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5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives

A pyridyl, phenyl technology, applied in the field of treating diseases, preparing these compounds, and preparing medicines, can solve problems such as lack of ATR inhibitors

Pending Publication Date: 2021-04-13
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Lack of effective ATR inhibitors

Method used

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  • 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
  • 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives
  • 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0371] Example 1: 1-methyl-5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyridine Azol-3-yl)-1H-pyrazolo[4,3-b]pyridine (1)

[0372]

[0373] The structural unit used in the synthesis of Example 1: (3R)-3-methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4, 3-b]pyridin-5-yl]morpholine

[0374]

[0375] 1-Methyl-5-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate (1g , 2.37mmol, 1.0 equiv), (6-methylpyridin-3-yl)boronic acid (680mg, 4.72mmol, 1.99 equiv), Pd(dppf)Cl 2 .CH 2 Cl 2 (210 mg, 0.23 mmol, 0.10 equiv) and sodium carbonate (790 mg, 7.08 mmol, 2.99 equiv) were suspended in DMF (12 mL), water (3 mL). The final reaction mixture was heated to 100 °C in the microwave for 1 h. (3R)-3-Methyl-4-[1-methyl-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine- 5-yl]morpholine (600 mg, 70%).

[0376] Structural unit used in the synthesis of Example 1: (3R)-4-[3-bromo-1-methyl-7-(6-methylpyridin-3-yl)-1H-pyraz...

Embodiment 2

[0387] Example 2: 5-((R)-3-methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-(1H-pyrazol-3-yl )-1H-pyrazolo[4,3-b]pyridine (2)

[0388]

[0389] Structural unit used in the synthesis of Example 2: 6-chloro-2-methyl-3-nitropyridin-4-amine

[0390]

[0391] 2,6-dichloro-3-nitropyridin-4-amine (1g, 4.33mmol, 1 equivalent), Pd(PPh 3 ) 4 (557mg, 0.46mmol, 0.11 equiv) and AlMe 3(2.64 mL, 23.94 mmol, 5.53 equiv) was dissolved in DMF (15 mL) and stirred at 70°C for 3 hours. The reaction was quenched by adding 50 mL of ice / salt. The solids were filtered off. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography (Method B). 6-Chloro-2-methyl-3-nitropyridin-4-amine was isolated as a yellow solid (500 mg, 55%).

[0392] Building block used in the synthesis of Example 2: 4-bromo-6-chloro-2-methyl-3-nitropyridine

[0393]

[0394] 6-Chloro-2-methyl-3-nitrop...

Embodiment 3

[0418] Example 3: (3R)-3-Methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)-7-(6-methylpyridin-3-yl)-1H- Pyrazolo[4,3-b]pyridin-5-yl]morpholine (3)

[0419] absolute

[0420]

[0421] Structural unit used in the synthesis of Example 3: 5-((R)-3-Methyl-morpholin-4-yl)-7-(6-methyl-pyridin-3-yl)-3-[5 -Methyl-2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-1H-pyrazolo[4,3-b]pyridine

[0422]

[0423](3R)-4-[3-iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-3-methyl phenoline (56 mg; 0.114 mmol; 0.789 equiv) and (3R)-4-[3-iodo-7-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine- 5-yl]-3-methylmorpholine (15 mg; 0.031 mmol; 0.211 equiv) was dissolved in tetrahydrofuran (1.42 ml) and water (142,00 μl). 1-BOC-3-methylpyrazole-5-boronic acid (49 mg; 0.217 mmol; 1.5 equiv), sodium carbonate (0.02 ml; 0.434 mmol; 3 equiv) and tetrakis(triphenylphosphine)-palladium(0) were added (20 mg; 0.017 mmol; 0.120 equiv). The reaction suspension was stirred at 80°C for 1 hour. Add 3-methy...

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Abstract

Compounds of the formula Ia and Ib in which R1, R2 and R3 have the meanings indicated in Claim 1, are inhibitors of ATR, and can be employed for the treatment of diseases such as cancer.

Description

Background technique [0001] The object of the present invention was to discover new compounds with valuable properties, especially those useful for the preparation of medicaments. [0002] The present invention relates to 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives that inhibit ATR (ataxia telangiectasia mutant and Rad3-related kinase). Accordingly, the compounds of the present invention are useful in the treatment of diseases such as cancer. [0003] The present invention also provides methods of making these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases using the pharmaceutical compositions comprising these compounds. [0004] The chemical entities of the present invention are inhibitors of ATR and have many therapeutic applications, especially in the treatment of cancer. [0005] Cancer is the result of uncontrolled cell growth in many different tissues. In many cases, new cells penetrate into existing tissue...

Claims

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Application Information

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IPC IPC(8): A61P35/00C07D471/04C07D519/00A61K31/5377A61P29/00A61P31/04
CPCC07D471/04C07D519/00A61P35/00A61P31/04A61P29/00
Inventor L·伯格多夫C·扎克拉基迪斯
Owner MERCK PATENT GMBH