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A 4-substituted pyrido[2,3-d]pyrimidin-7-one compound and its preparation method and application

A ketone compound, 3-d technology, applied in the field of medicine, achieves good inhibitory activity, promotion effect, and the effect of promoting tumor cell apoptosis

Active Publication Date: 2022-03-29
南京思聚生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for MLN4924, no other NEDD8 activating enzyme inhibitors have entered into clinical trials, and no NEDD8 activating enzyme inhibitors are on the market. Therefore, finding and developing new NEDD8 activating enzyme inhibitors will be of great significance for cancer treatment

Method used

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  • A 4-substituted pyrido[2,3-d]pyrimidin-7-one compound and its preparation method and application
  • A 4-substituted pyrido[2,3-d]pyrimidin-7-one compound and its preparation method and application
  • A 4-substituted pyrido[2,3-d]pyrimidin-7-one compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: 8-cyclopentyl-5-(3-(trifluoromethyl)phenyl)-2-(4-(phenethylamino)piperidin-1-yl)pyrido[2,3- d] Synthesis of pyrimidin-7-one (compound 1).

[0042]

[0043] The synthetic steps according to the above synthetic route are:

[0044] Step 1 Synthesis of Compound 1-1: Add 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester (36.5g, 156.9 mmol) into a 500mL round bottom flask, dissolve it in 300mLTHF, and then add cyclopentylamine in turn (20.0g, 235.3mmol) and triethylamine (31.8g, 313.8mmol), after stirring at room temperature for 1h, the reaction was complete. Filtrate, remove THF by distilling the filtrate under reduced pressure, add 300mL ethyl acetate to dissolve, and use saturated NH 4 Cl solution (200mL×3), then washed with saturated brine (200mL×3), the organic phase was washed with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was evaporated under reduced pressure to remove the solvent, and then 20 mL of toluene was added and...

Embodiment 2

[0063] Example 2: 8-cyclopentyl-2-(4-(phenethylamino)piperidin-1-yl)-5-phenylpyrido[2,3-d]pyrimidin-7-one (compound 2) Synthesis.

[0064]

[0065] According to the above synthetic route, referring to the preparation method of Example 1, the difference is that Compound 2-1 is obtained by reacting Compound 1-6 with phenylboronic acid, and then Compound 2-1 is reacted with m-chloroperoxybenzoic acid to obtain Compound 2 -2, then react compound 2-2 with compound 1-11 to obtain compound 2-3; finally react compound 2-3 with trifluoroacetic acid to obtain compound 2. 1 HNMR (500MHz, CDCl 3 ) δ: 9.75(s, 2H), 8.37(s, 1H), 7.46-7.45(t, J=5Hz, 3H), 7.39-7.38(t, J=7.5Hz, 2H), 7.28-7.25(q, J=14.5Hz, 2H), 7.23-7.20(t, J=14Hz, 1H), 7.15(d, J=7Hz, 2H), 6.30(s, 1H), 5.86-5.82(t, J=18Hz, 1H ), 4.93(d, J=13.5Hz, 2H), 3.31(s, 1H), 3.20(s, 2H), 3.04-2.96(m, 4H), 2.40-2.35(m, 2H), 2.18(d, J=11.5Hz, 2H), 1.98(s, 2H), 1.83-1.81(t, J=9Hz, 2H), 1.80-1.64(m, 4H).

[0066] HRMS(ESI)(m / z):494.292...

Embodiment 3

[0067] Example 3: 8-cyclopentyl-5-(3,4-dimethylphenyl)-2-(4-(phenethylamino)piperidin-1-yl)pyrido[2,3-d ] Synthesis of pyrimidin-7-one (compound 3).

[0068]

[0069] According to the above synthetic route, referring to the preparation method of Example 1, the difference is that compound 3-1 is obtained by reacting compound 1-6 with 3,4-dimethylphenylboronic acid, and compound 3-1 is reacted with m-chloroperoxybenzene React with formic acid to obtain compound 3-2, then react compound 3-2 with compound 1-11 to obtain compound 3-3, then react compound 3-3 with trifluoroacetic acid to obtain compound 3. 1 H NMR (300MHz, CDCl 3 )δ:9.75(s,1H),8.44(s,2H),7.31-7.23(m,4H),7.22-7.11(m,4H),6.29(s,1H),5.96-5.80(m, J= 17.7Hz, 1H), 4.98-4.93(d, J=13.5Hz, 2H), 3.31(s, 1H), 3.18(s, 2H), 3.06-2.92(m, 4H), 2.37(d, J= 10.8 Hz, 1H), 2.31(d, J=5.7Hz, 6H), 2.18(d, J=10.8Hz, 2H), 1.96(d, J=4.8Hz, 2H), 1.87(m, 3H), 1.81- 1.63(m,6H).HRMS(ESI)(m / z):522.3229[M+H] + , calculated for C 33 h 39 ...

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Abstract

The invention discloses 4-substituted pyrido[2,3-d]pyrimidin-7-one compounds with different general structures and pharmaceutically acceptable salts, solvates, polymorphs and tautomorphisms thereof Constructs, metabolites or prodrugs. The invention also discloses the effect of the above-mentioned compound as an inhibitor of NEDD8 activating enzyme and its use in the preparation of medicines for treating diseases related to the abnormality of NEDD8 activating enzyme. Pharmacological results show that the compound has good NEDD8 inhibitory activity, anti-tumor cell proliferation effect, and tumor cell apoptosis-promoting effect.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a 4-substituted pyrido[2,3-d]pyrimidin-7-one compound and a preparation method and application thereof. Background technique [0002] Malignant tumors are a large class of common multiple diseases that seriously endanger human health, with a high fatality rate, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, about 8.2 million people died of cancer in the world in 2012, and it is estimated that the number of deaths due to cancer will exceed 11 million in 2030. China is a country with a high incidence and mortality rate of cancer, which causes economic losses of hundreds of billions of yuan every year, and with the aging of the population, the deterioration of the ecological and living environment, this trend is more likely to intensify. Therefore, finding effective drugs for the treatment of tumors has at...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02
Inventor 陆鹏王亮张英王玉斌
Owner 南京思聚生物医药有限公司
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