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Fused ring compound, and preparation method and application thereof

A technology of compounds and mixtures, applied in the field of new fused-ring compounds, can solve the problems of colorectal tumor and colorectal cancer liver metastases and deterioration

Pending Publication Date: 2020-10-27
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Abstract
  • Description
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Problems solved by technology

Preclinical studies have also shown that NLRP3-deficient mice have a higher rate of colorectal tumor formation and worse colorectal cancer liver metastases

Method used

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  • Fused ring compound, and preparation method and application thereof
  • Fused ring compound, and preparation method and application thereof
  • Fused ring compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0238] Example 1: 2-(3-(Benzyloxy)propyl)-1,4-dimethyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thiophene And[3,2-b]pyridine(1)

[0239] 3-(1,4-Dimethyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propane Alcohol (2)

[0240]

[0241] The first step: the synthesis of compound (4-benzyloxy)-(7-(methylamino)thieno[3,2-b]pyridyl-6-yl)butyramide (1b)

[0242] DIPEA (1.44g, 11.16mmol), HATU (1.06g, 2.79mmol) were sequentially added to 4-benzyloxybutanoic acid (541.80mg, 2.79mmol), compound 1a (500mg, 2.79mmol) in DMF (4mL) , and then kept stirring at room temperature for 5hr. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried and concentrated to obtain compound 1b (850 mg).

[0243] MS(ESI,m / z):356.1[M+H] +

[0244] The second step: the synthesis of compound 2-(3-(benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1c)

[0245]Sodium hydroxide (184.55 mg, 4.61 mmol) was added to compound 1b (...

Embodiment 2

[0261] Example 2: 1,4-Dimethyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H-imidazo [4,5-d]thieno[3,2-b]pyridine (3)

[0262] 1,4-Dimethyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5 -d]thieno[3,2-b]pyridine hydrochloride (3a)

[0263]

[0264] The first step: 3-(7-bromo-1,4-dimethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propyl-1- Alcohol (2a)

[0265] Compound 1f (320mg, 0.74mmol) was added into 3mL of trifluoroacetic acid, heated to 80°C and stirred for 16h. The reaction solution was concentrated, redissolved in 3 mL of MeOH, adjusted to pH=9.0 with 2N sodium hydroxide solution, and continued to stir for 30 min. Compound 2a (180 mg) was obtained by flash column chromatography (eluent system A). MS(ESI,m / z):340.0[M+H] + .

[0266] The second step: 7-bromo-2-(3-chloropropane)-1,4-dimethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (2b)

[0267] Compound 2a (180mg, 0.53mmol), DMF (4mg, 0.05mmol) was added to 4mL thionyl chl...

Embodiment 3

[0276] Example 3: 2-(3-(azetidin-1-yl)propyl)-1,4-dimethyl-7-(1H-pyrazol-3-yl)-1H-imidazo[ 4,5-d]thieno[3,2-b]pyridine (5)

[0277]

[0278] The first step: 2-(3-(azetidin-1-yl)propyl)-7-bromo-1,4-dimethyl-1H-imidazo[4,5-d]thieno[ 3,2-b]pyridine (3a)

[0279]Compound 2b (50mg, 0.14mmol), azetidine (48mg, 0.84mmol), tetrabutylammonium iodide (10mg, 0.03mmol), TEA (85mg, 0.84mmol) were added in 3mL of toluene, N 2 Heated to 100°C under protection for 16h. The reaction solvent was spin-dried to obtain compound 3a (53 mg), and the crude product was directly used in the next step. MS(ESI,m / z):379.1[M+H] + .

[0280] The second step: 2-(3-(azetidin-1-yl)propyl)-1,4-dimethyl-7-(1H-pyrazol-3-yl)-1H-imidazo[ 4,5-d]thieno[3,2-b]pyridine (5)

[0281] Compound 3a (53mg, 0.13mmol), 1H-pyrazole-3-boronic acid pinacid (61mg, 0.31mmol), Pd(dppf)Cl 2 (10mg, 0.01mmol), sodium carbonate (40mg, 0.38mmol) was added to the mixed solvent of 4mL DMF and 1mL water, N 2 Heated to 100°C unde...

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Abstract

The present invention relates to a compound represented by formula X, a stereoisomer, a tautomer or a mixture, a pharmaceutically acceptable salt, an eutectic substance, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug thereof. These compounds are useful as modulators (such as agonists or partial agonists) of NLRP3 for the treatment of abnormal cell proliferation diseases (such as cancers).

Description

technical field [0001] The present invention relates to a new class of condensed ring compounds, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of the compounds , or a stable isotope derivative, metabolite or prodrug of said compound. As NLRP3 regulators (such as agonists or partial agonists), the compounds of the present invention can be used for the treatment of abnormal cell proliferation diseases (such as cancer). 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 immune diseases such as type 2 ...

Claims

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Application Information

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IPC IPC(8): C07D495/14C07D471/04A61K31/437A61P29/00A61P35/00
CPCC07D495/14C07D471/04A61P29/00A61P35/00
Inventor 何云蔡家强李桂英游泽金田强宋宏梅薛彤彤王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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