Pi3 kinase inhibitors and uses thereof

A technology of unsaturated compounds, applied in the fields of application, biocides, anti-inflammatory agents, etc., can solve the problems of unidentified class II PI3K regulatory subunits, etc.

Inactive Publication Date: 2014-01-08
CELGENE AVILOMICS RES 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

[0717]

[0718] 1-(4-(4-(2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)phenyl)piperazin-1-yl)-6-methylheptyl- 5-ene-1,4-dione (I-1). The title compound was synthesized according to the procedure described below.

[0719]

[0720] Step 1a: 4-(6-Chloro-4-iodopyridin-2-yl)morpholine (Intermediate 1a)

[0721]

[0722] 2,6-Dichloro-4-iodopyridine (2.0 g, 7.3 mmol), morpholine (700 uL, 8.0 mmol) and 1.5 mL of DIPEA were heated in 15 mL of anhydrous dioxane at 120° C. for 24 hours. After concentration and the usual aqueous work-up with ethyl acetate-water, the reaction mixture was column chromatographed on silica gel eluting with heptane / ethyl acetate (v / v 6 / 1) to obtain 1.74 g of the desired product as white crystals. MS: m / z 325.0 (ES+).

[0723] Step 1b: tert-butyl 4-(4-(2-chloro-6-morpholinylpyridin-4-yl)phenyl)piperazine-1-carboxylate (Intermediate 1b)

[0724]

[0725] Under Ar, intermediate 1a (97 mg, 0.3 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola...

example 2

[0733]

[0734] N-(4-((2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)ethynyl)phenyl)-6-methyl-4-oxohept-5 - enamide (I-2). The title compound was synthesized according to the following intermediates and the procedure described below.

[0735]

[0736] Step 2a: N-(4-((2-Chloro-6-morpholinopyridin-4-yl)ethynyl)phenyl)-6-methyl-4-oxohept-5-enamide (intermediate 2a)

[0737]

[0738] Intermediate 1a (55 mg, 170 umol), N-(4-ethynylphenyl)-6-methyl-4-oxohept-5-enamide (44 mg, 170 umol, readily available from 4 -ethynylaniline and 6-methyl-4-oxohept-5-enoic acid), PdCl 2 (PPh 3 ) 2 (6 mg), CuI (15 mg), 100 uL DIPEA in 2 mL DMA heated at 80° C. overnight. After working up with ethyl acetate and water, the reaction mixture was column chromatographed on silica gel eluting with heptane / ethyl acetate (v / v 3 / 2) to obtain 55 mg of the desired product as a white solid. MS: m / z 452.1 (ES+).

[0739] Step 2b: N-(4-((2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)ethyn...

example 3

[0743] The following compounds belong to the general structures shown in the table below, which were used in Step 1b in a manner similar to that described in Example 1 using 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester to synthesize.

[0744]

[0745] (a pair of conformers from tetrahydropyridine)

[0746]

[0747]

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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 US Provisional Application No. 61 / 451,022, filed March 9, 2011, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to compounds useful as inhibitors of PI3 kinase. 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] The search for new therapeutic agents in recent years has been greatly aided by a better understanding of the structure of enzymes and other biomolecules associated with disease. One important class of enzymes that has been the object of extensive research is the phosphatidylinositol 3-kinase superfamily. [0005] Phosphatidylinositol 3-kinases (PI3Ks) belong to the large family of PI3K-related kinases. PI3Ks phosphorylate lipid molecules but not protei...

Claims

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Application Information

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IPC IPC(8): A01N43/40A61K31/435C07D213/56C07D273/00
CPCC07D401/14C07D417/14C07D413/14C07D401/04A61P1/00A61P1/16A61P3/00A61P5/00A61P7/00A61P7/04A61P7/06A61P9/00A61P9/04A61P9/10A61P11/00A61P11/02A61P11/06A61P13/12A61P17/06A61P17/14A61P19/00A61P19/02A61P21/00A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor 乔立新牛德强拉塞尔·C·彼得朱振东
Owner CELGENE AVILOMICS RES INC
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