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Substituted triazine phenyl urea derivatives and application thereof

A kind of technology of substituent and compound, applied in the field of substituted triazine phenylurea derivatives and their uses, can solve problems such as no effect

Inactive Publication Date: 2011-11-23
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The variant form of B-RAF V599E can activate the RAF / MEK / ERK pathway of human melanoma cells in vitro and prevent the growth of melanoma cells in soft agar, but has no effect on the RNA of V599E B-RAF

Method used

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  • Substituted triazine phenyl urea derivatives and application thereof
  • Substituted triazine phenyl urea derivatives and application thereof
  • Substituted triazine phenyl urea derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: Compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(4-(4-hydroxypiperidin-1-yl)-6-methyl-1 Of, 3,5-triazinyl-2-amino)-4-methylphenyl)urea (HSCA-001)

[0135] Synthetic Route 1

[0136]

[0137] step one:

[0138]

[0139] Dissolve 1a (3.69g, 20mmol) in 20mL of anhydrous tetrahydrofuran, and slowly add methylmagnesium bromide in ether (8mL, 24mmol, 3M) with a syringe at -20°C. After the addition, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure. Add 20 mL saturated ammonium chloride solution to the residue, extract the solution with ethyl acetate (20 mL×2), wash the organic phase with 30 mL brine, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Obtained 3.2 g of solid, product 1b, with a yield of 97%. MS[M+1] + 165.2.

[0140] Step two:

[0141]

[0142] 1c (1.11g, 5mmol), 1d (837mg, 5.5mmol) and diisopropylethylamine (1.65mL) were a...

Embodiment 2

[0152] Example 2: Compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-(4-methyl-6-morpholinyl-1,3, Synthesis of 5-triazinyl-2-amino)phenyl)urea (HSCA-002)

[0153] Synthetic Route 2

[0154]

[0155] 1g (150mg, 0.319mmol) and morpholine (1mL) were added to 10mL ethanol solution and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, water was added, extracted with ethyl acetate, the organic phase was collected and concentrated. Purified with a preparative silica gel plate to obtain 60 mg of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-(4-methyl-6-morpholinyl-1) , 3,5-triazinyl-2-amino)phenyl)urea (HSCA-002), the yield is 36%. 1 H NMR(400MHz, DMSO-d 6 )δppm: 9.07 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.59 (m, 2H), 7.10 (m, 1H) ), 7.03(m, 1H), 3.68(m, 4H), 3.58(m, 4H), 2.20(s, 3H), 2.15(s, 3H); MS[M+1] + 522.0.

[0156] The following compounds can be obtained by the methods of Examples 1 and 2:

...

Embodiment 3

[0212] Example 3: Compound 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-(4-methyl-6-morpholinyl-1,3, Synthesis of 5-triazinyl-2-oxo)phenyl)urea (HSCA-003)

[0213] Synthetic Route 3

[0214]

[0215] step one:

[0216]

[0217] 3a (1.3 g, 7.9 mmol) and diisopropylethylamine (1.6 g, 15.8 mmol) were dissolved in 15 mL DMF, and morpholine (620 mg, 0.71 mmol) was added thereto at -5°C. After stirring for 2 hours at the same temperature, water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was collected, dried with anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to obtain 1.4 g of crude product 3b, which was directly used in the next reaction.

[0218] Step two:

[0219]

[0220] Compound 3c (544 mg, 3.55 mmol) was dissolved in 15 mL DMF, and sodium hydride (142 mg, 3.55 mmol) was added to the solution after cooling to -5°C. After stirring for 30 minutes at the same temperature, 0.7 g of compound...

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Abstract

The invention relates to substituted triazine phenyl urea derivatives and application of the derivatives used as protein kinases, especially as Raf-1 inhibitors. The compounds provided by the invention can be used for treating various disorders and diseases, especially the protein-kinase-related diseases such as cancers, miocardial infarction, cerebral thrombosis, anaemia, hepatitis C (HCV) and other diseases.

Description

Technical field [0001] The present invention relates to substituted triazine phenylurea derivatives and their application as inhibitors of protein kinases, especially Raf-1. The compounds of the present invention can be used to treat various disorders and diseases, especially diseases related to protein kinases, such as cancer. , Myocardial infarction, cerebral thrombosis, anemia and hepatitis C (HCV), etc. Background technique [0002] Many processes of tumor production, growth and metabolism are regulated by cell signaling pathways triggered by activated tyrosine kinases. RAS (a proto-oncogene, named after it was first discovered in the rat sarcoma virus) can regulate several downstream receptor tyrosine kinases (RTKs). The activation of the RAS cell signaling pathway is a key step in the growth of human cancer cells. The activation process of the RAS channel is caused by the activation of the mutation of the RAS oncogene, or the influencing factors of the downstream RAS. Th...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D251/18C07D251/16C07D403/04C07D405/04C07D251/22A61K31/53A61K31/5377A61P35/00A61P9/10A61P7/02A61P7/06A61P1/16A61P31/14C07C275/30C07C275/40
CPCC07D403/04A61K31/53C07D251/16C07D405/04C07C275/40C07C275/30A61K31/5377C07D251/22C07D401/04C07D251/18A61P1/16A61P7/02A61P7/06A61P9/10A61P31/14A61P35/00
Inventor 丁毅力白骅柴健晏青燕杨璇肯尼思史密斯
Owner ZHEJIANG HISUN PHARMA CO LTD
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