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4-hydroxypiperidine derivatives and their use as inhibitors of ubiquitin specific protease 19 (USP19)

A derivative, alkyl technology, applied in the field of inhibitors of ubiquitin-specific protease 19

Pending Publication Date: 2020-12-25
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, and thus, identifying such inhibitors with drug-like potential remains a top priority and high priority

Method used

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  • 4-hydroxypiperidine derivatives and their use as inhibitors of ubiquitin specific protease 19 (USP19)
  • 4-hydroxypiperidine derivatives and their use as inhibitors of ubiquitin specific protease 19 (USP19)
  • 4-hydroxypiperidine derivatives and their use as inhibitors of ubiquitin specific protease 19 (USP19)

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0615] For the preparation of solutions and syrups, excipients include, for example, water, polyols, sucrose, invert sugar and dextrose.

[0616] For injection solutions, excipients include, for example, water, alcohols, polyols, glycerin and vegetable oils.

[0617] For suppositories and topical and transdermal administration, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

[0618] The pharmaceutical composition may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavor enhancers, buffers, coating agents and / or antioxidants.

[0619] For combination therapy, the second drug may be provided in the pharmaceutical composition of the invention, or may be provided alone.

[0620] Pharmaceutical preparations for oral administration can thus be, for example, granules, tablets, dragees, capsules, pills, suspensions or emulsions. For parenteral injections for eg intra...

Embodiment 1

[0783] Example 1: 1-((1-((R)-3-cyclohexyl-2-methylpropionyl)-4-hydroxyl-3,3-dimethylpiperidin-4-yl) Methyl)pyrazin-2(1H)-one

[0784]

[0785] Step 1: tert-butyl 4-hydroxy-3,3-dimethyl-4-((2-oxopyrazin-1(2H)-yl)methyl)piperidine-1-carboxylate: follow 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, Hold for 3 hours for preparation to afford the title compound (50 mg, 47%). LCMS (Method A): R T =1.15min, m / z=338[M+H] + ;282[M-Butene+H] + .

[0786] Step 2: 1-((4-Hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrazin-2(1H)-one: Follow 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 room temperature for 2 hours to obtain the title compound (35 mg, quantitative). LCMS (Method A): R T =0.37min, m / z=238[M+H] + ....

Embodiment 2

[0788] Example 2: 1-((1-((R)-3-cyclohexyl-2-methylpropionyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl) Methyl)-5-phenylpyrazin-2(1H)-one

[0789]

[0790] Step 1: tert-butyl 4-((5-bromo-2-oxopyrazin-1(2H)-yl)methyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate: Following 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 20 hours to obtain the title compound (850 mg, 13%). LCMS (Method B): R T =1.18min, m / z=316,318[M-Boc+H] + .

[0791]Step 2: 5-Bromo-1-((4-hydroxy-3,3-dimethylpiperidin-4-yl)methyl)pyrazin-2(1H)-one: Follow 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) were prepared by stirring at room temperature for 30 min to afford the title compound (510 mg, 79%). LCMS (Method B): R T =0.41min, m / z=316,318[M+H] ...

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Abstract

Inhibitors of ubiquitin specific protease 19 (USP19) of Formula (I) are provided, together with pharmaceutical compositions comprising said inhibitors, and methods of use thereof. The compounds can beused in in the treatment of muscular atrophy, obesity, insulin resistance or type II diabetes or in reducing the loss of muscle mass.

Description

technical field [0001] The present invention relates to inhibitors of ubiquitin-specific protease 19 (USP19) 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. Dysregulation of the ubiquitin-proteasome system (UPS) has also been implicated 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., Can. 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 disorders (Wang J. et al., J. Cell Immunol. (2006), 3, 255-261; Corn J....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P3/04A61P21/00A61P3/10A61K31/4545C07D401/06C07D487/04C07D491/048C07D495/04
CPCC07D401/14A61K31/4545C07D401/06C07D487/04C07D491/048C07D495/04A61P3/04A61P21/00A61P3/10A61K31/438A61K31/454A61K31/4725A61K31/496A61K31/4985A61K31/506A61K31/513A61K31/517A61K31/519A61K31/5377A61K31/538A61K31/5383A61K31/541A61K31/55A61K31/497C07D413/06C07D498/04C07D471/04C07D405/14C07D409/14C07D413/14C07D417/14C07D491/107
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
Owner ALMAC DISCOVERY LIMITED
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