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PI3 kinase inhibitors and uses thereof

A technology of inhibitors and kinases, applied in the direction of enzymes, anti-inflammatory agents, antiviral agents, etc., can solve the problem that the regulatory subunit of class II PI3K has not been identified

Inactive Publication Date: 2012-08-01
AVILA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Regulatory subunits of class II PI3Ks have not been identified

Method used

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  • PI3 kinase inhibitors and uses thereof
  • PI3 kinase inhibitors and uses thereof
  • PI3 kinase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[1378]

[1379] 1-(4-((2-(1H-indazol-4-yl)-4-(N-morpholino)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazine- 1-yl)prop-2-en-1-one (II-a-2): The title compound was prepared according to the procedures and intermediates described below.

[1380]

[1381] Step 1a: 4-(2-Chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (intermediate 1a)

[1382]

[1383] To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (2.0 g, 9.7 mmol) in 30 ml MeOH was added 1.9 ml morpholine. After stirring at room temperature for 1 hour, the reaction mixture was filtered; the solid was washed with water and methanol to afford 2.0 g of the title compound. MS m / z: 256.0, 258.1 (M+1). 1 H NMR (400MHz, CDCl 3 ): δ: 7.78 (1H, d, J = 5.48Hz), 7.38 (1H, d, J = 5.48Hz), 4.02 (4H, t, J = 4.80Hz), 3.85 (4H, t, J = 4.82Hz ).

[1384] Step 1b: 2-Chloro-4-(N-morpholino)thieno[3,2-d]pyrimidine-6-carbaldehyde (intermediate 1b)

[1385]

[1386] To a suspension of intermediate 1a (1.02 g, 4.0 mmol) in 30 ml THF ...

example 2

[1416]

[1417] (E)-1-(4-((2-(1H-indazol-4-yl)-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl )piperazin-1-yl)hept-5-ene-1,4-dione (II-a-36): The title compound was prepared according to the procedures and intermediates described below.

[1418] Step 2a: (E)-4-oxohept-5-enoic acid (intermediate 2a)

[1419]

[1420] To a solution of succinic anhydride (0.50 g, 5.0 mmol) in 20.0 ml dry THF was slowly added 1-propenylmagnesium bromide (0.5 M in THF, 18.0 mL, 9.0 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 hour. 1N Aqueous HCl (9.0 ml) was added and the mixture was slowly warmed to room temperature. The pH was adjusted to about 3 with 1N HCl. Then THF was removed under vacuum and the remaining aqueous solution was extracted with DCM (3 x 20 mL). The organic layer was washed with Na 2 SO 4 Dry, filter and remove solvent. The residue was purified by silica gel chromatography (eluent: EtOAc / Hexane 1:1) to afford the acid. 1 H NMR (400MHz, CDCl ...

example 3

[1462]

[1463] N-(2-(4-((2-(1H-indazol-4-yl)-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl) Piperazin-1-yl)-2-oxoethyl)acrylamide (II-a-6): The title compound was prepared according to the procedures and intermediates described below.

[1464] Step 3a: 2-(4-((2-(1H-Indazol-4-yl)-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl) tert-butyl piperazin-1-yl)-2-oxoethylcarbamate (intermediate 3a)

[1465]

[1466] The title compound was prepared by coupling BOC-Gly-OH with intermediate 1e using HATU according to the procedure described in step 1f. MS m / z: 593.2 (M+H + ).

[1467] Step 3b: 1-(4-((2-(1H-indazol-4-yl)-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl) Piperazin-1-yl)-2-aminoethanone hydrochloride (intermediate 3b)

[1468]

[1469] The title compound was prepared by the BOC removal procedure described in Step 1e. MS m / z: 493.2 (M+H + ).

[1470] Step 3c: N-(2-(4-((2-(1H-indazol-4-yl)-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl) Methyl)pi...

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PUM

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 61 / 240,947, filed September 9, 2009, and U.S. Provisional Application No. 61 / 371,396, filed August 6, 2010, each incorporated in its entirety by Incorporated herein by reference. technical field [0003] The present invention relates to compounds useful as PI3 kinase inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using said compositions to treat various disorders. Background technique [0004] In recent years, a better understanding of the structure of enzymes and other biomolecules involved in disease has greatly aided the search for new therapeutic agents. An important class of enzymes that has been the object of extensive study is the phosphatidylinositol 3-kinase superfamily. [0005] Phosphatidylinositol 3-kinases (PI3Ks) belong to a large family of PI3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00
CPCC12N9/1205A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/04A61P17/06A61P17/14A61P19/00A61P19/02A61P21/02A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P31/12A61P35/00A61P35/02A61P37/00A61P37/04A61P43/00A61P5/00A61P7/00A61P7/06A61P9/00A61P9/10A61K31/517A61K31/52A61K47/00
Inventor 牛德强拉塞尔·C·彼得尤斯温德·辛格阿瑟·F·克卢格霍尔木兹·马兹迪亚斯尼朱振东乔立新凯文·孔茨
Owner AVILA THERAPEUTICS INC
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