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Inhibitors of erk and methods of use

A CR1R1, CR3R3 technology, applied in organic chemical methods, pill delivery, pharmaceutical formulations, etc., can solve problems such as inactivation of Ras complexes

Inactive Publication Date: 2016-06-01
KURA ONCOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Other mutations can lead to inactivation defects of the activated GTP-bound Ras complex, again leading to activation of the MAP kinase pathway

Method used

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  • Inhibitors of erk and methods of use
  • Inhibitors of erk and methods of use
  • Inhibitors of erk and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2452] Example 1. (6-Benzyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one )of synthesis

[2453]

[2454]3-Bromo-5-methyl-6-nitro-1H-indazole (EX1-2). To a stirred room temperature solution of 5-methyl-6-nitro-1H-indazole (1.77 g, 10 mmol) in 20 mL of anhydrous DMF was added NBS (2.14 g, 12 mmol) followed by KOH (1.12 g, 20 mmol ). The reaction mixture was stirred overnight at the same temperature. The reaction mixture was diluted with ethyl acetate, water and saturated NH 4 Cl aqueous solution washing. The organic solution was treated with anhydrous MgSO 4 Drying, filtration and concentration in vacuo gave the desired product (3.1 g) as a brown solid which was used in the next step without further purification.

[2455] 3-Bromo-5-methyl-6-nitro-1-trityl-1H-indazole (EX1-3). To a stirred solution of 3-bromo-5-methyl-6-nitro-1H-indazole (2.43 g, 9.5 mmol) in 30 mL of anhydrous THF at 0 °C was added NaH (60% in mineral oil, 0.76 g, 19 mmol...

Embodiment 2

[2461] Example 2. ((R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3- g]quinoline Synthesis of oxazolin-7(8H)-one)

[2462]

[2463] 5-Bromo-3-iodo-6-nitro-1H-indazole (EX2-2). To a stirred room temperature mixture of 5-bromo-6-nitro-1H-indazole (3.5 g, 14.5 mmol) in DMF (50 mL) was added KOH (2.84 g, 50.6 mmol, 3.5 eq) and the resulting mixture Stir at room temperature for 10 min. To the reaction mixture was added NIS (3.58 g, 15.91 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 10 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (200 mLx3). The combined organic layers were washed with H 2 O (200mLx3) washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give the desired product (4.2 g, 79% yield) as a yellow solid. The crude product was used directly in the next step without further purification.

[2464] 5-Bromo-3-iodo-6-nitro-1-trityl-1H-indazole (...

Embodiment 3

[2473] Example 3: 6-(4-fluorobenzyl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinazoline - Synthesis of 7(8H)-ketone

[2474] N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(4-fluorophenyl)methanamine. To 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (500 mg, 1.0 mmol) and NBS (268 mg, 1.5 mmol) in 10 mL of CCl 4 AIBN (98mg, 0.6mmol) was added to the room temperature solution of . The reaction mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, and the solids were removed by filtration. (4-Fluorophenyl)methanamine (500 mg, 4.0 mmol) and 1 mL of DMF were added. The resulting mixture was stirred at the same temperature for 1 h. The solvent was removed and the residue was taken up in ethyl acetate, washed with saturated NH 4 Cl aqueous solution and brine washing. The organic solution was treated with anhydrous MgSO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel column chromatography (...

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Abstract

The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as ERK (MAPK). Also provided are methods of using such compounds or compositions, and methods of using these compositions to modulate the activities of one or more of these kinases, especially for therapeutic applications such as the treatment disorders such as cancer.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Application Serial No. 61 / 886,552, filed October 3, 2013, and U.S. Provisional Application Serial No. 62 / 032,446, filed August 1, 2014, each of which is incorporated by reference incorporated herein in its entirety. Background technique [0003] ERK kinases are serine / threonine kinases that mediate intracellular signal transduction pathways involved in tumor growth, progression and metastasis. ERK participates in the Ras / Raf / MEK / ERK pathway, which relays receptors from ligand-bound cell surface receptor tyrosine kinases (RTKs) such as ErbB (e.g., EGFR, HER-2, etc.), VEGF, PDGF, and FGF. Extracellular signaling of somatic tyrosine kinases, thus playing a central role in regulating cellular processes. Activation of RTKs triggers a cascade of phosphorylation events that begins with activation of Ras, followed by recruitment and activation of Raf. Activated Raf then phosphorylates MAP kinas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/415A61K31/495C07D471/14
CPCA61P35/00A61K9/0053A61K31/4439A61K31/4745A61K31/513A61K31/5377A61K31/5517A61K45/06C07B59/002C07D471/04C07D487/04C07D519/00C07B2200/05A61K9/20A61K9/48A61K31/415A61K31/4162A61K31/495A61K31/519
Inventor 李连生吴涛冯军任平达刘异
Owner KURA ONCOLOGY
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