Degradation agents for cell cycle-dependent kinases, preparation method thereof, pharmaceutical compositions and use thereof

A technology of compounds and hydrates, which can be used in drug combinations, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc. question

Inactive Publication Date: 2020-02-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Representative small molecule inhibitors include Flavopiridol, Roscovitine, SNS-032, R547, TG-02, AT-7519, etc.; however, highly selective small molecule inhibitors targeting CDK7 or CDK9, or targeting CDK7 and CDK9 There are relatively few researches on pharmaceutical agents (US2007179161A1, US2015111873A1, WO2016193939A1, WO2016142855A2)
Although sm...

Method used

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  • Degradation agents for cell cycle-dependent kinases, preparation method thereof, pharmaceutical compositions and use thereof
  • Degradation agents for cell cycle-dependent kinases, preparation method thereof, pharmaceutical compositions and use thereof
  • Degradation agents for cell cycle-dependent kinases, preparation method thereof, pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] [C001]N-(6-(4-(((5-((6-n-hexylamino)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino) Methyl)phenyl)n-hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy) Preparation of acetamide

[0209]

[0210] Dissolve p-bromobenzylamine (1g, 5.37mmol) in dichloromethane, add triethylamine (1.23mL, 5.37mmol, 1 equiv), add di-tert-butyl dicarbonate dropwise at 0°C, and react at room temperature for 12 hours. Dichloromethane was added to the reaction solution, saturated NaHCO 3 Wash, anhydrous Na 2 SO 4 After drying and column chromatography, the product 1.1 (1.35 g) was obtained with a yield of 88%. 1 H NMR (400MHz, CDCl 3 ) δ 7.43 (d, J=7.5Hz, 2H), 7.15 (d, J=8.0Hz, 2H), 4.25 (d, J=5.6Hz, 2H), 1.45 (s, 9H).

[0211] 6-Chlorohexyne (1g, 8.58mmol), potassium phthalimide (2.54g, 13.72mmol, 1.6equiv) were dissolved in 10mL of DMF, reacted at 70°C for 18 hours, added water to the reaction solution, extracted with ethyl acetate , combined ethyl acetate layers...

Embodiment 2

[0223] [C012]7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamido) -N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5] Preparation of Triazin-4-yl)amino)methyl)phenyl)heptanamide

[0224]

[0225] 4-Nitrobenzylamine hydrochloride was dissolved in (590 mg, 3.13 mmol) in 15 mL of dichloromethane, and DIPEA (1.03 mL, 6.26 mmol, 2 equiv), Fmoc-OSU (1.1 g, 3.28 mmol, 1.05 equiv) was dissolved in dichloromethane, added dropwise to the reaction solution, reacted at room temperature for 4 hours, added 100mL of dichloromethane to the reaction, washed several times with 0.5N aqueous HCl solution, washed with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, filtering, removing the solvent under reduced pressure, and column chromatography, the product 2.1 (1.15 g) was obtained with a yield of 98%. 1 H NMR (400MHz, CDCl 3 )δ8.18(d, J=8.5Hz, 2H), 7.78(d, J=7.6Hz, 2H), 7.59(d, J=7.4Hz, 2H), 7.46-7.29(m, 6H), 4.54( d, J=6.4Hz, 2H), 4.45(d, ...

Embodiment 3

[0238] [C014]N-(4-(dimethylamino)-3-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1, 5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-7-(2-((2-(2,6-dioxo-3-yl)- 1,3-dioxoisoindol-4-yl)oxy)acetamido)heptanamide

[0239]

[0240] 2-Fluoro-5-nitrobenzonitrile (2g, 12.04mmol), dimethylamine hydrochloride (1.96g, 24.08mmol, 2equiv), potassium carbonate (5g, 36.12mmol, 3equiv) were dissolved in DMF, and reacted at room temperature for 12 hours, Add 150mL ethyl acetate to the reaction, wash with water several times, wash with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, filtering, and removing the solvent under reduced pressure, the product 3.1 (2.24 g) was obtained in a yield of 97%. 1 HNMR (400MHz, CDCl 3 ) 8.38 (d, J=2.8Hz, 1H), 8.15 (dd, J=9.6, 2.8Hz, 1H), 6.78 (d, J=9.6Hz, 1H), 3.32 (s, 6H).

[0241] Compound 3.1 (2.24 g, 11.72 mmol) was dissolved in EtOH (20 mL) / H 2 O (10mL) / THF (20mL), add iron powder (3.27g, 58.58mmol, 5equiv) and NH 4 Cl (3.13g, 58.58mm...

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Abstract

The present invention relates to cell cycle-dependent kinase (CDKs) degradation agents shown as a general formula (I), and/or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and use of the derivatives, as pharmaceutically active agents, in medicines for preventing and/or treating diseases related to abnormal activity of CDKs. The compounds have good cell proliferation inhibiting effect on both solid tumors and hematological tumors, indicating that the compounds have potentials to treat related cancers and autoimmune diseases.

Description

technical field [0001] The present invention belongs to the field of pharmacy, and specifically relates to a class of compounds represented by the general formula (I), its preparation method, pharmaceutical composition and its use in the preparation of degradation agents targeting cell cycle-dependent kinases (CDKs) in the prevention and / or Or use in medicines for treating diseases or symptoms related to abnormal activity of cell cycle-dependent kinases, and treating diseases or diseases related to selective transcription CDKs. The invention also provides pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions to treat diseases or conditions associated with selectively transcribed CDKs. Background technique [0002] Important targets for cell cycle-dependent kinase (CDK) tumor therapy: [0003] Cyclin dependent kinase (CDK) is a class of serine / threonine kinases, most of which are heterodimeric complexes composed...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D473/00C07D471/04A61P35/00A61P35/02A61K31/519A61K31/52A61K31/53A61K31/4545
CPCC07D487/04C07D473/00C07D471/04A61P35/00A61P35/02A61K31/4545A61K31/519A61K31/53A61K31/52C07D495/04Y02P20/55
Inventor 陈小华李佳冯序乐周宇波田洪涛张凯祥王培培
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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