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5-heteroaryl substituted indazoles as kinase inhibitors

A compound, heteroaryl technology, applied in the field of 5-heteroaryl substituted indazole compounds used as kinase inhibitors, can solve the problem of neurotoxic effect block and so on

Inactive Publication Date: 2010-07-28
ABBOTT LAB INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, this hyperphosphorylated and neurotoxic effect of β-amyloid could be blocked by lithium chloride and GSK-3β antisense mRNA

Method used

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  • 5-heteroaryl substituted indazoles as kinase inhibitors
  • 5-heteroaryl substituted indazoles as kinase inhibitors
  • 5-heteroaryl substituted indazoles as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0662] 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole and 5-(1-benzyl-1H-1,2,3-triazole-5- base)-1H-indazole mixture;

Embodiment 1A

[0664] tert-Butyl 5-iodo-1H-indazole-1-carboxylate

[0665] To an ice-bath-cooled solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was added dropwise a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and isoamyl nitrite (22.3 mL, 166.48 mmol) were added, and the mixture was heated at 70° C. for 20 hours. The cooled mixture was washed with saturated NaHCO 3 The aqueous solution was quenched to pH 7. The mixture was extracted with dichloromethane, the organic layer was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL), and treated with hot KOH (60 g) in water (200 mL). The resulting mixture was stirred for 15 minutes and treated to pH 1 with 6N HCl. The layers were separated, ...

Embodiment 1B

[0667] tert-butyl 5-((trimethylsilyl)ethynyl)-1H-indazole-1-carboxylate

[0668] Example 1A (10.81 g, 31.4 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.57 mmol) and cuprous(I) iodide (365 mg, 1.92 mmol) were mixed under inert gas Mix in triethylamine (70 mL). Trimethylsilylacetylene (5.0 mL, 36.0 mmol) was added, and the resulting mixture was stirred at 60°C overnight. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane and washed with 1N hydrochloric acid. The resulting mixture was adsorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS(ESI+)m / z 215.0(M-99) + .

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PUM

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Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A, R1, R2, R3 and m, 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 Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

Description

technical field [0001] The present invention relates to compounds comprising 5-substituted indazoles, processes for preparing said compounds, compositions comprising said compounds, said compounds being effective in inhibiting kinases such as glycogen synthase kinase 3 (GSK-3), Rho kinase ( ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2. Background of the invention [0002] Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue located on a protein substrate. It is clear that protein kinases play an important role in normal cell growth. Many growth factor receptor proteins have intramolecular regions that function as protein kinases, through which they affect signaling. The interaction between growth factors and their receptors is an essential event for the normal regulation of cell growth, and the phosphorylation status of substrate prote...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D413/04C07D417/04
CPCC07D403/04C07D413/04C07D417/04A61P1/04A61P11/00A61P11/06A61P13/10A61P13/12A61P15/00A61P15/10A61P15/12A61P17/06A61P17/14A61P19/02A61P19/10A61P21/02A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P27/02A61P27/06A61P29/00A61P3/10A61P31/04A61P31/12A61P35/00A61P3/04A61P35/02A61P35/04A61P37/02A61P43/00A61P5/00A61P9/04A61P9/10A61P9/12
Inventor I·阿克里托普罗-赞泽B·D·沃克菲尔德H·马克S·C·特纳A·F·加西基V·J·格拉恰斯K·萨里斯D·M·卡尔文M·J·米奇默惠岑Q·帅J·R·帕特尔M·巴克N·托伊施P·J·科瓦S·W·久里克A·J·龙A·瓦苏德文A·霍布森N·圣约翰穆尔L·王D·乔治B·李K·弗兰克E·F·约翰逊
Owner ABBOTT LAB INC
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