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Thienopyrimidinone compound and medical application thereof

A technology of compounds and medicinal salts, applied in the fields of pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc.

Pending Publication Date: 2021-07-09
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is still no drug marketed globally for the USP7 target, and all the compounds under development are in the preclinical research stage

Method used

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  • Thienopyrimidinone compound and medical application thereof
  • Thienopyrimidinone compound and medical application thereof
  • Thienopyrimidinone compound and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] Embodiment one (R)-3-((4-Hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-7-(1H-indazole-6- base) Thieno[3,4-d]pyrimidin-4(3H)-one (compound 1)

[0302]

[0303] Step 1: (R)-7-bromo-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)thieno[3,4-d]pyrimidine- Synthesis of 4(3H)-ketone (compound 1-2)

[0304] At room temperature, compound 1-1 (0.13g, 0.56mmol), (R)-3-phenyl-1-(1-oxa-6-aza-spiro[2.5]oct-6-yl)butanone (Synthesis method reference WO2018073602) (0.15g, 0.56mmol) was dissolved in DMF (4mL), potassium carbonate (0.16g, 1.13mmol) was added, and the reaction solution was heated to 80°C for 8h. The reaction mixture was cooled to room temperature, separated and purified by preparative high performance liquid chromatography (method D), and lyophilized to obtain the title compound, 0.14 g. ESI-MS(m / z):490.1,492.1[M+H] + .

[0305] Step 2: (R)-3-((4-Hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-7-(1H-indazol-6-yl)thieno Synthesis of [3,4-d]pyrimid...

Embodiment 2

[0309] Embodiment two (R)-3-((4-Hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)-7-(4-hydroxybenzene base) Thieno[3,4-d]pyrimidin-4(3H)-one (compound 2)

[0310]

[0311] At room temperature, compound 1-2 (30mg, 0.06mmol), 4-hydroxyphenylboronic acid (20mg, 0.09mmol), potassium carbonate (25mg, 0.18mmol) were added to the reaction flask in turn, and then 1,4-diox Hexacyclic (4 mL) and water (0.8 mL). Finally, palladium tetrakistriphenylphosphine (7.1 mg, 0.006 mmol) was added, and nitrogen was replaced three times. Under the protection of nitrogen, it was heated to 80°C and stirred for 4h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (method D), and lyophilized to give the title compound, 20 mg.

[0312] Its structure is characterized as follows:

[0313] 1 H NMR (400MHz, DMSO-d 6 )δ9.74(s,1H),8.34(s,1H),7.97(d,J=10.4Hz,1H),7.91-7.83(m,2H),7.28-7.22(m,4H)...

Embodiment 3

[0314] Embodiment Three (R)-7-(4-(aminomethyl)phenyl)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidine-4- Synthesis of yl)methyl)thieno[3,4-d]pyrimidin-4(3H)-one (compound 3)

[0315]

[0316]Step 1: (R)-4-(3-((4-Hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl-4-oxo-3,4-dihydrothiophene Synthesis of tert-butyl[3,4-d]pyrimidin-7-yl)benzylcarbamate (compound 3-1)

[0317] According to the operation described in Example 2, compound 1-2 (20mg, 0.04mmol) and 4-(N-tert-butoxycarbonylaminomethyl)phenylboronic acid (15mg, 0.06mmol) were used as the reaction raw materials to replace compound 1 respectively -2 (30mg, 0.06mmol) was reacted with 4-hydroxyphenylboronic acid, and the reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound, 21mg, which was directly used in the next reaction. ESI-MS(m / z):617.3[M+H] + .

[0318] Step 2: (R)-7-(4-(aminomethyl)phenyl)-3-((4-hydroxy-1-(3-phenylbutyryl)piperidin-4-yl)methyl)thiophene Syn...

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Abstract

The invention relates to a thienopyrimidinone compound and a medical application thereof. The invention belongs to the field of medicines, and particularly relates to a compound as shown in a formula I, and pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, prodrug, any crystal form, and metabolite thereof or a mixture of the compound, the pharmaceutically acceptable salt, the ester, the solvate, the stereoisomer, the tautomer, the prodrug, any crystal form, and the metabolite. The invention also relates to the medical application of the compound shown in the formula I, the pharmaceutically acceptable salt, the ester, the solvate, the stereoisomer, the tautomer, the prodrug, any crystal form, the metabolite or the mixture of the compound, the pharmaceutically acceptable salt, the ester, the solvate, the stereoisomer, the tautomer, the prodrug and the metabolite. The compound provided by the invention can be used for inhibiting the activity of deubiquitinating enzyme USP7, and can also be used for preventing or treating USP7 regulation related diseases or symptoms (such as cancers).

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to thienopyrimidinone compounds and the medical application of the compounds. Background technique [0002] The ubiquitin-proteasome system (UPS) is a basic physiological regulation process in cells. Through a series of cascade reactions, proteins are degraded by proteases after being modified by ubiquitin. The abnormality of UPS is closely related to diseases such as tumors, neurodegenerative diseases, and viral infections. At present, drugs are mainly developed for five types of targets in the UPS system: protease, E1 activating enzyme, E2 conjugating enzyme, E3 ligase and deubiquitinases (DUBs). [0003] Deubiquitinase can specifically cut off the isopeptide bond formed between the glycine residue at the carbon terminal of ubiquitin and the target protein, so that ubiquitin can be separated from the target protein, so that the target protein is not degraded, relocated or acti...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61P35/00A61P25/00A61P3/10A61P19/08A61P19/02A61P19/10A61P37/00A61P9/00A61P9/10A61P31/12A61P31/04
CPCC07D495/04A61K31/519A61P35/00A61P25/00A61P3/10A61P19/08A61P19/02A61P19/10A61P37/00A61P9/00A61P9/10A61P31/12A61P31/04
Inventor 陈寿军宋帅蒋小玲田强宋宏梅薛彤彤王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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