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Pyrazolylaminopyridine derivatives useful as kinase inhibitors

A kind of amino, carbamoyl technology, applied in the field of novel pyrazole derivatives, can solve problems such as Trk expression increase

Inactive Publication Date: 2008-04-02
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, although Trk is expressed at low levels outside the nervous system in adults, Trk expression is increased in advanced prostate cancer

Method used

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  • Pyrazolylaminopyridine derivatives useful as kinase inhibitors
  • Pyrazolylaminopyridine derivatives useful as kinase inhibitors
  • Pyrazolylaminopyridine derivatives useful as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0463] (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino) Nicotinonitrile

[0464] In a sealed test tube, combine 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1; 0.8g, 2.8mmol) and (S) -1-(4-Fluorophenyl)ethanamine (0.8 g, 5.6 mmol) was added in one portion to a solution of n-BuOH (4 ml) and DIEA (0.5 g, 3.7 mmol). The reaction was heated to 140°C for 48 hours, then cooled to 25°C and concentrated. The obtained residue was purified by column chromatography (DCM-MeOH=50:1) to obtain the title compound (0.55 g, 50%). 1 H NMR (400MHz, CDCl 3)δ8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24- 5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calculated: 380; Found: [M+H] + 381.

[0465] (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino) Nicotinamide

[0466] At 25°C, t...

Embodiment 3

[0468] (S)-3-(Aminomethyl)-N 6 -(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N 2 -(1-(4-fluorobenzene Base) ethyl) pyridine-2,6-diamine

[0469] To MeOH solution (5ml) was added (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethyl Amino)nicotinonitrile (Example 1; 0.15 g, 0.4 mmol), conc. HCl (0.1 ml) and Pd (10% by weight dry on activated carbon, 0.12 g). Then, the mixture was washed with N 2 Flood, empty, then place it at 40psi H 2 Set aside for 6 hours. Then, the reaction was evacuated with N 2 Flooded, filtered, washed with MeOH (3 x 30ml) and concentrated. The resulting solid was dissolved in a mixture of DCM-MeOH (50:1, 100ml), to which was added Na 2 CO 3 Saturated aqueous solution (100ml) and the mixture was shaken vigorously for 30 minutes. Then, the layers were separated and the aqueous layer was extracted with DCM (3 x 100ml). The combined organic layers were dried, filtered and concentrated. The obtained solid was purifi...

Embodiment 4

[0471] (S)-N-((6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethyl Amino)pyridin-3-yl)methyl)acetamide

[0472] To a THF-DCM (1:1, 3ml) mixture in a round bottom flask at 0°C was placed (S)-3-(aminomethyl)-N 6 -(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N 2 -(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08g, 0.2mmol) and TFP resin loaded with acetic acid (1.4mmol / g loading, 0.2mmol ). The resulting solution was shaken vigorously at 0°C for 45 minutes and filtered. The obtained resin was washed with THF-DCM solution (1:1, 3×5 ml, 30 minutes each time). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse phase column chromatography (5-50% 2 CH in O 3 CN, over 400ml) to give the title compound (0.045g, 50%). 1 H NMR (400MHz, CD 3 OD) δ7.34-7.33(m, 2H), 7.11(d, J=10.7Hz, 1H), 7.01-6.97(m, 2H), 5.14-5.04(m, 1H), 4.30-4.17(m, 2H ), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.50 (d, J=6.8Hz, 3...

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Abstract

This invention relates to novel compounds having the formula (I): and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

Description

technical field [0001] The present invention relates to novel pyrazole derivatives, their pharmaceutical compositions and methods of use. In addition, the present invention also relates to methods for treating and preventing cancer and the use of these pyrazole derivatives in the preparation of medicaments for treating and preventing cancer. Background technique [0002] Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases that play key roles in cell signaling and are involved in many cancer-related processes including cell proliferation, survival, angiogenesis and metastasis. Up to 100 different RTKs have been identified, including tropomyosin-related kinase (Trk). [0003] Trk is a high affinity receptor activated by a soluble growth factor called neurotrophin (NT). The Trk receptor family has three members - TrkA, TrkB and TrkC. In NT, there are (i) nerve growth factor (NGF) that activates TrkA, (ii) brain-derived growth factor (BDNF) that activates TrkB...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D405/14C07D413/14A61K31/4439C07D401/12A61P35/00C07D409/14
CPCC07D409/14C07D413/14C07D401/12C07D405/14C07D401/04C07D401/14A61P35/00A61P35/02A61P43/00A61K31/4439
Inventor A·戴维斯M·拉姆P·利恩P·莫尔王斌王弢余定伟
Owner ASTRAZENECA AB
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