A kind of substituted arylamino aromatic heterocyclic compound and its application as antitumor drug

Abstract

The present invention discloses substituted arylaminoaromatic heterocyclic compounds as shown in formula (I) and their pharmaceutically acceptable salts, their preparation methods and their use in the preparation of antitumor drugs, wherein: X is selected from C , N; Y is selected from C, N; R 2 Choose from H, C 1‑3 Alkyl or halogen; Ar is selected from the following groups: where: R 1 Choose from H, C 1‑3 Alkyl, substituted C 1‑3 Alkyl, saturated heterocyclyl, carboxyl, alkoxyacyl, carbamoyl, N-alkylcarbamoyl; said R 1 The position of the substituent on the benzene ring is not limited; Z is selected from C, N or O; n is selected from an integer of 0-3. After activity testing, the compound of the present invention has multi-target inhibitory activity on tumor cell signal transduction pathways, has good inhibitory effect on target enzymes c-Met, VEGFR-2 and EGFR, and has shown It has good inhibitory activity and the prospect of anti-tumor cell drug resistance, and is suitable for use as a broad-spectrum, high-efficiency and low-toxicity anti-tumor drug.

Description

technical field

[0001] The invention relates to a substituted arylamino aromatic heterocyclic compound, a preparation method thereof and the application of the compound in preventing and treating related diseases such as tumors by blocking the HGF / c-Met signaling pathway. Background technique

[0002] Local invasion and metastasis of primary tumors to other tissues is one of the most important factors affecting the survival of cancer patients. The death of most cancer patients is caused by tumor metastasis, and the process of metastasis is greatly dependent on the movement of tumor cells sex and cell proliferation.

[0003] Hepatocyte growth factor (HGF), also known as discrete factor (ScatterFactor, SF), is a multifunctional cytokine that can promote the growth of various types of cells such as liver cells, epithelial cells, endothelial cells, and hematopoietic cells. The role of growth, migration and morphogenesis. c-Mesenchymal-epitheliatransition factor, or c-Met tyros...

Examples

Embodiment 1

[0139] Synthesis of 1-[(4-fluorophenyl)amido]cyclopropanecarboxylic acid (intermediate 3)

[0140]

[0141] 1,3-Cyclopropanedicarboxylic acid (13.01g, 0.10mol) was dissolved in 120mL of THF, under nitrogen protection, triethylamine (10.12g, 0.10mol) was slowly added dropwise thereto at 0°C, and stirred for 15min. Slowly add SOCl dropwise to the above system 2 (9.95g, 0.10mol), maintain this temperature and continue to stir for 30min. Finally, 60 mL of a THF solution dissolved in 4-fluoroaniline (12.22 g, 0.11 mol) was added dropwise to the reaction solution, and the reaction was completed under ice bath conditions. After the reaction, the pH of the reaction solution was adjusted to 9.0 with 10% sodium hydroxide solution, and after stirring for 10 min, the pH of the system was adjusted to 5.0 with 1N HCl, and a solid precipitated out, which was filtered after stirring for 15 min. The filter cake was washed with water until neutral, and dried in vacuum to obtain 14.71 g of ...

Embodiment 2

[0145] Synthesis of N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-diamide (intermediate 4)

[0146]

[0147] 4-aminophenol (15, 0.59g, 5.38mmol) and intermediate 3 (1g, 4.48mmol) were dissolved in DMF 15mL, EDC.HCl (1.03g, 5.38mmol) was added thereto, and the reaction was stirred at room temperature for 3h. After the reaction, add water to the reaction solution to precipitate a white solid, add 1N HCl to adjust the pH to 4.0-5.0, stir for 15 minutes, filter, wash the filter cake with water until neutral, and dry in vacuo to obtain 1.23 g of a white solid with a yield of 87.9 %.

[0148] ESI-MS[M+H] + : m / z 315.4

[0149] 1 H NMR (400MHz, DMSO-d 6 )δppm: 10.17 (s, 1H, CONH), 9.73 (s, 1H, CONH), 9.23 (s, 1H, OH), 6.68~7.83 (m, 8H, Ar-H), 1.48 (s, 4H, CH 2 CH 2 ).

Embodiment 3

[0151] Synthesis of N-(4-((2-chloropyrimidin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Intermediate 6)

[0152]

[0153] Dissolve intermediate 4 (3.14g, 10mmol) and raw material 2,4-dichloropyrimidine (5, 1.48g, 10mmol) in DMF: 15mL, add potassium carbonate (1.52g, 11mmol) to it, and heat up to 80°C , Reaction 5h. After the reaction, cool to room temperature, slowly add 60 mL of water in an ice-water bath, and a white solid precipitates out. After stirring for 30 min, filter and dry to obtain 3.72 g of an off-white solid, with a yield of 87.4%. ESI-MS[M+H] + :m / z 427.19

technical field

[0001] The invention relates to a substituted arylamino aromatic heterocyclic compound, a preparation method thereof and the application of the compound in preventing and treating related diseases such as tumors by blocking the HGF / c-Met signaling pathway. Background technique

[0002] Local invasion and metastasis of primary tumors to other tissues is one of the most important factors affecting the survival of cancer patients. The death of most cancer patients is caused by tumor metastasis, and the process of metastasis is greatly dependent on the movement of tumor cells sex and cell proliferation.

[0003] Hepatocyte growth factor (HGF), also known as discrete factor (ScatterFactor, SF), is a multifunctional cytokine that can promote the growth of various types of cells such as liver cells, epithelial cells, endothelial cells, and hematopoietic cells. The role of growth, migration and morphogenesis. c-Mesenchymal-epitheliatransition factor, or c-Met tyros...

Examples

Embodiment 1

[0139] Synthesis of 1-[(4-fluorophenyl)amido]cyclopropanecarboxylic acid (intermediate 3)

[0140]

[0141] 1,3-Cyclopropanedicarboxylic acid (13.01g, 0.10mol) was dissolved in 120mL of THF, under nitrogen protection, triethylamine (10.12g, 0.10mol) was slowly added dropwise thereto at 0°C, and stirred for 15min. Slowly add SOCl dropwise to the above system 2 (9.95g, 0.10mol), maintain this temperature and continue to stir for 30min. Finally, 60 mL of a THF solution dissolved in 4-fluoroaniline (12.22 g, 0.11 mol) was added dropwise to the reaction solution, and the reaction was completed under ice bath conditions. After the reaction, the pH of the reaction solution was adjusted to 9.0 with 10% sodium hydroxide solution, and after stirring for 10 min, the pH of the system was adjusted to 5.0 with 1N HCl, and a solid precipitated out, which was filtered after stirring for 15 min. The filter cake was washed with water until neutral, and dried in vacuum to obtain 14.71 g of ...

Embodiment 2

[0145] Synthesis of N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-diamide (intermediate 4)

[0146]

[0147] 4-aminophenol (15, 0.59g, 5.38mmol) and intermediate 3 (1g, 4.48mmol) were dissolved in DMF 15mL, EDC.HCl (1.03g, 5.38mmol) was added thereto, and the reaction was stirred at room temperature for 3h. After the reaction, add water to the reaction solution to precipitate a white solid, add 1N HCl to adjust the pH to 4.0-5.0, stir for 15 minutes, filter, wash the filter cake with water until neutral, and dry in vacuo to obtain 1.23 g of a white solid with a yield of 87.9 %.

[0148] ESI-MS[M+H] + : m / z 315.4

[0149] 1 H NMR (400MHz, DMSO-d 6 )δppm: 10.17 (s, 1H, CONH), 9.73 (s, 1H, CONH), 9.23 (s, 1H, OH), 6.68~7.83 (m, 8H, Ar-H), 1.48 (s, 4H, CH 2 CH 2 ).

Embodiment 3

[0151] Synthesis of N-(4-((2-chloropyrimidin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Intermediate 6)

[0152]

[0153] Dissolve intermediate 4 (3.14g, 10mmol) and raw material 2,4-dichloropyrimidine (5, 1.48g, 10mmol) in DMF: 15mL, add potassium carbonate (1.52g, 11mmol) to it, and heat up to 80°C , Reaction 5h. After the reaction, cool to room temperature, slowly add 60 mL of water in an ice-water bath, and a white solid precipitates out. After stirring for 30 min, filter and dry to obtain 3.72 g of an off-white solid, with a yield of 87.4%. ESI-MS[M+H] + :m / z 427.19

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