Indazole inhibitors of kinase

A technology of aryl and heterocyclic groups, which is used in medical preparations containing active ingredients, drug combinations, sexual diseases, etc.

Inactive Publication Date: 2013-03-06
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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  • Indazole inhibitors of kinase
  • Indazole inhibitors of kinase
  • Indazole inhibitors of kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0320] A solution of 6-bromo-1H-indazole (10 g, 50.8 mmol, commercially available) in dioxane (200 ml) was treated with 3N aqueous NaOH (100 ml). The well stirred mixture was treated with iodine (27.1 g, 107 mmol), added in portions over 5 min, then stirred for 60 min. with 200 ml of 20% citric acid solution, followed by 160 ml of saturated NaHSO 3 The solution was quenched before partitioning between ethyl acetate and water. with MgSO 4 The organic extracts were dried and concentrated to a solid which was triturated with ether and pentane to afford the title compound.

Embodiment 1A

[0322] 6-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0323] Example 1A (14.4 g, 44.6 mmol) was added to a 0° C. aqueous solution of potassium hydroxide (50.0 g, 892 mmol) in 200 mL of water. The concentrated suspension was stirred for 10 min and washed with CH 2 Cl 2 (400 ml) and treated with tetrabutylammonium bromide (1.437 g, 4.46 mmol). Then, (2-(chloromethoxy)ethyl)trimethylsilane (9.05 ml, 51.3 mmol) was added dropwise with a dropping funnel within 50 min. The reaction was stirred at 0 °C for 1.5 h and washed with CH 2 Cl 2 (2X) extracted and washed with water. with MgSO 4 The combined organics were dried, concentrated, and flashed by silica gel chromatography with CH 2 Cl 2 / hexane to obtain the title compound.

Embodiment 1B

[0325] 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0326] Example 1B (0.500 g, 1.103 mmol) and 1-methyl-4-(4,4,5,5 - A solution of tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.275 g, 1.324 mmol) in toluene (8 ml) and ethanol (8 ml) . Add Pd(PPh 3 ) 4 (0.217 g, 0.188 mmol), and the resulting heterogeneous mixture was refluxed at 80°C for 2 hours and then stirred at room temperature for 18 hours. The reaction mixture was diluted with brine and extracted twice with ethyl acetate. with MgSO 4 The combined organics were dried, concentrated, and chromatographed on silica gel using 0.5% methanol in CH 2 Cl 2 The residue was purified by elution to obtain the title compound.

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Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts,formula (I) wherein A1, A2, A3 and L 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 and KDR.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 333,843, filed May 12, 2010, which is incorporated by reference in its entirety. field of invention [0003] The present invention relates to compounds that inhibit protein kinases such as Aurora kinase and the VEGFR and PDGFR family of kinases, compositions containing the compounds, and methods of using the compounds to treat disease. Background of the invention [0004] Mitosis is the process by which the replicated complete copy of the genome is separated by the microtubule spindle into two daughter cells. Aurora kinases - key mitotic regulators required for genome stability - have been found to be overexpressed in human tumors There is therefore an ongoing need in the therapeutic arts for compounds that inhibit Aurora kinase, compositions comprising such inhibitors, and methods of treating diseases during which Aurora kinase is un...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D403/04C07D409/04C07D413/14A61K31/416A61P35/00
CPCC07D401/14C07D403/04C07D409/04C07D413/14A61P1/04A61P1/18A61P11/00A61P13/08A61P13/10A61P15/00A61P17/00A61P35/00A61P5/00
Inventor M.R.麦克利德斯J.H.霍尔姆斯D.H.施泰因曼
Owner ABBVIE INC
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