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Aromatic heterocyclic amide compounds and uses thereof

A compound and hydrate technology, used in aromatic heterocyclic amide compounds as ASK1 inhibitors and their preparation, in the field of drug preparation, can solve the problems of poor compound drug-like properties, poor ASK1 target selectivity, and poor molecular-level activity. , to achieve the effect of improved activity, excellent liver metabolic stability, and good inhibitory effect

Pending Publication Date: 2021-12-24
WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Some ASK1 kinase small molecule inhibitors reported in the literature have potential problems such as poor molecular level activity, poor ASK1 target selectivity, and poor drug-like properties of the compound, and some compounds have potential problems of chemical stability and in vivo metabolic stability

Method used

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  • Aromatic heterocyclic amide compounds and uses thereof
  • Aromatic heterocyclic amide compounds and uses thereof
  • Aromatic heterocyclic amide compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Embodiment 1: the synthesis of target compound I-1

[0125] 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-(3-hydroxyl-3-methylazetidin-1-yl)-N-(6-( 4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzamide (compound I-1)

[0126]

[0127] The synthetic route of target compound I-1 is as follows:

[0128]

[0129] The first step: Synthesis of 2-fluoro-4-(3-hydroxy-3-methylazetidin-1-yl)-5-nitrobenzoic acid methyl ester (I-1B)

[0130] At 0°C, 3-methyl-3-hydroxyazetidine hydrochloride (0.63g, 5mmol) was added in batches to methyl 2,4-difluoro-5-nitrobenzoate (1.1g , 5mmol), DIEA (0.97g, 7.5mmol) in THF (15mL) solution. Stir at 0 °C for 1 h. After the reaction, add distilled water (50mL) to dilute, extract with ethyl acetate (50mL×3), combine the organic phases, wash the organic phase with saturated brine (70mL×2), separate the layers, and dry the organic phase with anhydrous sodium sulfate , filtered, concentrated, and the residue was purified by silica gel colu...

Embodiment 2

[0141] Embodiment 2: the preparation of target compound 1-2

[0142]

[0143] The synthetic route of target compound 1-2 is as follows:

[0144]

[0145] The first step: the synthesis of methyl 2-fluoro-4-(4-(methylcarbamoyl)piperidin-1-yl)-5-nitrobenzoate (I-2B)

[0146] At 0°C, N-methylpiperidine-4-carboxamide hydrochloride (5.18g, 29.0mmol) was added dropwise to methyl 2,4-difluoro-5-nitrobenzoate (6g, 27.6mmol ), DIEA (7.86g, 60.8mmol) in THF (80mL), stirred at 0°C for 2h. After the reaction, add water (80mL) to dilute, extract with ethyl acetate (80mL×3), combine the organic phases, wash the organic phase with saturated brine (70mL×2), separate the layers, and dry the organic phase with anhydrous sodium sulfate , filtered, concentrated, and the residue was purified by a silica gel column to obtain yellow solid 2-fluoro-4-(4-(methylcarbamoyl)piperidin-1-yl)-5-nitrobenzoic acid methyl ester (5g, yield rate 53.3%).

[0147] LC-MS, M / Z(ESI):340.3[M+H] + .

[0148]...

Embodiment 3

[0164] Embodiment 3: the preparation of target compound 1-3

[0165]

[0166] The synthesis route of the target compound is as follows:

[0167]

[0168] The first step: the synthesis of 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (I-3B)

[0169] 8-Hydroxyquinoline (0.338g, 2.331mmol), cesium carbonate (11.39g, 35.0mmol), cuprous iodide (0.167g, 1.165mmol) were added to the solution containing 2-chloro-5-fluoro-4-iodine Pyridine (3g, 11.65mmol), 4-cyclopropyl-1H-imidazole (1.386g, 12.82mmol) in n-butyronitrile (50ml) solution. Under nitrogen protection, stir at 65°C for 16h. After the reaction, add distilled water (50mL) to dilute, extract with ethyl acetate (70mL×3), combine the organic phases, wash the organic phase with saturated brine (50mL), separate the layers, dry the organic phase with anhydrous sodium sulfate, and filter , concentrated, and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V)=3:1) to give yellow ...

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Abstract

The invention provides aromatic heterocyclic amide compounds and uses thereof. Specifically, the compounds can effectively inhibit ASK1 kinase activity, and are compounds represented by formulas (I) to (III), or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds represented by formulas (I) to (III). The formulas are described in the specification.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, specifically, the present invention relates to aromatic heterocyclic amide compounds as ASK1 inhibitors, more specifically, the present invention relates to aromatic heterocyclic amide compounds as ASK1 inhibitors and their preparation methods, and their preparation Uses in medicine. Background technique [0002] Apoptosis signal-regulating kinase 1 (ASK1) is a serine / threonine kinase, also called mitogen-activated protein kinase kinase kinase 5 (MAP3K5), Belongs to one of the members of the MAP3K family. ASK1 can be regulated by upstream factors such as oxidative stress, calcium influx, lipopolysaccharide (LPS), reactive oxygen species (reactive oxygen species, ROS), and various cytokines such as tumor necrosis factor (tumour necrosis factor, TNF), Activate the downstream c-Jun N-terminal protein kinase (c-Jun N-terminal kinase, JNK) and p38-MAPK kinase signaling pathways to respond ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D491/107C07D471/10C07D403/14C07D487/10A61K31/4439A61K31/4545A61K31/444A61K31/497A61P9/00A61P13/12A61P11/00A61P1/16A61P25/28A61P3/00A61P35/00A61P7/02A61P9/10A61P3/10A61P3/06A61P9/12A61P25/16
CPCC07D401/14C07D491/107C07D471/10C07D403/14C07D487/10A61P9/00A61P13/12A61P11/00A61P1/16A61P25/28A61P3/00A61P35/00A61P7/02A61P9/10A61P3/10A61P3/06A61P9/12A61P25/16
Inventor 张学军常少华叶大炳王永刚刘哲赵双孙红娜丁肖华魏用刚田华李莉娥张春华
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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