphatidylinositol 3,4,5-trisphosphate...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00C07D487/04C07D491/147A61K31/519A61K31/5377A61K31/4439A61P35/00
Inventor 关慧平吴成德于涛黄磊郝冬玲高波孙继奎施能扬陈曙辉
Owner SHANGHAI JIA TAN PHARMATECH CO LTD
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