Condensed heteroaryl derivative, and preparation method and application thereof

A kind of derivative and heteroaryl technology, applied in the field of condensed heteroaryl derivatives and preparation thereof, can solve the problems such as no explanation, no disclosure of inhibitory effect, etc.

Inactive Publication Date: 2011-04-20
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there is neither disclosure nor description for PI3K inhibition

Method used

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  • Condensed heteroaryl derivative, and preparation method and application thereof
  • Condensed heteroaryl derivative, and preparation method and application thereof
  • Condensed heteroaryl derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] 3-(4-Morpholinopyrazino[3′,2′:4,5]thieno[3,2-d](2-pyrimidinyl))anisole

[0072]

[0073] Starting with 2-chloro-3-cyanopyrazine. 2-Chloro-3-cyanopyrazine is ring-closed with compound (Ia-1) to obtain compound (Ib-1). Compound (Ib-1) is reacted with m-methoxybenzoyl chloride to give compound (Ic-1) as an acylated product. Compound (Ic-1) is reacted with ammonia to give compound (Id-1). Compound (Id-1) undergoes a ring-closing reaction in the presence of a base to obtain compound (Ie-1). (Ie-1) compounds are converted into reactive (If-1) compounds by conventional methods. Compound (If-1) (9.2 mmol) was dissolved in 50 ml of anhydrous tetrahydrofuran, 30 ml of morpholine was added dropwise thereto under an ice-water bath, and heated to reflux for 1.5 hours. Cool down to room temperature, extract repeatedly 3 times with ethyl acetate, combine the organic phases, wash 3 times with saturated brine, and dry over anhydrous sodium sulfate. Silica gel column chromatograp...

Embodiment 2

[0078] 3-(4-Morpholinopyrazino[3′,2′:4,5]thieno[3,2-d](2-pyrimidinyl))phenol

[0079] The compound (1) (6.33 mmol) was dissolved in 100 ml of acetic acid and 120 ml of hydrogen bromide (40% aqueous solution), and heated under reflux overnight. Cool down to room temperature, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate solution to adjust to weak alkalinity, extract with ethyl acetate three times, combine organic phases, and dry over anhydrous sodium sulfate. Column chromatography separated to obtain 0.58 g of a yellow solid (compound 2), with a yield of 25.1%.

[0080] h 1 -NMR(DMSO):

[0081] δ9.59(s, 1H), δ9.02(d, 1H), δ8.91(d, 1H), δ7.99-7.94(m, 2H), δ7.34(t, 1H), δ6.92 (d, 1H), δ4.05(t, 4H), δ3.85(t, 4H)

[0082] ESI (+) m / z: 366

Embodiment 3

[0084] 3-(4-Morpholinopyrazino[3′,2′:4,5]furo[3,2-d](2-pyrimidinyl))phenol

[0085]

[0086] Starting with 2-chloro-3-cyanopyrazine. 2-Chloro-3-cyanopyrazine is ring-closed with compound (Ia-3) to obtain compound (Ib-3). The compound (Ib-3) reacts with m-methoxybenzoyl chloride to obtain the acylated compound (Ic-3). Compound (Ic-3) is reacted with ammonia to give compound (Id-3). Compound (Id-3) undergoes a ring-closing reaction in the presence of a base to obtain compound (Ie-3). (Ie-3) compounds are converted into reactive (If-3) compounds by conventional methods. Compound (If-3) is reacted with morpholine to give compound (Ig-3). Compound (Ig-3) (3.2 mmol) was dissolved in 50 ml of acetic acid and 60 ml of hydrogen bromide (40% aqueous solution), and heated to reflux overnight. Cool down to room temperature, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate solution to adjust to weak alkalinity, extract with ethyl acetate three times, com...

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PUM

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Abstract

The invention discloses a condensed heteroaryl derivative, and a preparation method and application thereof. The derivative disclosed by the invention is a phosphoinositide 3-kinase (PI3K) inhibitor which has the good inhabitation effect of the PI3K and the effect of inhibiting proliferation of cancer cells, so that the derivative can be used as a therapeutical agent for treating tumor.

Description

technical field [0001] The present invention relates to fused heteroaryl derivatives and their preparation methods, as well as the application of such derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors and anticancer agents. Background technique [0002] Phosphotidylinositol (PI) is one of various phospholipids found in cell membranes and plays an important role in intracellular signal transduction. Phosphoinositide 3-kinases (Phosphoinositide 3-kinases, PI3Ks) are enzymes that phosphorylate the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al., 1988, Nature, 332, 664). PI3K catalyzes the formation of phosphatidylinositol 3,4-bisphosphate (phosphatidylinositol 3,4bisphosphate, PI(3,4)) P2 and 3,4,5-trisphosphate (phosphatidylinositol 3,4,5trisphosphate , PI(3,4,5)P3), causing activation of protein kinase C and intracellular calcium mobilization [MJ Berridge et al., Nature, 312, 315 (1984), Y Nishizuka, Science, 225, 1365 (1984)]. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/14C07D491/147A61K31/5377A61K31/541A61P35/00
CPCC07D491/147C07D487/14C07D495/14A61P35/00
Inventor 匡荣仁胡涛郭建辉
Owner SHANGHAI ALLIST PHARM CO LTD
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