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Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof

An aryl and heteroaryl technology, applied in the field of aryl urea compounds, can solve problems such as drug resistance limitation, and achieve the effect of excellent thermal stability

Inactive Publication Date: 2015-07-22
王若文
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current applications show that small molecule inhibitors of Raf kinase have good therapeutic effects on the above diseases, but there are also limitations in these applications such as drug resistance

Method used

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  • Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof
  • Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof
  • Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof

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Experimental program
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preparation example Construction

[0086] The preparation method of the compound of formula I of the present invention comprises the step of generating the compound of formula I through the coupling reaction between the compound of formula II and the compound of formula V:

[0087]

[0088] Among the various types, Z, R 1 , R 3 , R 2 , m, n are defined as previously mentioned;

[0089] R is selected from: -NH 2 , -NCS, -NCO, -NHC(=O)R 6 , R 6 Selected from: H, hydroxyl, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C6-C20 aryl, C3-C8 cycloalkyl, C1-C10 heterocycloalkyl, C5 -C20heteroaryl.

[0090] In another preferred embodiment, R is -NH 2 , the compound of formula X and the compound of formula V undergo a coupling reaction under the action of 1,1'-carbonyl-diimidazole to generate the compound of formula I.

[0091] In another preference, the preparation of the compound of formula II may comprise the following steps:

[0092]

[0093] (a) the compound of formula IIa is reduced to generate th...

Embodiment 1

[0146] Preparation of 3-bromo-5-(pentafluorothio)-aniline:

[0147]

[0148] step one:

[0149] 3-(Pentafluorothio)-nitrobenzene (748 mg, 3 mmol) was dissolved in trifluoroacetic acid TFA (1.5 mL) and concentrated H 2 SO 4 (7.5 mL) of the mixed solvent, vigorously stirred. N-bromosuccinimide NBS (800 mg, 4.5 mml) was added in batches and reacted overnight at room temperature.

[0150] After the reaction, the reaction solution was put into ice water, CH 2 Cl 2 Extract three times, combine the organic phases, and wash three times with saturated brine. Dry over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography (ethyl acetate / petroleum ether=1 / 5) to obtain a yellow solid 3-bromo-5-(pentafluorosulfuryl)-nitrobenzene (870mg, 89 %Yield).

[0151] 1 H NMR (300MHz, CDCl 3 )δ8.56(t,J=1.9Hz,1H),8.54(t,J=1.8Hz,1H),8.22(t,J=1.9Hz,1H); 19 F NMR (282MHz, CDCl 3 )δ80.81-78.58 (m, 1F...

Embodiment 2

[0156] Preparation of N-methyl-2-pyridinecarboxamide derivatives

[0157]

[0158] 3.12 g of 4-chloro-2-pyridinecarboxylic acid (20 mmol), 1.65 g of methylamine hydrochloride (24 mmol), 3.50 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiene Amine (23 mmol), 3.0 grams of 1-hydroxybenzotriazole (22 mmol), and 4.0 mL of triethylamine were added to dichloromethane (80 mL). After the reaction mixture was stirred at room temperature for 16 hours, the solvent was removed by rotary evaporation under reduced pressure, and the solid was purified by column chromatography to obtain 4-chloro-N-methyl-2-pyridinecarboxamide (2.96 g, 87% yield of white solid) Rate): MS(ESI+):m / e=171(M+1).

[0159]

[0160] 4.04 g of 4-bromo-2-pyridinecarboxylic acid (20 mmol), 1.65 g of methylamine hydrochloride (24 mmol), 3.50 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiene Amine (23 mmol), 3.0 grams of 1-hydroxybenzotriazole (22 mmol), and 4.0 mL of triethylamine were added to dichloromethane (80 mL...

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Abstract

The invention relates to Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and a preparation method and applications thereof. The structure of pentafluoride sulfur-based aryl urea is represented by formula I, wherein Z, R1, R3, R2, m, and n are defined by the patent claims and the patent specification. Pntafluoride sulfur-based aryl urea can be used as a Raf kinase inhibitor, possesses excellent stability, and can be used for preparing medicines used for preventing and / or treating Raf kinase induced diseases.

Description

technical field [0001] The present invention relates to aryl urea compounds, in particular to a class of sulfur pentafluoride aryl urea compounds that can be used as Raf kinase inhibitors or pharmaceutically available salts and preparation methods thereof. The present invention also relates to compounds containing sulfur pentafluoride A pharmaceutical composition of an aryl urea compound or a pharmaceutically acceptable salt thereof. Background technique [0002] Raf protein kinase is a signal enzyme molecule with very active functions. It not only plays an important role in the cell proliferation signal pathway, but also acts as a cross-link point in the interaction of various other cell signal transduction pathways. It is related to the regulation of various cell biological effects such as differentiation, apoptosis, cell cycle arrest and stress response of cells. Many kinases are associated with the pathogenesis of cancer or other diseases (such as diabetes, hypertension...

Claims

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Application Information

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IPC IPC(8): C07D213/81C07D215/22A61K31/44A61K31/47A61P35/00A61P35/02
CPCC07D213/81C07D215/22
Inventor 王若文
Owner 王若文
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