Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (USP19)

A compound and hydrate technology, applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc.

Pending Publication Date: 2021-09-07
ALMAC DISCOVERY LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to the best of our knowledge, no inhibitors targeting USP19 have been reported, so identifying such inhibitors with drug-like potential remains a first and high priority

Method used

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  • Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (USP19)
  • Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (USP19)
  • Pharmaceutical compounds and their use as inhibitors of ubiquitin specific protease 19 (USP19)

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0722] For the preparation of tablets, coated tablets or hard gelatine capsules, the compounds of the invention can be mixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.

[0723] For the preparation of solutions and syrups, excipients include, for example, water, polyols, sucrose, invert sugar and dextrose.

[0724] For injectable solutions, excipients include, for example, water, alcohols, polyols, glycerol and vegetable oils.

[0725] For suppositories and topical and transdermal applications, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

[0726] The pharmaceutical composition may also contain preservatives, solubilizers, stabilizers, wetting agen...

Embodiment 1

[0949] Example 1: 1-((1-((R)-3-cyclohexyl-2-methylpropionyl)-4-hydroxyl-3,3-dimethylpiperidin-4-yl) Methyl)pyrazin-2(1H)-one

[0950]

[0951] Step 1: tert-butyl 4-hydroxy-3,3-dimethyl-4-((2-oxopyrazin-1(2H)-yl)methyl)piperidine-1-carboxylate: according to general procedure 2 , using pyrazin-2(1H)-one (30 mg, 0.312 mmol), epoxide 1 (98 mg, 0.406 mmol) and cesium carbonate (204 mg, 0.624 mmol) in NMP (1 mL) (heated to 80 °C for 3h) Preparation to give the title compound (50 mg, 47%). LCMS (Method A): R T =1.15min, m / z=338[M+H] + ;282[M-Butene+H] + .

[0952] Step 2: 1-((4-Hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrazin-2(1H)-one: According to general procedure 3, using 4-hydroxy-3, 3-Dimethyl-4-((2-oxopyrazin-1(2H)-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.148 mmol), DCM (1 mL) and TFA ( 0.5 mL) (stirred at rt for 2 h) to afford the title compound (35 mg, quantitative). LCMS (Method A): R T =0.37min, m / z=238[M+H] + .

[0953] Step 3: 1...

Embodiment 2

[0954] Example 2: 1-((1-((R)-3-cyclohexyl-2-methylpropionyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl) Methyl)-5-phenylpyrazin-2(1H)-one

[0955]

[0956] Step 1: tert-butyl 4-((5-bromo-2-oxopyrazin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate: According to general procedure 2, using 5-bromopyrazin-2(1H)-one (2.62 g, 15 mmol), epoxide 1 (3.98 g, 16.5 mmol) and DIPEA (13.1 mL, 75 mmol) in NMP (30 mL) ) (heated to 110°C for 20h) to obtain the title compound (850mg, 13%). LCMS (Method B): R T =1.18min, m / z=316,318[M-Boc+H] + .

[0957]Step 2: 5-Bromo-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrazin-2(1H)-one: According to general procedure 3, using 4- ((5-Bromo-2-oxopyrazin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylic acid tert-butyl ester (850mg, 2.04mmol) , DCM (10 mL) and TFA (5 mL) (stirring at rt for 30 min) gave the title compound (510 mg, 79%). LCMS (Method B): R T =0.41min, m / z=316,318[M+H] + .

[0958] Step 3: 5-Bro...

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Abstract

Provided are USP19 inhibitors, methods of treating obesity, metabolic syndrome and / or diabetes using the USP19 inhibitor compounds, as well as those compounds for use in methods of treating obesity, metabolic syndrome and / or diabetes. Also provided are methods of treating muscular atrophy, for example cachexia or sarcopenia with USP19 inhibitor compounds, plus those compounds for use in methods of treating muscular atrophy.

Description

technical field [0001] The present invention relates to ubiquitin-specific protease 19 (USP19) inhibitors and methods of use thereof. Background technique [0002] Over the past decade, protein ubiquitination has emerged as an important post-translational modification that plays a role in numerous cellular processes, including proteolysis, gene expression, DNA repair, immune response, metabolism or cell cycle regulation, among others. It has also been established that dysregulation of the ubiquitin-proteasome system (UPS) is involved in the pathogenesis of various human diseases, including but not limited to cancer (Hoeller D. et al., Nat. Rev. Cancer (2006), 6, 776-788), viral infection ( Gao et al., J.Physiol., Pharmacol.(2006), 84,5-14), metabolic or neurodegenerative disorders (Loosdregt J. et al., Immunity (2013), 39, 259-271; Rubinsztein D. et al., Nature (2006) ,443,780-786) and immune and inflammation-related medical conditions (Wang J. et al., J.Cell Immunol.(2006)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/04A61P3/10A61P21/00C07D401/06C07D401/14C07D487/04C07D491/048C07D495/04A61K31/4545
CPCC07D401/14C07D401/06C07D487/04C07D491/048C07D495/04A61P3/04A61P3/10A61P21/00A61K31/497A61K31/5377A61K31/519A61P35/00C07D413/06C07D498/04C07D471/04C07D413/14C07D405/14C07D417/14
Inventor 詹姆士·塞缪尔·沙恩·朗特里S·K·怀特海德A·P·特雷德L·E·普罗克特史蒂文·D·谢泼德弗兰克·布尔坎普J·R·C·科斯塔科林·奥多德蒂莫西·哈里森M·D·赫尔姆E·罗兹卡A·克兰斯顿X·雅克
Owner ALMAC DISCOVERY LIMITED
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