CN-121085942-B - 3, 5-Substituted imidazothiadiazole heterocyclic derivative and preparation method and application thereof

CN121085942BCN 121085942 BCN121085942 BCN 121085942BCN-121085942-B

Abstract

The invention provides 3, 5-substituted imidazothiadiazole heterocyclic derivatives, a preparation method and application thereof, in particular to a series of 3, 5-substituted imidazothiadiazole heterocyclic derivatives which can be used for preventing and/or treating metabolic diseases, thrombotic diseases, sepsis acute kidney injury, MASLD (metabolic fatty liver disease), MASH (metabolic steatohepatitis) and the like related to disorder of the phosphorylation level of eIF4E by inhibiting eIF4E phosphorylation, reducing p-eIF4E generation, reducing weight gain, reducing fat accumulation, reducing inflammation and other changes. The metabolic disease associated with deregulation of eIF4E phosphorylation levels is selected from the group consisting of type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, complications thereof and conditions associated therewith.

Inventors

JIANG TAO
YIN RUIJUAN
QIU TINGTING
LIU LU
LI HONGWEI
ZHANG LICAN
ZHUANG HUIYING
LIU KANG

Assignees

中国海洋大学

Dates

Publication Date: 20260508
Application Date: 20250828

Claims (9)

1.3,5-Substituted imidazothiadiazole heterocycle derivatives, or pharmaceutically acceptable salts thereof, characterized in that the 3, 5-substituted imidazothiadiazole heterocycle derivatives have a structure represented by formula (I): Formula (I) Formula (I) includes formula one and formula two, R 1 is selected from one of the following groups: 、、、、、、、、 Wherein R 5 is any C1-C6 alkyl group selected from H, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3-to six-membered heterocyclyl, aryl, heteroaryl, 3-to six-membered heterocycle substituted with one or more C1-C6 alkyl, halogen, hydroxy, alkynyl, alkenyl, methoxy, cyano, nitro, C1-C6 alkylcarbonyl, C1-C6 alkylalkynyl, C1-C6 alkenyl, C1-C6 alkylthio, C1-C6 alkoxy, amino, C1-C6 alkylamino, carbonyl, sulfonyl, phosphoryl, 3-to six-membered heterocyclyl, aryl, heteroaryl, unsubstituted aryl or heteroaryl, aryl or heteroaryl substituted with one or more C1-C6 alkyl, halogen, hydroxy, alkynyl, alkenyl, methoxy, cyano, nitro, C1-C6 alkylcarbonyl, C1-C6 alkinyl, C1-C6 alkenyl, C1-C6 alkylthio, C1-C6 alkoxy, amino, C1-C6 alkylamino, carbonyl, sulfonyl, phosphoryl, 3-to six-membered heterocyclyl, aryl, heteroaryl; R 2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkylcarbonyl, hydroxy-substituted C1-C6 alkyl, halogen, hydroxy, cyano, nitro, amino, carbonyl; R 3 is selected from H, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted by one or more alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3-to six-membered heterocyclyl, aryl, heteroaryl, carbonyl substituted by C1-C6 alkyl; R 4 is optionally any one of H, halogen, methoxy, hydroxy, cyano, nitro, carbonyl, amino, N-dimethylamino, trifluoromethyl, trifluoromethoxy; The aryl is selected from monocyclic or polycyclic aryl groups containing 6-12 carbon atoms, the heteroaryl is selected from 5-to 6-membered heteroaryl groups, and 5-to 6-membered heteroaryl groups refer to heteroaryl groups having ring carbon atoms and 1-3 ring heteroatoms in the heteroaryl system, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur.
2. The 3, 5-substituted imidazothiadiazole heterocycle derivative or pharmaceutically acceptable salt according to claim 1, wherein the pharmaceutically acceptable salt is a salt formed by reacting a compound having a structure represented by formula (I) with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
3. The method for producing a 3, 5-substituted imidazothiadiazole heterocycle derivative or a pharmaceutically acceptable salt according to any one of claims 1 to 2, comprising: the synthesis method of the general formula I comprises the following specific steps: Firstly, carrying out ester amine exchange reaction on a compound of a formula (II) and piperazine-1-carboxylic acid tert-butyl ester to obtain a compound of a formula (I-X), then removing tert-butoxycarbonyl groups under the condition of trifluoroacetic acid to generate a compound of a formula (III), and finally, carrying out condensation reaction on the compound of the formula (III) and a corresponding acyl chloride compound or a corresponding amine compound or a corresponding isothiocyanate compound to obtain the compound, wherein R 1 、R 2 、R 4 、R 5 is defined as above; The synthesis method of the general formula II comprises the following specific steps: Firstly, carrying out transesterification reaction on a compound of the formula (II) and 4-N-tert-butoxycarbonyl aminopiperidine substituted by 4-N-substituent groups to obtain a compound of the formula (I-Y), then removing tert-butoxycarbonyl groups under the condition of trifluoroacetic acid to generate a compound of the formula (V), and finally, carrying out condensation reaction on the compound of the formula (V) and a corresponding acyl chloride compound or a corresponding amine compound or a corresponding isothiocyanate compound to obtain a compound of the formula (I) in general formula II, wherein R 1 、R 2 、R 3 、R 4 、R 5 is defined as above.
4. A process according to claim 3, wherein the intermediate compound of formula (II) is prepared by: Taking thiosemicarbazide and a compound of formula (i) as starting materials, carrying out nucleophilic addition reaction to obtain a Schiff base intermediate compound of formula (II), then carrying out intramolecular cyclization reaction under the condition of ferric trichloride to obtain an intermediate compound of formula (iii), carrying out cycloaddition reaction between the intermediate compound of formula (iii) and 2-bromo-1, 1-diethoxyethane to obtain an intermediate compound of formula (iv), carrying out bromination reaction under the condition of NBS to obtain an intermediate compound of formula (v), then carrying out Suzuki coupling reaction between the intermediate compound of formula (v) and corresponding 4-substituted phenylboronic acid to obtain an intermediate compound of formula (vi), then carrying out hydrolysis reaction under the condition of lithium hydroxide to obtain an intermediate compound of formula (vii), and finally carrying out condensation reaction with N-hydroxysuccinimide to obtain the compound of formula (II), wherein R 2 、R 4 is defined as above.
5. Use of a 3, 5-substituted imidazothiadiazole heterocycle derivative, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-2 in the manufacture of a medicament for inhibiting eIF4E phosphorylation and reducing p-eIF4E production.
6. Use of a 3, 5-substituted imidazothiadiazole heterocycle derivative, or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the manufacture of a medicament for the prevention and/or treatment of metabolic diseases associated with deregulation of eIF4E phosphorylation levels, thrombotic diseases, sepsis acute kidney injury, MASLD and the severe stage MASH thereof.
7. A pharmaceutical composition comprising the 3, 5-substituted imidazothiadiazole heterocycle derivative of any one of claims 1-2, or a pharmaceutically acceptable salt.
8. The pharmaceutical composition of claim 7, further comprising an additional therapeutic agent for a disorder associated with deregulation of eIF4E phosphorylation levels.
9. A formulation comprising the pharmaceutical composition of claim 7, or the 3, 5-substituted imidazothiadiazole heterocycle derivative of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

3, 5-Substituted imidazothiadiazole heterocyclic derivative and preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to 3, 5-substituted imidazothiadiazole heterocyclic derivatives, and a preparation method and application thereof. Background The metabolic syndrome is a group of clinical syndrome which is determined by genes and environmental factors and is characterized by the combined occurrence of various metabolic diseases such as obesity, type 2 diabetes (T2D) and the like, and can further cause dyslipidemia, hypertension, nonalcoholic fatty liver, gout and the like. With the development of socioeconomic performance, changes in lifestyle (increased energy intake, reduced exercise, etc.), the incidence of metabolic syndrome has shown a year-by-year trend worldwide, and has become a public health challenge facing the world. Metabolic fatty liver disease (MASLD) is a genetic-environmental-metabolic-stress related liver disease characterized by hepatic parenchymal cell steatosis and fat storage as pathological features. Clinically, the liver disease comprises three types of simple fatty liver, steatohepatitis (MASH) and fatty liver cirrhosis. Platelets are the second largest cell population in the blood circulation, are involved in physiological hemostasis of the body and in the formation of pathological thrombi, and act as "first responders" in injury, inflammation, and metastasis of tumors. Thromboses mediated by abnormal increases in platelet activity are important causes of cardiovascular and cerebrovascular diseases. Meanwhile, platelets participate in myocardial injury by modulating inflammatory responses. Clinically, antiplatelet therapy is a key for preventing and treating thrombosis diseases, however, the role of platelets in disease occurrence is not completely elucidated, and in-depth research on the regulation and control effects of platelets in cardiovascular diseases provides a new target and theoretical basis for targeting platelets to prevent and treat thrombosis diseases. The treatment methods of thrombotic diseases, sepsis acute kidney injury and MASLD are focused on single-link regulation or only aiming at symptom relief, and have the defects of limited curative effect, easy generation of side effects and the like. Although the three diseases are different in clinical manifestations, the three diseases have close connection in pathological mechanism, namely, inflammatory reaction plays an important role in the occurrence and development of the three diseases, excessive inflammatory reaction not only can lead to direct damage of kidney tissues in acute kidney injury of sepsis, but also can cause hypercoagulable state of blood to increase occurrence risk of thrombotic diseases, and meanwhile, chronic inflammation is one of key factors for promoting MASLD disease progress. In addition, metabolic disorders are equally prevalent in three diseases, thrombotic patients often have abnormal lipid metabolism, sepsis interferes with normal metabolism of the body, and metabolic disorders are the central mechanism of MASLD pathogenesis. Eukaryotic initiation factor 4E (eIF 4E) is a cap-binding protein that specifically recognizes the 5' cap structure of mRNA and plays an important role in the initiation of eukaryotic translation, thereby regulating protein synthesis in organisms. It has been found that abnormally increased p-eIF4E drives the synthesis of a large amount of thrombopoietin in thrombotic disease, exacerbates platelet activation and thrombosis, that p-eIF4E promotes increased synthesis of pro-inflammatory factors in sepsis acute kidney injury, exacerbates inflammatory response and kidney tissue injury, that p-eIF4E exacerbates liver lipid metabolism disorders in MASLD progression, and that regulation of the phosphorylation level of eIF4E regulates body weight, glucose tolerance, enhances insulin sensitivity, energy expenditure, accumulation of liver fat and inflammation in animal fat. Thus, inhibition of eIF4E phosphorylation and reduction of p-eIF4E production can treat metabolic diseases such as diabetes, obesity, NAFLD, etc., as well as thrombotic diseases, sepsis acute kidney injury and MASLD. There is a strong need in the art for a greater variety of small molecule compounds that better inhibit eIF4E phosphorylation and reduce p-eIF4E production. Disclosure of Invention The invention aims to provide 3, 5-substituted imidazothiadiazole heterocyclic derivatives, a preparation method and application thereof, which inhibit eIF4E phosphorylation, reduce p-eIF4E generation, reduce weight gain, reduce fat accumulation, reduce inflammation and other changes, further improve the conditions of obese patients and other metabolic diseases patients, and are used for treating thrombotic diseases, sepsis acute kidney injury and the like. To achieve the above object, the present invention provides a 3, 5-su