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Bicyclic compound, preparation method and application thereof

A technology of compounds and mixtures used in the field of medicine

Active Publication Date: 2020-06-09
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Four patent applications (WO2017184746, WO2017040670, WO2017184735, WO2018152396) of Bristol-Myers Squibb company and IFM Therapeutis, INC (acquired by Bristol-Myers Squibb company) cover compounds of the same type of mother core, which have certain effects on TLR7 and TLR8 Selective, currently in preclinical research stage

Method used

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  • Bicyclic compound, preparation method and application thereof
  • Bicyclic compound, preparation method and application thereof
  • Bicyclic compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0357] Example 1: 3-(4-amino-1-methyl-6-(5-phenylthiophen-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl)propane-1 - alcohol (1)

[0358]

[0359] The first step: 2,6-dichloro-N-methyl-3-nitropyridin-4-amine (1b)

[0360] Compound 1a (5.0g, 24.15mmol), K 2 CO 3 (6.66g, 48.30mmol) was added into 40mL of acetonitrile, heated to 80°C and stirred for 12h. After the reaction was completed, it was filtered with diatomaceous earth, and the filtrate was spin-dried and subjected to flash column chromatography (eluent system B) to obtain compound 1b (4.80 g). MS(ESI,m / z):222.0[M+H] + .

[0361] The second step: 6-chloro-N-methyl-3-nitro-N-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine (1c)

[0362] Compound 1b (4.80g, 21.71mmol), tert-octylamine (5.61g, 43.42mmol) and triethylamine (6.58mg, 65.13mmol) were added to 40mL of dichloromethane, heated to 40°C and stirred for 12h. After the reaction was completed, the solvent was spin-dried and subjected to flash column chromatography (eluen...

Embodiment 2

[0379] Example 2: 3(4-amino-6-(5-(3-fluorophenyl)thiophen-2-yl)-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl ) propan-1-ol (2)

[0380]

[0381] The first step: 2-(3-(benzyloxy)propyl)-6-(5-(3-fluorophenyl)thiophen-2-yl)-1-methyl-1H-imidazo[4, 5-c]pyridin-4-amine (2a)

[0382] Compound 1h (32.12mg, 70.22μmol), 3-fluorophenylboronic acid (19.65mg, 140.45μmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (6mg, 7.02μmol), potassium carbonate (19.41mg, 140.45μmol) were added to 5mL 1,4-dioxane and 0.5mL water, N 2 Heated to 90°C under protection for 5h. After the reaction was completed, it was filtered with celite and purified by flash column chromatography (elution system A) to obtain compound 2a (20 mg). MS(ESI,m / z):473.2[M+H] + .

[0383] The second step: 3(4-amino-6-(5-(3-fluorophenyl)thiophen-2-yl)-1-methyl-1H-imidazo[4,5-C]pyridin-2-yl ) propan-1-ol (2)

[0384] Compound 2a (20 mg, 12.33 μmol) was dissolved in 4 mL of trifluoroacetic acid, N 2 Under protection, the reaction was heated t...

Embodiment 3

[0387] Example 3: 3-(4-amino-6-(5-(4-methoxyphenyl)thiophen-2-yl)-1-methyl-1H-imidazo[4,5-c]pyridine- 2-yl)propan-1-ol (3)

[0388]

[0389] The first step: 2-(3-(benzyloxy)propyl)-6-(5-(4-methoxyphenyl)thiophen-2-yl)-1-methyl-1H-imidazo[ 4,5-c]pyridin-4-amine (3a)

[0390] Compound 1h (90mg, 127.90μmol), 4-methoxyphenylboronic acid (38.87mg, 255.80μmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (12mg, 14.04μmol), potassium carbonate (53.03mg, 383.70μmol) were added to 5mL 1,4-dioxane and 0.5mL water, N 2 Heated to 90°C under protection for 5h. After the reaction was completed, it was filtered with celite and purified by flash column chromatography (elution system A) to obtain compound 3a (35 mg). MS(ESI,m / z):485.2[M+H] + .

[0391] The second step: 3-(4-amino-6-(5-(4-methoxyphenyl)thiophen-2-yl)-1-methyl-1H-imidazo[4,5-c]pyridine- 2-yl)propan-1-ol (3)

[0392] Compound 3a (35 mg, 72.3 μmol) was dissolved in 4 mL of trifluoroacetic acid, N 2 Under protection, the reaction was hea...

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Abstract

The invention belongs to the field of medicines, and particularly relates to a compound represented by a formula I, a stereoisomer, a tautomer or a mixture of the stereoisomer and the tautomer of thecompound, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a ring compound, a stereoisomer, a tautomer or a mixture thereof, and a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound. substances, or stable isotopic derivatives, metabolites or prodrugs of said compounds. The compounds of the present invention are useful as NLRP3 modulators (eg, agonists) for the treatment of diseases associated with NLRP3 inflammasome activity (eg, tumor diseases). Background technique [0002] NLRP3 (NLR family pyrin domain containing 3) belongs to the NOD-like receptor family and is the most studied intracellular pattern recognition receptor in recent years. It is mainly expressed in macrophages and neutrophils and participates in the body's innate immunity. Resists pathogenic infection and stress damage. The NLRP3 inflammasome has a clear role in inflammatory and metabolic diseases, and its overactivation can lead to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/5377A61K31/497A61K31/506A61K31/501A61K31/496A61K45/06A61P29/00A61P3/00A61P3/10A61P19/02A61P9/10A61P35/00
CPCC07D471/04A61P35/00
Inventor 李桂英何云游泽金王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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