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Suppression of usp36

A C3-C6 compound technology, applied in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve the problems of lack of resources in cells and reduce hyperactivity of nucleoli

Pending Publication Date: 2022-03-22
瓦洛健康股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reduced ribosome production due to USP36 inhibition is expected to counteract MYC-induced nucleolar hyperactivity and starve cells of resources needed to sustain proliferation

Method used

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  • Suppression of usp36
  • Suppression of usp36
  • Suppression of usp36

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0288] N-(4-[[(1S)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl]carbamoyl]-1,2,3-thiadiazole-5 -yl)-5-(trifluoromethyl)pyridine-3-carboxamide and N-(4-[[(1R)-1-(4-chlorophenyl)-2-(pyrrolidin-1-yl) Synthesis of ethyl]carbamoyl]-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (16)

[0289]

[0290] Step 1. 5-[5-(Trifluoromethyl)pyridine-3-amido]-1,2,3-thiadiazole-4-carboxylic acid ethyl ester

[0291] Under nitrogen atmosphere, ethyl 5-amino-1,2,3-thiadiazole-4-carboxylate (1.50 g, 8.66 mmol) and 5-(trifluoromethyl)pyridine- 3-Formic acid (1.99g, 10.4mmol) was added dropwise to a mixture of pyridine (40mL) with POCl 3 (11.0 mL, 113 mmol). The resulting mixture was stirred at 25°C for 2 hours under nitrogen atmosphere. The reaction mixture was poured into water / ice (100 mL). The mixture was washed with saturated NaHCO at 0 °C 3 (aqueous solution) was basified to pH 8. The resulting mixture was washed with CH 2 Cl 2 (3x600 mL) extraction. The combined ...

Embodiment 2

[0305] Synthesis of 2-(4-chlorobenzenesulfonamido)-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide (17)

[0306]

[0307] Step 1. 2-Nitro-N-(4-phenylthiazol-2-yl)-4-(trifluoromethyl)benzamide

[0308] DIEA ( 10.2 mL, 61.9 mmol) and 4-phenylthiazol-2-amine (4.00 g, 22.7 mmol). The resulting mixture was stirred at 25°C for 2 hours. The mixture was diluted with water / ice (100 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (3 x 100 mL), and washed with anhydrous Na 2 SO 4 dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc (1:1) to afford 2-nitro-N-(4-phenyl-1,3-thiazol-2-yl)-4-( Trifluoromethyl)benzamide (2.00 g, 23%) as a light brown solid. LCMS (ES, m / z): 394 [M+H] + .

[0309] Step 2. 2-amino-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide

[0310] Under hydrogen atmosphere, 2-nitro-N-(4-p...

Embodiment 3

[0315] Synthesis of 5-(3-chlorobenzamido)-N-[2-(3-chlorophenyl)propan-2-yl]-1,2,3-thiadiazole-4-carboxamide (18)

[0316]

[0317] Step 1. Ethyl 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4-carboxylate

[0318] To a mixture of 3-chlorobenzoic acid (2.20 g, 13.2 mmol) and HATU (5.00 g, 13.2 mmol) in DMF (60 mL) was added 5-amino-1,2,3-thiadiol dropwise at 0°C Ethyl azole-4-carboxylate (2.00 g, 11.0 mmol) and DIEA (5.90 mL, 32.9 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x30 mL), washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc (1:1) to give 5-(3-chlorobenzamido)-1,2,3-thiadiazole-4- as a white solid Ethyl formate (2.50 g, 73%). LCMS (ES, m / z): 312,314 [M+H] + .

[0319] Step 2. 5-(3-Chlorobenzamido)...

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Abstract

The present disclosure relates to compounds of formulae (I)-(VI), which are useful as modulators of USP36. The compounds are also useful for inhibiting USP36 and treating diseases or disorders associated with inhibition of USP36. For example, the present disclosure relates to compounds and compositions for inhibiting USP36, methods of treating diseases associated with inhibition of USP36, such as certain forms of cancer, and methods of synthesizing these compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 840,737, filed April 30, 2019, which is hereby incorporated by reference in its entirety. [0003] field of invention [0004] The present disclosure relates to compounds useful for inhibiting ubiquitin-specific peptidase 36 (USP36) and methods for their preparation. USP36 inhibitors are useful in the treatment of many forms of cancer. [0005] Background of the invention [0006] Aggressive cancers include subtypes of pancreatic, colorectal, lung, brain, ovarian, and prostate cancers that are characterized by rapid tumor formation, growth, and spread. They often present significant challenges to effective treatment and are particularly prone to resistance, so this treatment option is exhausted relatively quickly and the prognosis is often poor. Aggressive cancers present a serious unmet medical need and an opportunity to develop therapies that ...

Claims

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Application Information

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IPC IPC(8): A61K31/454A61K45/06C07D401/14
CPCA61P35/00C07D417/12C07D417/14C07D285/06C07D285/08C07D277/46C07D275/03C07D495/04
Inventor B.韩K.凯撒-布里克C.刘
Owner 瓦洛健康股份有限公司
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