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Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases

An alkyl and aryl technology, applied in the field of pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases

Inactive Publication Date: 2013-03-20
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many different cell types produce VEGF, but its biological activity is largely restricted to the vasculature via endothelial-selective expression of KDR

Method used

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  • Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases
  • Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases
  • Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0494] 1-(5-{5-chloro-2-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine -4-yl}-1,3-thiazol-2-yl)cyclobutanol

Embodiment 1A

[0496] 1-(thiazol-2-yl)cyclobutanol

[0497] To a cold (-78°C) solution of thiazole (6.59ml, 93mmol) in tetrahydrofuran (238ml) was added n-butyllithium (58.0ml, 93mmol) dropwise. The reaction was stirred for 15 minutes and cyclobutanone (5.0 g, 71.3 mmol) was added via syringe. The reaction was stirred for 10 minutes then quenched by the addition of saturated aqueous bicarbonate solution. The cooling bath was removed and the reaction was allowed to warm to room temperature. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2x). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound which was used in the next step without further purification. MS ESI(+) m / z 156 [M+H] + .

Embodiment 1B

[0499] 2-(1-(Methoxymethoxy)cyclobutyl)thiazole

[0500]To a cold (0 °C) suspension of sodium hydride (1.07 g, 44.4 mmol) in N,N-dimethylformamide (50 mL) was added 1-(thiazol-2-yl)cyclobutanol (for Example 1A) (5.3 g, 34.1 mmol) in N,N-dimethylformamide (18 ml). After 0.5 hour, chloro(methoxy)methane (3.89 mL, 51.2 mmol) was added and the reaction was stirred for 16 hours. The reaction was quenched by adding ether and water. The layers were separated and the aqueous layer was extracted with additional ether. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m / z 200 [M+H] + .

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Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A, B, R1, R2, R3, R4a, R5, and Z are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as aurora.

Description

[0001] Cross reference for related applications [0002] This application requires the preferred right of temporary application number No. 61 / 333,850 submitted on May 12, 2010, and its full text is cited into this article by this. Area of invention [0003] The present invention involves inhibiting protein kinases, such as aurora kinase and Vegfr and PDGFR family kinase compounds, compositions containing the compound and how to treat diseases with the compound. Invention background [0004] Silk division is a process of copying the complete copy of the genome that is separated by two sub -cells by the microtuba.The key required for the aurora kinase -genomic stability is the wire split regulator -excessive expression of human tumors has been found.Therefore, in the field of treatment, compounds that need to inhibit the aurora katzyra, compositions containing the inhibitors, and treatment of diseases that have not been adjusted or excessive during this period of the aurora kithera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/437A61K31/519A61P35/00
CPCC07D471/04C07D487/04A61P35/00A61P35/04A61P43/00
Inventor M.麦克利德斯A.朱德S.菲克斯-斯滕策尔
Owner ABBVIE INC