3,5-substituted imidazothiadiazole heterocyclic derivatives, processes for their preparation and use

Abstract

The present application provides 3,5-substituted imidazothiadiazole heterocyclic derivatives, and a preparation method and application thereof. Specifically, a series of 3,5-substituted imidazothiadiazole heterocyclic derivatives are screened, which can inhibit eIF4E phosphorylation, reduce p-eIF4E generation, reduce body weight gain, reduce fat accumulation, reduce inflammation and the like, and are used for preventing and / or treating metabolic diseases, thrombotic diseases, sepsis acute kidney injury, MASLD (metabolic fatty liver disease), MASH (metabolic fatty hepatitis) and the like related to eIF4E phosphorylation level disorder. The metabolic diseases related to eIF4E phosphorylation level disorder are selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, and complications and conditions related thereto.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to 3,5-substituted imidazothiadiazole heterocyclic derivatives, their preparation methods, and applications. Background Technology

[0002] Metabolic syndrome is a group of clinical syndromes determined by both genetic and environmental factors, characterized by the co-occurrence of multiple metabolic diseases such as obesity and type 2 diabetes (T2D), which can further lead to dyslipidemia, hypertension, non-alcoholic fatty liver disease, gout, and other conditions. With socioeconomic development and changes in lifestyle (increased energy intake and decreased physical activity), the incidence of metabolic syndrome is showing a year-on-year increasing trend globally, becoming a global public health challenge.

[0003] Metabolic fatty liver disease (MASLD) is a genetic-environment-metabolic-stress-related liver disease characterized by steatosis and fat accumulation in hepatocytes. Clinically, it includes three types: simple fatty liver, steatohepatitis (MASH), and fatty liver cirrhosis.

[0004] Platelets are the second largest cell group in the bloodstream, participating in physiological hemostasis and pathological thrombus formation, and acting as "first responders" in injury, inflammation, and tumor metastasis. Abnormally increased platelet activity-mediated thrombus formation is a significant cause of cardiovascular and cerebrovascular diseases. Simultaneously, platelets participate in myocardial injury by regulating inflammatory responses. Clinically, antiplatelet therapy is crucial for the prevention and treatment of thrombotic diseases; however, the role of platelets in disease development is not fully understood. In-depth research into the regulatory role of platelets in cardiovascular diseases will provide new targets and theoretical basis for targeted platelet therapy in the prevention and treatment of thrombotic diseases.

[0005] Treatments for thrombotic diseases, septic acute kidney injury, and MASLD often focus on regulating a single aspect or merely alleviating symptoms, resulting in limited efficacy and a high risk of side effects. While these three diseases present with different clinical manifestations, they are closely linked in their pathological mechanisms: inflammatory responses play a crucial role in the development of all three. Excessive inflammation not only leads to direct damage to kidney tissue in septic acute kidney injury but also triggers a hypercoagulable state, increasing the risk of thrombotic diseases. Simultaneously, chronic inflammation is a key factor driving the progression of MASLD. Furthermore, metabolic disorders are prevalent in all three diseases. Patients with thrombotic diseases often exhibit abnormal lipid metabolism, sepsis interferes with normal metabolism, and metabolic imbalance is a core mechanism in the pathogenesis of MASLD.

[0006] Eukaryotic initiation factor 4E (eIF4E) is a cap-binding protein that specifically recognizes the 5′ cap structure of mRNA, playing a crucial role in the initiation of eukaryotic translation and thus regulating protein synthesis in organisms. Studies have found that in thrombotic diseases, abnormally increased p-eIF4E drives the synthesis of prothrombotic proteins, exacerbating platelet activation and thrombus formation; in septic acute kidney injury, p-eIF4E promotes increased synthesis of pro-inflammatory factors, worsening the inflammatory response and kidney tissue damage; in the progression of MASLD, p-eIF4E exacerbates hepatic lipid metabolism disorders; furthermore, regulating eIF4E phosphorylation levels can modulate body weight, glucose tolerance, enhance insulin sensitivity, energy expenditure capacity, hepatic fat accumulation, and inflammation in animal fat. Therefore, inhibiting eIF4E phosphorylation and reducing p-eIF4E production may be therapeutic for metabolic diseases such as diabetes, obesity, and NAFLD, as well as thrombotic diseases, septic acute kidney injury, and MASLD.

[0007] There is an urgent need in this field for more types of small molecule compounds that can better inhibit eIF4E phosphorylation and reduce p-eIF4E formation. Summary of the Invention

[0008] The purpose of this invention is to provide 3,5-substituted imidazothiadiazole heterocyclic derivatives, their preparation methods and applications, which can improve the condition of obese patients and other patients with metabolic diseases by inhibiting eIF4E phosphorylation, reducing p-eIF4E production, reducing weight gain, reducing fat accumulation, and reducing inflammation, as well as for the treatment of thrombotic diseases, sepsis, and acute kidney injury.

[0009] To achieve the above objectives, the present invention provides a 3,5-substituted imidazothiadiazole heterocyclic derivative, or precursor, or pharmaceutically acceptable salt, wherein the 3,5-substituted imidazothiadiazole heterocyclic derivative has the structure shown in formula (I):

[0010]

[0011] Formula (I) includes general formula I and general formula II, where R1 is selected from one of the following groups: R5 is selected from H, unsubstituted or substituted C1-C6 alkyl groups (either alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkylthiol, amino, C1-C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic groups, substituted aryl, substituted heteroaryl groups), unsubstituted or substituted C1-C6 alkyl groups (either alkynyl, hydroxyl, alkynyl, alkenyl, methoxy, cyano, nitro, carbonyl, etc.), halogen, alkynyl, alkenyl, alkylthiol, C1-C6 alkoxy, cyano, amino, C1-C6 alkylalkynyl, alkylalkenyl, C1-C6 ...alkynyl, alkylthiol, C1-C6 alkoxy, cyano, amino, C1-C6 alkylalkynyl, alkylalkynyl, alkylthiol, C1-C6 alkylamine, halogen, alkylalkynyl, alkylalkynyl, alkylthiol, C1-C6 alkylamine, halogen, alkylalkynyl, alkylalkynyl, C1-C6 alkylamine, C1-C6 alkylalkynyl, alkylalkynyl, C1-C6 alkylamine, C1-C6 alkylamine, alkylalkynyl, alkylalkynyl, C1-C6 alkylamine, C1-C6 alkylamine, alkylalkynyl, alkylalkynyl, C1-C6 alkylamine, C1-C6 alkylamine, alkylalkynyl, -C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic group, substituted aryl, substituted heteroaryl substituted 3- to 6-membered heterocyclic group, unsubstituted or substituted with one or more C1-C6 alkyl, halogen, hydroxyl, alkyne, alkenyl, methoxy, cyano, nitro, carbonyl, etc., C1-C6 alkyl, C1-C6 alkynyl, C1-C6 alkenyl, C1-C6 alkoxy, cyano, amino, C1-C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic group, substituted aryl, substituted heteroaryl substituted aryl or heteroaryl;

[0012] R2 can be selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkylcarbonyl, hydroxy-substituted C1-C6 alkyl, halogen, hydroxyl, cyano, nitro, amino, carbonyl;

[0013] R3 is selected from H, unsubstituted or substituted with one or more alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkylthiol, amino, C1-C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic group, substituted aryl, substituted heteroaryl-substituted C1-C6 alkyl, and C1-C6 alkyl-substituted carbonyl.

[0014] R4 can be selected from any one of H, halogen, methoxy, hydroxyl, cyano, nitro, carbonyl, amino, N,N-dimethylamino, trifluoromethyl, and trifluoromethoxy.

[0015] The C1-C6 alkyl group mentioned in this invention refers to a straight-chain or branched saturated monovalent hydrocarbon group containing 1, 2, 3, 4, 5 or 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0016] The C1-C6 haloalkyl group described in this invention refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms. Representative examples include, but are not limited to, trifluoromethyl, bromomethyl, bromoethyl, chloromethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, etc.

[0017] The C1-C6 alkoxy, C1-C6 alkylthiol, and C1-C6 alkynyl groups mentioned in this invention refer to -OR 1 -SR 1 -CCR 1 , where R 1 The term is selected from "C1-C6 alkyl" as defined above, and representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, methyl mercapto, ethyl mercapto, propyl mercapto, isopropyl mercapto, methyl alkynyl, ethyl alkynyl, propyl alkynyl, isopropyl alkynyl, etc.

[0018] The C1-C6 alkylamine group mentioned in this invention refers to the substitution of one or two hydrogen atoms of the amino group (-NH2) by the same or different "C1-C6 alkyl" groups as defined above; it can be represented as -NR. 2 R 3 R 2 R 3 Each is independently selected from H, C1-C6 alkyl groups, and R 2 R 3 They cannot both be H.

[0019] The C1-C6 alkylene group described in this invention refers to the substitution of one or two hydrogen atoms of the CH2 group in vinyl (-CHCH2) by the same or different "C1-C6 alkyl" groups as defined above; it can be represented as -CHCR. 4 R 5 R 4 R 5 Each is independently selected from H, C1-C6 alkyl groups, and R 4 R 5 They cannot both be H.

[0020] The C1-C6 alkyl carbonyl group mentioned in this invention refers to -C(O)R 6 , where R 6 Selected from "C1-C6 alkyl" as defined above.

[0021] The 3- to 6-membered heterocycles described in this invention refer to a ring system having a cyclic carbon atom and 1-3 cyclic heteroatoms, wherein each cyclic heteroatom is independently selected from nitrogen, oxygen, and sulfur; in a heterocyclic group containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, as long as the valence allows. Representative examples include, but are not limited to, ethylene oxide rings, propylene oxide rings, piperazine rings, morpholine rings, piperidine rings, hexahydropyran rings, tetrahydrofuran rings, tetrahydrothiophene rings, pyrrole rings, and tetrahydropyrrole rings.

[0022] The aryl group described in this invention is preferably a monocyclic or polycyclic aryl group containing 6-12 carbon atoms, preferably phenyl, naphthyl, etc.; the heteroaryl group is preferably a 5- to 6-membered heteroaryl group, which refers to a heteroaryl system having a cyclic carbon atom and 1-3 cyclic heteroatoms, wherein each cyclic heteroatomum is independently selected from nitrogen, oxygen, and sulfur. Representative examples include, but are not limited to, furanyl, thiophene, pyridyl, thiazolyl, imidazolyl, etc.

[0023] The halogen atom or halogen in this invention is preferably fluorine, chlorine, bromine, or iodine.

[0024] The precursor described in this invention refers to a compound, or a salt or solution of a compound, that, when taken in a suitable manner, undergoes metabolism or chemical reaction in the human body to transform into a compound with the structure shown in formula (I), or such a compound. The precursor includes, but is not limited to, carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of compounds with the structure shown in formula (I).

[0025] The pharmaceutically acceptable salts described in this invention refer to salts formed by the reaction of the aforementioned compounds with inorganic acids, organic acids, alkali metals, or alkaline earth metals. These salts include, but are not limited to:

[0026] (1) Salts formed with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid;

[0027] (2) Salts formed with the following organic acids, such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine.

[0028] (3) Other salts, including salts formed with alkali metals or alkaline earth metals (such as sodium, potassium, calcium or magnesium), ammonium salts or water-soluble amine salts (such as N-methylglucosamine salts), lower alkanol ammonium salts and other pharmaceutically acceptable amine salts (such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively), or other conventional forms of "prodrugs".

[0029] This invention provides a method for preparing the aforementioned 3,5-substituted imidazothiadiazole heterocyclic derivative, precursor, or pharmaceutically acceptable salt, comprising:

[0030] The specific steps for synthesizing Formula 1 are as follows:

[0031]

[0032] First, compound (II) undergoes an ester-amine exchange reaction with piperazine-1-carboxylic acid tert-butyl ester to obtain compound (IX). Then, under trifluoroacetic acid conditions, the tert-butyloxycarbonyl group is removed to generate compound (III). Finally, compound (III) undergoes a condensation reaction with the corresponding acyl chloride compound, the corresponding amine compound, or the corresponding isothiocyanate compound to obtain the compound. R1, R2, R4, and R5 are defined as above.

[0033] The specific steps for synthesizing Formula 2 are as follows:

[0034]

[0035] First, the compound of formula (II) undergoes an ester-amine exchange reaction with a 4-N-substituted 4-N-tert-butoxycarbonylaminopiperidine to obtain the compound of formula (IY). Then, the tert-butoxycarbonyl group is removed under trifluoroacetic acid conditions to generate the compound of formula (V). Finally, the compound of formula (V) undergoes a condensation reaction with the corresponding acyl chloride compound, the corresponding amine compound, or the corresponding isothiocyanate compound to obtain the compound of general formula (I), wherein R1, R2, R3, R4, and R5 are defined as above.

[0036] The intermediate compound of formula (II) described in this invention is prepared by the following method:

[0037]

[0038] Starting with aminothiourea and compound (i), a nucleophilic addition reaction is carried out to obtain Schiff base intermediate compound (ii). Subsequently, an intramolecular cyclization reaction is carried out under ferric chloride conditions to generate intermediate compound (iii). Intermediate compound (iii) undergoes a cycloaddition reaction with 2-bromo-1,1-diethoxyethane to obtain intermediate compound (iv). Under NBS conditions, a bromination reaction is carried out to obtain intermediate compound (v). Then, intermediate compound (v) undergoes a Suzuki coupling reaction with the corresponding 4-substituted phenylboronic acid to obtain intermediate compound (vi). Subsequently, a hydrolysis reaction is carried out under lithium hydroxide conditions to obtain intermediate compound (vii). Finally, a condensation reaction is carried out with N-hydroxysuccinimide to obtain compound (II), wherein R2 and R4 are defined as above.

[0039] This invention provides the use of 3,5-substituted imidazothiadiazole heterocyclic derivatives, precursors, or pharmaceutically acceptable salts in the preparation of medicaments that inhibit eIF4E phosphorylation and reduce p-eIF4E formation.

[0040] This invention provides the use of 3,5-substituted imidazothiadiazole heterocyclic derivatives, precursors, or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of metabolic diseases, thrombotic diseases, septic acute kidney injury, MASLD (metabolic dysfunction-associated fatty liver disease), and severe stages of MASH, all associated with dysregulation of eIF4E phosphorylation levels. The metabolic diseases associated with dysregulation of eIF4E phosphorylation levels are selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, and their complications and related conditions.

[0041] The present invention provides a pharmaceutical composition comprising the aforementioned 3,5-substituted imidazothiadiazole heterocyclic derivative, or precursor, or pharmaceutically acceptable salt.

[0042] Preferably, the pharmaceutical composition also includes other therapeutic agents (marketed therapeutic agents) for diseases associated with dysregulation of eIF4E phosphorylation levels.

[0043] The present invention provides a formulation comprising the aforementioned pharmaceutical composition, or an active ingredient being a 3,5-substituted imidazothiadiazole heterocyclic derivative, a precursor, or a pharmaceutically acceptable salt thereof.

[0044] Preferably, the formulation further includes pharmaceutically acceptable excipients.

[0045] Preferably, the dosage form of the preparation can be a solid dosage form, a liquid dosage form, or a semi-solid dosage form, and more preferably tablets, capsules, injections, etc.

[0046] The present invention has the following beneficial effects:

[0047] This invention provides 3,5-substituted imidazothiadiazole heterocyclic derivatives, their preparation methods, and applications. A series of imidazothiadiazole heterocyclic derivatives were screened and obtained, which can reduce weight gain, decrease fat accumulation, and alleviate inflammation by inhibiting eIF4E phosphorylation, reducing p-eIF4E production, and reducing inflammation. These compounds can be used in the prevention and / or treatment of metabolic diseases, thrombotic diseases, septic acute kidney injury, MASLD (metabolic fatty liver disease), and its severe stage MASH (metabolic steatohepatitis) associated with dysregulation of eIF4E phosphorylation levels. The metabolic diseases associated with dysregulation of eIF4E phosphorylation levels are selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, their complications, and related conditions.

[0048] In addition to the objectives, features, and advantages described above, the present invention has other objectives, features, and advantages. The invention will now be described in further detail with reference to the figures. Attached Figure Description

[0049] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0050] Figure 1 This is a Western blotting image showing the inhibition of p-eIF4E expression in cells by the inventive compound of Example 12 of this invention;

[0051] Figure 2 This is a graph showing the change in mouse body weight in Example 14 of the present invention;

[0052] Figure 3 The results of OilRed O staining of mouse liver tissue sections in Example 14 of this invention;

[0053] Figure 4 The results of H&E staining of mouse liver tissue sections in Example 14 of this invention;

[0054] Figure 5 The results of ELISA detection of the expression of pro-inflammatory cytokines TNF-α (A), IL-6 (B), IL-1β (C), and MCP-1 (D) in mouse serum in Example 15 of this invention;

[0055] Figure 6 The data for spleen index (A), kidney index (B), and renal function indicators blood urea nitrogen (C) and creatinine (D) in mice in Example 15 of this invention are as follows:

[0056] Figure 7 This is an image of a PAS-stained mouse kidney tissue sample from Example 15 of the present invention;

[0057] Figure 8 This is an image of an H&E-stained mouse spleen tissue sample from Example 15 of the present invention.

[0058] Figure 9 The images show the wet weight, length, and dry weight of thrombi in mice with deep vein thrombosis in Example 16 of this invention. In the images, A represents the wet weight of the thrombus, B is a statistical chart of the thrombus length, C is the dry weight of the thrombus, and D is a chart of the wet weight of the thrombus. Detailed Implementation

[0059] The embodiments of the present invention will be described in detail below with reference to the accompanying drawings. However, the present invention can be implemented in many different ways as defined and covered by the claims.

[0060] This invention aims to obtain 3,5-substituted imidazothiadiazole heterocyclic derivatives by introducing acyl, ester, sulfonyl, thiourea, isothiourea, and phosphoryl substituents into imidazothiadiazole derivatives. The compounds described in the examples were evaluated at the cellular level for inhibiting eIF4E phosphorylation, for toxicity to normal cells, for animal-level treatment of metabolic diseases such as obesity and fatty liver, for animal-level anti-inflammatory activity, and for animal-level antithrombotic activity. Some of the obtained imidazothiadiazole derivatives exhibit good eIF4E phosphorylation inhibition activity, low cytotoxicity, and excellent in vivo activity for treating obesity and fatty liver, making them suitable for use in the field of drugs for treating metabolic diseases; some of the obtained imidazothiadiazole derivatives exhibit good eIF4E phosphorylation inhibition activity, low cytotoxicity, and excellent in vivo activity for treating acute kidney injury caused by sepsis, making them suitable for use in the field of drugs for inflammation-related diseases; and some of the imidazothiadiazole derivatives exhibit good eIF4E phosphorylation inhibition activity, low cytotoxicity, and excellent in vivo antithrombotic activity, making them suitable for use in the field of drugs for thrombosis-related diseases.

[0061] The present invention will be further described in detail below with reference to the embodiments.

[0062] Example 1: Preparation of 2,5-dioxopyrrolidine-1-yl-4-(5-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-substituted benzoate

[0063] This embodiment aims to prepare the starting material compound (II) of the synthetic compound (I), and the preparation route is shown in reaction formula III.

[0064] The structural formula of the 1,2,5-dioxopyrrolidone-1-yl-4-(5-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-substituted benzoate synthesized in this embodiment is as follows:

[0065]

[0066] R2 and R4 are defined as above.

[0067] 1. Preparation of methyl 4-((2-aminothiohydrazine-1-methyl)benzoate (intermediate ii-1)

[0068] In a 5L round-bottom flask, 60.0 g (0.66 mol) of aminothiourea and 300 mL of water were added and stirred until partially dissolved. Then, a tetrahydrofuran solution (300 mL) of methyl p-formylbenzoate (108.4 g (0.66 mol) was slowly added over 20 minutes. The reaction was continued at 20°C with stirring for 3 hours. After the reaction was complete, 1 L of water was added to the reaction solution, and the precipitated solid was filtered. The solid was washed three times with ethyl acetate and dried to obtain 148.5 g of off-white solid, with a yield of 95%.

[0069] 2. Preparation of methyl 4-((2-aminothiohydrazine-1,2-methyl)-2-fluorobenzoate (intermediate ii-2)

[0070] The preparation was carried out in the same manner as step 1 in Example 1, except that one of the raw materials was methyl 4-formyl-2-fluorobenzoate, yielding 151.6 g of a light yellow solid with a yield of 90%.

[0071] 3. Preparation of methyl 4-(5-amino-1,3,4-thiadiazol-2-yl)benzoate (intermediate iii-1)

[0072] In a 5L round-bottom flask, a methanol solution (240 mL) of the above compound ii-1 (140.0 g, 0.58 mol) was added and stirred until dissolved. Then, a methanol solution (950 mL) of ferric chloride hexahydrate (473 g, 1.24 mol) was added. The mixture was heated to 70°C and stirred under reflux for 4 h. The reaction was monitored by TLC. After the reaction was complete, heating was stopped. The mixture was cooled to room temperature and 1.5 L of water was added. After stirring, the solid precipitated was filtered, washed with water, and dried to obtain 132.9 g of yellow solid, with a yield of 96%.

[0073] 4. Preparation of methyl 4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzoate (intermediate iii-2)

[0074] The preparation was carried out in the same manner as step 3 in Example 1, except that the starting material was compound ii-2, yielding 129.3 g of a light yellow solid with a yield of 88%.

[0075] 5. Preparation of methyl 4-(imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate iv-1)

[0076] In a 5L round-bottom flask, the above intermediate iii-1 (100.0 g, 0.58 mol) and anhydrous ethanol (2 L) were added. Under stirring, bromoacetaldehyde diethanol condensate (416.0 g) and p-toluenesulfonic acid hydrate (8.0 g) were added sequentially. The mixture was heated to 80°C and stirred under reflux for 40 h. Then, bromoacetaldehyde diethanol condensate (100.0 g) and p-toluenesulfonic acid hydrate (7.0 g) were added. The mixture was heated under reflux for another 20 h. TLC analysis showed that the reaction was basically complete. The mixture was cooled to 0°C, filtered, and dried to give 55 g of a yellow solid, with a yield of 51%.

[0077] 6. Preparation of methyl 2-fluoro-4-(imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate iv-2)

[0078] The preparation was carried out in the same manner as step 5 in Example 1, except that one of the raw materials was compound iii-2, yielding 88.4 g of a pale yellow solid with a yield of 55%.

[0079] 7. Preparation of methyl 4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate v-1)

[0080] In a 5L round-bottom flask, a solution of intermediate iv-1 (60.0 g, 0.23 mol) in dichloromethane (1.2 L) was added. NBS (N-bromosuccinimide, 30.9 g, 0.17 mol) was added in batches with stirring. The mixture was stirred at room temperature for 25 min and detected by TLC. After the reaction was complete, dichloromethane and saturated ammonium chloride solution were added for extraction three times. The organic phases were combined, the solvent was evaporated under reduced pressure, and the product was dried to obtain 57.8 g of yellow solid, with a yield of 75%.

[0081] 8. Preparation of methyl 2-fluoro-4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate v-2)

[0082] The preparation was carried out in the same manner as step 7 in Example 1, except that one of the raw materials was compound iv-2, yielding 42.4 g of a pale yellow solid with a yield of 70%.

[0083] 9. Preparation of methyl 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-1)

[0084] In a 5L single-necked flask, 2.7L of dioxane (100.0g, 0.29mol) of the above intermediate v-1 and 800mL of water were added, followed by the addition of cesium fluoride (110.0g, 0.72mol), p-cyanoboronic acid (64.0g, 0.43mol), and tetrakis(triphenylphosphine)palladium (50.0g, 43mmol). Under nitrogen protection, the mixture was heated under reflux at 105℃ for 24h. Samples were taken and analyzed by TLC. After the reaction was complete, the reaction solution was cooled to 0℃, filtered, and dried to obtain 75.1g of a yellow solid, with a yield of 72%.

[0085] 10. Preparation of methyl 4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-2)

[0086] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was p-hydroxyphenylboronic acid, yielding 70.3 g of yellow solid with a yield of 69%.

[0087] 11. Preparation of methyl 2-fluoro-4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-3)

[0088] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was intermediate v-2, yielding 71.3 g of yellow solid with a yield of 65%.

[0089] 12. Preparation of methyl 4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-4)

[0090] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was 4-trifluoromethylphenylboronic acid, yielding 84.2 g of yellow solid with a yield of 72%.

[0091] 13. Preparation of methyl 4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-5)

[0092] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was p-fluorophenylboronic acid, yielding 84.0 g of yellow solid with a yield of 82%.

[0093] 14. Preparation of methyl 4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-6)

[0094] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was p-chlorophenylboronic acid, yielding 82.6 g of yellow solid with a yield of 77%.

[0095] 15. Preparation of methyl 4-(5-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate vi-7)

[0096] The preparation was carried out in the same manner as step 9 in Example 1, except that one of the raw materials was p-nitrophenylboronic acid, yielding 76.1 g of yellow solid with a yield of 69%.

[0097] 16. Preparation of 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-1)

[0098] In a 5L round-bottom flask, a mixed solution of tetrahydrofuran (320mL) and water (320mL) containing intermediate vi-1 (36.0g, 0.1mol) was added, followed by the addition of lithium hydroxide (8.4g, 0.2mol). The mixture was heated to 40℃ and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (400mL) was added to the reaction solution. The pH was adjusted to 5-6 with 1mol / L hydrochloric acid solution. The solid obtained after filtration was slurried with a mixed solvent of tetrahydrofuran and acetonitrile (volume ratio 1:1), filtered, and dried to obtain 32.0g of yellow solid, with a yield of 90%.

[0099] 17. Preparation of 4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-2)

[0100] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-2, yielding 27.0 g of yellow solid with a yield of 80%.

[0101] 18. Preparation of 2-fluoro-4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-3)

[0102] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-3, yielding 32.4 g of yellow solid with a yield of 89%.

[0103] 19. Preparation of 4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-4)

[0104] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-4, yielding 33.9 g of yellow solid with a yield of 87%.

[0105] 20. Preparation of 4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-5)

[0106] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-5, yielding 30.9 g of yellow solid with a yield of 91%.

[0107] 21. Preparation of 4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-6)

[0108] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-6, yielding 32.7 g of yellow solid with a yield of 92%.

[0109] 22. Preparation of 4-(5-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (intermediate vii-7)

[0110] The preparation was carried out in the same manner as step 16 in Example 1, except that one of the raw materials was intermediate vi-7, yielding 31.5 g of yellow solid with a yield of 86%.

[0111] 23. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (intermediate II-1)

[0112] In a 5L round-bottom flask, a solution of intermediate vii-1 (32.0 g, 92 mmol) in N,N-dimethylformamide (320 mL), (1-ethyl-3-(3-dimethylpropylamine)carbodiimide) (35.2 g, 184 mmol), and then N-hydroxysuccinimide (21.8 g, 189 mmol) were added sequentially. The mixture was stirred at 15–25 °C for 8 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered and dried to give 32.6 g of a yellow solid, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ8.31(d,J=8.6Hz,2H),8.12(dd,J=12.6,8.5Hz,4H),7.78(d,J=8.5Hz,3H),2.95(s,4H).MS(ESI):m / z:442.07[M+H] + .

[0113]

[0114] 24. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (compound II-2)

[0115] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-2, yielding 30.0 g of a yellow solid with a yield of 75%. MS (ESI): m / z: 485.07 [M+H] + .

[0116]

[0117] 25. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-fluorobenzoate (compound II-3)

[0118] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-3, yielding 29.7 g of a yellow solid with a yield of 70%. MS (ESI): m / z: 462.07 [M+H] + .

[0119]

[0120] 26. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (compound II-4)

[0121] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-4, yielding 31.8 g of a yellow solid, with a yield of 71%. MS (ESI): m / z: 485.07 [M+H] + .

[0122]

[0123] 27. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (compound II-5)

[0124] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-5, yielding 32.9 g of a yellow solid with a yield of 82%. MS (ESI): m / z: 433.07 [M+H] + .

[0125]

[0126] 28. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (compound II-6)

[0127] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-6, yielding 32.5 g of a yellow solid with a yield of 78%. MS (ESI): m / z: 451.04 [M+H] + .

[0128]

[0129] 29. Preparation of 2,5-dioxopyrrolidone-1-yl-4-(5-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (compound II-7)

[0130] The preparation was carried out using the same method as step 23 in Example 1, except that one of the raw materials was intermediate vii-7, yielding 31.5 g of a yellow solid, with a yield of 74%. MS (ESI): m / z: 462.06 [M+H] + .

[0131]

[0132] Example 2: Preparation of imidazothiadiazole derivatives modified with acyl groups on piperazine N

[0133] This embodiment aims to prepare imidazothiadiazole derivatives modified with acyl groups on the N-side of piperazine in the compound of general formula (I), and the preparation route is shown in reaction formula I.

[0134] The structural formula of the imidazothiadiazole derivative modified with an acyl group on N-type piperazine synthesized in this embodiment is as follows:

[0135]

[0136] R2, R4, and R5 are defined as above.

[0137] 1. Preparation of tert-butyl-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X1)

[0138] In a 500 mL round-bottom flask, a solution of intermediate compound II-1 (8.8 g, 20 mmol) in dichloromethane (200 mL) was added, followed by the addition of piperazine-1-carboxylic acid tert-butyl ester (7.4 g, 40 mmol) and triethylamine (5.5 mL, 40 mmol). The mixture was stirred at room temperature for 8 hours. After the reaction was confirmed to be complete by TLC, water and dichloromethane were added for extraction three times. The organic phase was dried and the solvent was evaporated to obtain 16.5 g of yellow solid, which was directly used for the next step of the reaction without purification. 1 H NMR (500MHz, CDCl3) δ8.05–7.89(m,1H),7.85–7.82(m,2H),7.79–7.72(m,1H),3.81–3.76(m,2H),3.45–3.39(m,2H). 13 C NMR (125MHz, CDCl3) δ170.85,167.42,160.33,154.15,137.62,136.11,135.05,133.89 ,131.14,130.28,129.87,128.01,127.65,118.94,111.72,79.98,47.53,45.01,28.96.

[0139]

[0140] 2. Preparation of tert-butyl-4-(4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X2)

[0141] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-2, yielding 15.3g of a yellow solid crude product. 1 H NMR (500MHz, CDCl3) δ8.10–8.02(m,1H),7.95–7.90(m,1H),7.59–7.47(m,1H),6.89–6.79(m,1H),3.68–3.59(m,2H),3.47–3.35(m,2H). 13C NMR (125MHz, CDCl3) δ170.92,166.15,160.38,157.89,155.71,137.52,132.64 ,131.03,130.85,129.47,129.01,127.42,118.03,79.87,47.55,44.98,28.76.

[0142]

[0143] 3. Preparation of tert-butyl-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-fluorobenzoyl)piperazine-1-carboxylate (Formula I-X3)

[0144] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-3, yielding 17.4g of a yellow solid crude product. 1 H NMR (500MHz, CDCl3) δ7.99–7.90(m,3H),7.82–7.79(m,2H),7.67(dd,J=7.3,2 .2Hz,1H),7.53(dd,J=12.1,2.1Hz,1H),3.67–3.62(m,4H),3.44–3.38(m,4H). 13 C NMR (125MHz, CDCl3) δ167.85,166.37,165.28,166.74,160.89,161.27,157.63,155.61,137.42,136.15,133.94,135.88,130.45 ,129.78,131.05,127.93,129.41,127.05,127.83,124.12,126.47,118.34,120.91,117.28,113.42,80.11,47.65,44.92,27.56.

[0145]

[0146] 4. Preparation of tert-butyl-4-(4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X4)

[0147] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-4, yielding 15.3g of a yellow solid crude product. 1H NMR (500MHz, CDCl3) δ8.08–8.02(m,1H),7.95–7.91(m,1H),7.79–7.75(m,1H),7.61-7.56(m,1H),3.76–3.59(m,2H),3.52–3.46(m,2H). 13 C NMR (125MHz, CDCl3)δ

[0148] 171.05,167.63,160.25,155.67,138.52,135.14,134.16,131.68,133.01,130.15,132.65,130.89,130.42,128.37,127.71,129.43,127.62,129.31,127.85,126.42,128.15,126.37,128.92,126.08,124.15,123.67,119.82,80.11,47.85,44.68,27.45.

[0149]

[0150] 5. Preparation of tert-butyl-4-(4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X5)

[0151] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-5, yielding 14.8g of a yellow solid crude product. 1 H NMR (500MHz, CDCl3) δ8.06–7.81(m,1H),7.96–7.91(m,1H),7.77–7.73(m,1H),7.21(s,2H),3.77–3.72(m,2H),3.59–3.55(m,2H). 13 C NMR (125MHz, CDCl3) δ170.98,167.45,162.83,160.12,159.87,155.64,137.82,134.15,131.42,133 .11,130.05,132.76,128.25,130.52,127.89,127.03,118.67,116.45,80.12,47.85,44.91,27.65.

[0152]

[0153] 6. Preparation of tert-butyl-4-(4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X6)

[0154] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-6, yielding 15.3g of a yellow solid crude product. 1 H NMR (500MHz, CDCl3) δ8.99–7.94(m,1H),7.89–7.84(m,1H),7.65–7.60(m,1H),7.45–7.39(m,1H),3.70–3.65(m,2H),3.53–3.47(m,2H). 13 C NMR (125MHz, CDCl3)δ

[0155] 171.85,165.12,162.05,155.67,137.82,135.41,132.89,134.15,132.76,130.45,132.08,128.12,127.56,127.91,80.21,47.85,44.68,27.45.

[0156]

[0157] 7. Preparation of tert-butyl-4-(4-(5-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylic acid ester (Formula I-X7)

[0158] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was intermediate II-7, yielding 15.7g of a yellow solid crude product. 1 H NMR (500MHz, CDCl3) δ8.29–8.23(m,1H),8.10–8.04(m,1H),8.03–8.00(m,1H),7.95–7.92(m,1H),3.76–3.71(m,2H),3.59–3.53(m,2H). 13 C NMR (125MHz, CDCl3)δ

[0159] 171.05,167.62,159.88,155.67,148.51,139.12,137.83,134.15,132.76,130.05,128.37,127.63,126.48,124.42,80.21,47.85,44.68,27.56.

[0160]

[0161] 8. Preparation of 4-(2-(4-(1-piperazinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (intermediate III-1)

[0162] In a 500 mL round-bottom flask, a solution of crude compound I-X1 (16.5 g) prepared above in dichloromethane (200 mL) was added, followed by the addition of trifluoroacetic acid (50 mL). The mixture was stirred for 2 hours. After the reaction was confirmed to be complete by TLC, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (dichloromethane:methanol = 100:1, v / v) to give 6.3 g of a yellow solid, with a two-step yield of 76%. 1 HNMR(400MHz,DMSO-d6)δ8.28(dt,J=8.6,1.9Hz,2H),8.11(dd,J=6.4,1.8Hz,2H),8.00 –7.91(m,3H),7.70–7.61(m,2H),3.69(s,3H),2.97(qd,J=8.9,3.7Hz,3H),2.86(s,2H). 13 C NMR(101MHz,DMSO-d6)δ170.23,163.02,157.75,136.13,135.91,134.67,130 .69,128.60,128.18,127.92,127.75,127.40,117.56,113.31,46.56,45.61.

[0163]

[0164] 9. Preparation of (4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)phenyl)(piperazin-1-yl)methyl ketone (intermediate III-2)

[0165] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X2. After purification, 5.5 g of yellow solid was obtained, with a two-step yield of 68%. 1 H NMR (500MHz, CDCl3) δ7.98–7.93(m,2H),7.88–7.83(m,2H),7.77–7.52(m,2H),7. 07(s,1H),6.89–6.82(m,2H),3.65–3.60(m,4H),3.00–2.92(m,4H),2.20(s,1H). 13C NMR (125MHz, CDCl3) δ171.12,167.65,160.05,157.18,137.85,134.15,132.76,130.15,129.12,128.37,128.25,126.98,117.68,49.28,44.72.

[0166]

[0167] 10. Preparation of 4-(2-(3-fluoro-4-(piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (intermediate III-3)

[0168] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X3. After purification, 6.1 g of yellow solid was obtained, with a two-step yield of 70%. 1 H NMR (500MHz, CDCl3) δ7.99–7.91(m,3H),7.90–7.85(m,2H),7.79(dd,J=7.3,2.2Hz,1 H),7.67(dd,J=12.2,2.1Hz,1H),3.77–3.69(m,4H),3.07–3.01(m,4H),2.28(s,1H). 13 C NMR (125MHz, CDCl3) δ168.12,166.05,167.03,164.96,162.46,159.41,157.42,137.64,134.62,135.11,133.06,132. 13,129.15,131.09,127.75,129.65,127.62,127.31,125.95,123.83,120.26,118.09,117.12,113.60,47.63,44.70.

[0169]

[0170] 11. Preparation of 1-piperazinyl-4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzophenone (intermediate III-4)

[0171] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X4. After purification, 6.6 g of yellow solid was obtained, with a two-step yield of 72%. 1H NMR (500MHz, CDCl3) δ7.99–7.94(m,1H),7.89–7.78(m,2H),7.69(m,1H),3.66–3.60(m,2H),3.00–2.94(m,2H). 13 C NMR (125MHz, CDCl3) δ171.12,167.75,160.15,138.65,137.85,134.25,133.45,131.28,130.95,132.76,130.68,132.08,128. 25,129.53,127.58,129.47,127.45,129.01,126.32,128.18,126.22,128.12,126.10,126.95,123.77,121.60,49.28,44.72.

[0172]

[0173] 12. Preparation of 1-piperazinyl-4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzophenone (intermediate III-5)

[0174] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X5. After purification, 6.1 g of yellow solid was obtained, with a two-step yield of 75%. 1 H NMR (500MHz, CDCl3) δ8.05–8.00(m,2H),7.95–7.90(m,2H),7.77–7.71(m,2H),7.08(s,3H),3.64–3.58(m,4H),3.06–3.00(m,4H),2.27(s,1H). 13 C NMR (125MHz, CDCl3) δ171.12,167.75,162.58,160.68,159.07,137.85,134.25,131.60, 133.52,132.76,130.05,128.95,130.82,128.25,127.43,118.38,116.25,49.28,44.72.

[0175]

[0176] 13. Preparation of 1-piperazinyl-4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzophenone (intermediate III-6)

[0177] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X6. After purification, 6.6 g of yellow solid was obtained, with a two-step yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.07–8.02(m,1H),7.97–7.92(m,1H),7.74–7.66(m,1H),7.41–7.55(m,1H),3.62–3.58(m,2H),3.08–3.02(m,2H). 13 C NMR (125MHz, CDCl3) δ171.12,167.75,160.05,137.85,135.52,133.41,134.25,132.76,130.28,132.08,128.95,128.25,127.35,49.28,44.72.

[0178]

[0179] 14. Preparation of 1-piperazinyl-4-(5-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzophenone (intermediate III-7)

[0180] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-X7. After purification, 6.0 g of yellow solid was obtained, with a two-step yield of 69%. 1 H NMR (500MHz, CDCl3) δ8.20–8.14(m,1H),8.02–7.91(m,2H),7.87–7.82(m,1H),3.65–3.59(m,2H),3.00–2.94(m,2H). 13 C NMR (125MHz, CDCl3)δ

[0181] 171.12,167.75,159.05,148.59,141.12,137.85,134.25,132.76,130.05,128.37,127.63,126.48,124.42,49.28,44.72.

[0182]

[0183] 15. Preparation of 4-(2-(4-(4-acetylpiperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-1)

[0184] In a 25 mL round-bottom flask, anhydrous dichloromethane (10 mL) solution of intermediate III-1 (0.3 g, 0.7 mmol), anhydrous triethylamine (0.4 mL, 2.8 mmol), and acetyl chloride (0.22 g, 2.8 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours under nitrogen protection. After the reaction was confirmed to be complete by TLC, the reaction solution was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1, v / v) to obtain 272 mg of a pale yellow solid, with a product yield of 85%. 1 H NMR (400MHz, CDCl3) δ8.08–8.02(m,2H),7.98–7.92(m,2H),7.72–7.65(m,3H),7.57–7.51(m,2H),3.65(q,J=58.7,54.7Hz,8H),2.08(s,3H). 13 C NMR (101MHz, CDCl3) δ169.24,169.13,161.79,147.02,138.59,132.96,132. 77,132.56,131.38,128.26,127.29,126.41,124.79,110.57,30.30,21.40.

[0185] 16. Preparation of 4-(2-(4-(4-(3-methylbutyryl)-piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-2)

[0186] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was isovaleryl chloride. After purification, 248 mg of white solid was obtained, with a yield of 71%. 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.2Hz,2H),7.95(d,J=8.1Hz,2H),7.67(d,J=8.2Hz,3H),7 .54(d,J=8.0Hz,2H),3.57(t,J=67.1Hz,8H),1.61(q,J=7.5Hz,2H),0.91(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.81,169.12,161.76,138.62,132.75,131.35,128.25,127.26,124.76,118.83,110.51,35.19,18.63,13.97.

[0187] 17. Preparation of 4-(2-(4-(4-(cyclopropanecarbonyl-piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile) (General Formula I-3)

[0188] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was cyclopropylformyl chloride. After purification, 230 mg of white solid was obtained, with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ8.08–8.03(m,2H),7.98–7.93(m,2H),7.74–7.66(m,3H),7.57–7.5 2(m,2H),3.90–3.30(m,8H),1.80(s,2H),0.99–0.93(m,2H),0.76(dt,J=8.5,3.9Hz,2H). 13 C NMR (101MHz, CDCl3) δ171.81,168.54,162.40,139.59,134.30,133.44,132 .85,130.76,128.69,127.63,126.02,124.95,119.38,109.71,10.84,7.64.

[0189] 18. Preparation of 1-(4-(4-(5-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethane-1-one (general formula I-4)

[0190] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate III-4. After purification, 280 mg of white solid was obtained, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.2Hz,2H),7.95(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,3H),7.53(d,J=8.3Hz,2H),3.64(d,J=91.6Hz,8H),2.08(s,3H). 13 C NMR (101MHz, CDCl3) δ169.21,161.41,146.43,138.42,132.25,131.74,131.59,129.42,129 .10,128.22,127.25,126.87,125.93,125.90,125.86,124.83,77.27,46.09,41.57,21.39.

[0191] 19. Preparation of 1-(4-(4-(5-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethane-1-one (general formula I-5)

[0192] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate III-5. After purification, 236 mg of white solid was obtained, with a yield of 75%. 1 H NMR (400MHz, d-DMSO) δ8.15–8.07(m,4H),7.84(s,1H),7.70–7.64(m,2H),7.40–7.33(m,2H),3.70–3.39(m,8H),2.10–1.98(m,3H). 13 CNMR(101MHz,d-DMSO)δ169.00,168.59,163.06,161.75,145.41,139.43,131.63, 130.94,128.65,127.53,127.13,127.05,126.76,125.17,116.54,116.32,21.72.

[0193] 20. Preparation of 1-(4-(4-(5-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethane-1-one (general formula I-6)

[0194] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate III-2. After purification, 219 mg of white solid was obtained, with a yield of 70%. 1 H NMR (400MHz, d-DMSO) δ8.15–8.07(m,4H),7.84(s,1H),7.70–7.64(m,2H),7.40–7.33(m,2H),3.71–3.39(m,8H),2.08–1.99(m,3H). 13 CNMR(101MHz,d-DMSO)δ168.99,168.61,161.24,157.60,144.27,139.33, 131.09,129.90,128.65,128.09,127.49,126.73,119.55,116.25,21.73.

[0195] 21. Preparation of 1-(4-(4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethane-1-one (general formula I-7)

[0196] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate III-6. After purification, 235 mg of white solid was obtained, with a yield of 72%. 1 H NMR (400MHz, d-DMSO) δ8.10–8.07(m,4H),7.89(s,1H),7.69–7.65(m,2H),7.58–7.53(m,2H),3.74–3.45(m,8H),2.03(t,J=3.6Hz,3H). 13 C NMR (101MHz, d-DMSO) δ169.00,168.96,168.57,161.86,145.86,139.45,132.27,130.88,129.45,128.64,127.42,126.44,46.13,21.69.

[0197] 22. Preparation of 1-(4-(4-(5-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethane-1-one (general formula I-8)

[0198] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate III-7. After purification, 250 mg of white solid was obtained, with a yield of 75%. 1 H NMR (400MHz, d-DMSO) δ8.10–8.07(m,4H),7.89(s,1H),7.69–7.65(m,2H),7.58–7.53(m,2H),3.74–3.45(m,8H),2.03(t,J=3.6Hz,3H). 13 C NMR (101MHz, d-DMSO) δ168.99,168.55,162.62,147.74,146.18,134.97,134.84,130.73,128.66,127.70,125.82,125.17,124.95,21.74.

[0199] Example 3: Preparation of imidazothiadiazole derivatives modified with sulfonyl groups on piperazine N

[0200] This embodiment aims to prepare imidazothiadiazole derivatives modified with sulfonyl groups on piperazine N in the compound of general formula (I), and the preparation route is shown in reaction formula I.

[0201] The structural formula of the imidazothiadiazole derivative modified with a sulfonyl group on piperazine N synthesized in this embodiment is as follows:

[0202]

[0203] R2, R4, and R5 are defined as above.

[0204] 1. Preparation of 4-(2-(4-(4-(4-(methanesulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-9)

[0205] In a 25 mL round-bottom flask, anhydrous dichloromethane (10 mL) solution of intermediate III-1 (0.3 g, 0.7 mmol), anhydrous triethylamine (0.4 mL, 2.8 mmol), and methanesulfonyl chloride (0.32 g, 2.8 mmol) were added sequentially. The mixture was stirred at room temperature for 10 hours under nitrogen protection. After the reaction was confirmed to be complete by TLC, the reaction solution was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 80:1, v / v) to obtain 272 mg of a pale yellow solid, with a product yield of 85%. 1 H NMR(400MHz, DMSO-d6)δ8.27(d,J=8.5Hz,2H),8.11(d,J=8.6Hz,3H),7.98–7.90(m,2H) ,7.65(d,J=8.3Hz,2H),3.73(s,2H),3.27–3.17(m,2H),3.16–2.97(m,4H),2.89(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.41,161.34,146.21,138.29,133.25,132.41,131.81,129.8 0,127.61,126.63,124.98,123.93,118.31,108.68,45.02,33.63,7.97.HRMS(ESI+):m / z calcd for C 23 H 21 N6O3S2: 493.1097 [M+H] + ;found:493.1111[M+H] + .

[0206] 2. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N,N-dimethylpiperazine-1-sulfonamide (general formula 1-10)

[0207] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was dimethylaminosulfonyl chloride. After purification, 164 mg of a pale yellow solid was obtained, with a yield of 45%. 1 H NMR(400MHz, DMSO-d6)δ8.26(d,J=8.4Hz,2H),8.13–8.06(m,3H),7.99–7.89(m,2H),7.70–7.62(m ,2H),3.68(s,2H),3.37(s,1H),3.22(d,J=26.0Hz,4H),3.04(qd,J=7.3,4.7Hz,3H),2.76(s,6H). 13 C NMR(101MHz,DMSO-d6)δ167.42,166.38,161.35,146.21,138.36,133.25,132.40,131.00,129.74,128.06,127 .65,126.59,123.93,118.31,108.67,44.94,37.29,30.54,29.19,27.75,21.79,13.29,10.20.HRMS(ESI+):m / z calcd for C 24 H 24 N7O3S2: 522.1363 [M+H] + Found: 522.1377 [M+H] + .

[0208] 3. Preparation of 4-(2-(4-(4-(ethylsulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-11)

[0209] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was ethyl sulfonyl chloride. After purification, 163 mg of a pale yellow solid was obtained, with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ8.15–8.08(m,2H),8.05–7.98(m,2H),7.79–7.71(m,3H), 7.63–7.55(m,2H),4.01–3.20(m,8H),2.99(q,J=7.4Hz,2H),1.04–0.65(m,3H). 13C NMR (101MHz, CDCl3) δ169.18,161.79,138.44,132.79,128.37,127.42,124.89,118.95,110.66,45.93,44.66,29.80,7.92,1.12.HRMS(ESI+):m / z calcdfor C 24 H 23 N6O3S2: 507.1258 [M+H] + ;found:507.1268[M+H] + .

[0210] 4. Preparation of 4-(2-(4-(4-(propylsulfonyl)piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-12)

[0211] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was propyl sulfonyl chloride. After purification, 164 mg of a pale yellow solid was obtained, with a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ8.29(dq,J=8.5,3.2Hz,2H),8.13(tt,J=5.6,2.4Hz,3H),7.97(ddt,J=6.7,4.7,2.8Hz,2H),7.69(dt,J =7.9,1.2Hz,2H),3.59(d,J=123.3Hz,4H),3.26(d,J=31.0Hz,4H),3.10–3.02(m,2H),1.79–1.65(m,2H),1.00(t,J=7.4Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ166.13,160.39,145.18,140.95,137.83,137.37,132.25,131.41,130.83,128.53,128. 09,126.26,125.59,124.75,123.97,122.93,117.32,107.66,48.17,44.10,19.37,9.48.HRMS(ESI+):m / zcalcd for C 25 H 25 N6O3S2: 521.1409[M+H] + ;found:521.1424[M+H] + .

[0212] 5. Preparation of 4-(2-(4-(4-(isopropylsulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-13)

[0213] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was propyl sulfonyl chloride. After purification, 163 mg of a pale yellow solid was obtained, with a yield of 45%. 1 H NMR (400MHz, CDCl3) δ8.06–7.95(m,4H),7.82(d,J=8.4Hz,2H),7.68(s,1H),7.56(d,J=8.3Hz,2H),4.00–2.80(m,9H),1.34(d,J=6.8Hz,6H). 13 C NMR (101MHz, CDCl3) δ168.14,165.30,160.07,137.19,133.54,130.81,129.90,127.15,126.40,12 6.20,123.56,52.71,50.71,28.71(d,J=7.5Hz),26.19,21.67,15.70,13.11,7.57.HRMS(ESI+):m / z calcd for C 25 H 25 N6O3S2: 521.1411[M+H] + ;found:521.1424[M+H] + .

[0214] 6. Preparation of 4-(2-(4-(4-((4-ethylphenyl)sulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-14)

[0215] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was 4-ethylbenzenesulfonyl chloride. After purification, 188 mg of a pale yellow solid was obtained, with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.3Hz,2H),7.97(d,J=8.1Hz,2H),7.74(d,J=8.3Hz,3H),7.65(d,J=8.1Hz,2H),7.5 1(d,J=8.1Hz,2H),7.38(d,J=8.1Hz,2H),4.05–3.42(m,4H),3.17–2.93(m,4H),2.75(q,J=7.6Hz,2H),1.70(s,3H). 13C NMR (101MHz, CDCl3) δ168.98,161.77,150.49,138.32,133.15,132.87,132.45,131.53,128.93,128.36,127.97, 127.32,126.48,124.88,118.94,110.65,45.91,29.80,28.95,22.79,15.17,14.24,8.74,1.12.HRMS(ESI+):m / z calcd forC 30 H 27 N6O3S2: 583.1569 [M+H] + ;found:583.1581[M+H] + .

[0216] 7. Preparation of 4-(2-(4-(4-(cyclopropylsulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-15)

[0217] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was cyclopropylsulfonyl chloride. After purification, 152 mg of a pale yellow solid was obtained, with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=8.4Hz,2H),8.11–8.04(m,3H),7.91(d,J=8.3Hz,2H),7.65(d,J=8.2 Hz,2H),3.72(s,2H),3.42(s,2H),3.30–3.12(m,4H),2.61(dq,J=11.2,4.1Hz,1H),1.04–0.86(m,4H). 13 C NMR(101MHz,DMSO-d6)δ168.54,162.39,147.25,139.31,134.30,133.45,132.85,130.84,130.11,128.73,127.66,126.0 1,124.94,119.39,109.71,35.58,31.75,30.84,29.70–29.22,29.04,27.01,25.53,22.57,14.42,4.49.HRMS(ESI+):m / z calcd for C 25 H 25 N6O3S2: 519.1252[M+H] + ;found:519.1268[M+H] + .

[0218] 8. Preparation of 4-(2-(4-(4-(cyclopropylsulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-16)

[0219] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was morpholinosulfonyl chloride. After purification, 174 mg of a pale yellow solid was obtained, with a yield of 44%. 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.4Hz,2H),8.02(d,J=8.1Hz,2H),7.79–7.72(m,3H),7.59(d ,J=8.3Hz,2H),3.73(t,J=4.7Hz,4H),3.24(dd,J=5.8,3.6Hz,4H),1.64(s,4H),1.24(s,4H). 13 C NMR (101MHz, CDCl3) δ168.02,160.66,145.98,137.34,132.05,131.77,131.57,130.47,127 .22,126.28,125.39,123.78,117.82,109.56,65.30,45.54,28.68,28.30.HRMS(ESI+):m / z calcd for C 26 H 26 N7O4S2: 564.1470 [M+H] + Found: 564.1482 [M+H] + .

[0220] 9. Preparation of 4-(2-(4-(4-(cyclohexylsulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-17)

[0221] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was cyclohexylsulfonyl chloride. After purification, 169 mg of a pale yellow solid was obtained, with a yield of 43%. 1H NMR (400MHz, DMSO-d6) δ8.31(d,J=8.4Hz,2H),8.17–8.11(m,3H),7.98(d,J=8.4Hz,2H),7.70(d,J=8.0Hz,2H),3.71(s ,2H),3.38(s,4H),3.14(s,1H),2.06–1.97(m,2H),1.78(d,J=11.9Hz,2H),1.63(d,J=12.9Hz,1H),1.46–1.05(m,6H). 13 C NMR(101MHz,DMSO-d6)δ171.43,170.24,160.53,135.42,135.57,135.25,132.47,130.37,131.13,1 29.23,128.75,128.32,118.12,112.60,57.33,43.46,45.71,26.50,25.22,24.27.HRMS(ESI+):m / z calcd for C 28 H 29 N6O3S2: 561.1723 [M+H] + Found: 561.1737 [M+H] + .

[0222] 10. Preparation of 4-(2-(4-(4-((2-fluorophenyl)sulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-18)

[0223] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was 2-fluorophenylsulfonyl chloride. After purification, 172 mg of a pale yellow solid was obtained, with a yield of 42%. 1 H NMR(400MHz, DMSO-d6)δ8.29(d,J=8.5Hz,2H),8.17–8.06(m,3H),7.97(d,J=8.5Hz,2H),7.87–7.76( m,2H),7.65(d,J=8.2Hz,2H),7.59–7.42(m,2H),3.75(s,2H),3.53–3.40(m,2H),3.28–3.11(m,4H). 13C NMR(101MHz,DMSO-d6)δ168.54,162.40,160.11,157.58,147.26,139.27,136.77,136.69,134.31,133.47,132.87, 131.39,130.79,128.75,126.02,125.76,124.97,124.45,124.30,119.40,118.37,118.15,109.71.HRMS(ESI+):m / z calcd for C 28 H 22 N6O3FS2: 573.1165 [M+H] + ;found:573.1173[M+H] + .

[0224] 11. Preparation of 4-(2-(4-(4-((4-methylphenyl)sulfonyl)piperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-19)

[0225] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was 4-methylphenylsulfonyl chloride. After purification, 159 mg of a pale yellow solid was obtained, with a yield of 40%. 1 H NMR(400MHz, CDCl3)δ8.01–7.96(m,2H),7.94–7.86(m,4H),7.86–7.80(m,2H),7.70 –7.64(m,2H),7.46–7.40(m,2H),3.82–3.76(m,4H),3.45–3.39(m,4H),2.39(s,3H). 13 C NMR (125MHz, CDCl3) δ172.08,170.17,161.08,142.40,136.96,136.64,135.62,133.28,132.32,131.82, 131.13,129.73,129.23,128.75,128.32,128.13,118.12,112.60,47.28,45.68,21.55.HRMS(ESI+):m / z calcd forC 29 H 25 N6O3S2: 569.1411 [M+H] + ;found:569.1424[M+H] + .

[0226] 12. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-yl)benzoyl)-N-ethylpiperazine-1-sulfonamide (general formula I-20)

[0227] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was ethylaminosulfonyl chloride. After purification, 150 mg of a pale yellow solid was obtained, with a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ8.33–8.26(m,1H),8.16–8.09(m,1H),8.00–7.93(m,1H),7.72–7.66(m, 1H),7.36(t,J=5.6Hz,0H),3.73(s,1H),3.43(s,1H),3.22–2.91(m,2H),1.08(t,J=7.2Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ168.58,162.49,147.33,139.50,134.39,133.54,132.94,130 .86,128.80,127.72,126.09,125.02,119.46,109.78,38.33,15.65.HRMS(ESI+):m / z calcd for C 24 H 24 N7O3S2: 522.1362 [M+H] + Found: 522.1377 [M+H] + .

[0228] 13. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N,N-diethylpiperazine-1-sulfonamide (general formula I-21)

[0229] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was N,N-diethylaminosulfonyl chloride. After purification, 169 mg of a pale yellow solid was obtained, with a yield of 44%. 1 H NMR(400MHz, CDCl3)δ8.12(d,J=8.5Hz,2H),8.01(d,J=8.0Hz,2H),7.79–7.71(m,3H),7.58 (d,J=8.0Hz,2H),3.86(s,2H),3.52(s,2H),3.28(q,J=7.1Hz,8H),1.55(d,J=115.5Hz,6H). 13C NMR (101MHz, CDCl3) δ172.08,170.17,161.08,136.96,136.64,135.62,133.28,131.82,131 .13,129.23,128.75,128.32,118.12,112.60,46.67,45.61,41.69,13.65.HRMS(ESI+):m / z calcd forC 26 H 28 N7O3S2: 550.1679 [M+H] + Found: 550.1690 [M+H] + .

[0230] Example 4: Preparation of imidazothiadiazole derivatives modified with thiourea groups on piperazine N

[0231] This embodiment aims to prepare imidazothiadiazole derivatives modified with thiourea groups on piperazine N in the compound of general formula (I), and the preparation route is shown in reaction formula I.

[0232] The structural formula of the imidazothiadiazole derivative modified with a thiourea group on piperazine N synthesized in this embodiment is as follows:

[0233]

[0234] R2, R4, and R5 are defined as above.

[0235] 1. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-ethylpiperazine-1-thioamide (general formula I-22)

[0236] In a 25 mL round-bottom flask, an anhydrous ethanol (10 mL) solution of intermediate III-1 (0.3 g, 0.7 mmol), ethyl isothiocyanate (96 mg, 1.1 mmol), and anhydrous triethylamine (0.2 mL, 1.4 mmol) were added sequentially. The mixture was stirred at 70 °C for 4 h. After the reaction was complete as detected by TLC, the mixture was extracted three times with water and ethyl acetate. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1, v / v) to give 281 mg of a white solid, with a yield of 81%. 1HNMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.13(d,J=8.3Hz,3H),8.00–7.95(m,2H),7.77(t,J=5.3Hz,1H) ,7.73–7.67(m,2H),3.91(s,2H),3.76(d,J=58.3Hz,4H),3.53(qd,J=7.1,5.1Hz,4H),1.11(t,J=7.1Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ181.78,168.59,147.27,139.56,134.32,133.49,132.89,130.81,128.79,127.62,

[0237] 126.05, 124.99, 119.40, 109.73, 49.08, 14.94.

[0238] 2. Preparation of N-(tert-butyl)-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-thioamide (general formula I-23)

[0239] The preparation was carried out in the same manner as step 1 in Example 4, except that one of the raw materials was butyl isothiocyanate. After purification, 301 mg of white solid was obtained, with a yield of 81%. 1 H NMR (400MHz, DMSO-d6) δ8.35–8.28(m,2H),8.18–8.09(m,3H),8.02–7.94(m,2H),7.75–7.68(m,2H),7.37(d,J=8.0Hz,1H),3.88( d,J=23.6Hz,4H),3.55(d,J=103.0Hz,4H),3.17(d,J=5.3Hz,1H),1.65–1.42(m,2H),1.11(d,J=6.5Hz,3H),0.84(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ181.59,168.58,147.30,139.60,134.34,133.52,132.92,13 0.82,128.80,127.64,126.07,125.03,119.41,109.75,53.29,29.00,20.23,11.30.

[0240] 3. Preparation of N-(tert-butyl)-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-thioamide (general formula I-24)

[0241] In a 25 mL round-bottom flask, an anhydrous N,N-dimethylformamide (3 mL) solution of N,N'-thiocarbonyldiimidazole (195 mg, 1.1 mmol) was added. The flask was cooled to approximately 0 °C in an ice bath under nitrogen protection. While stirring, an anhydrous N,N-dimethylformamide (3 mL) solution of 3-pentanylamine (126 mg, 1.4 mmol) was slowly added. After the addition was complete, the temperature was raised to room temperature, and stirring was continued for 2 h. Subsequently, an anhydrous N,N-dimethylformamide (6 mL) solution of intermediate III-1 (0.3 g, 0.7 mmol) and N,N-diisopropylethylamine (378 μL, 2.2 mmol) were added, and the reaction was continued at 60 °C with stirring for 4 h. After the reaction was confirmed to be complete by TLC, water and ethyl acetate were added and extracted three times. The organic layer was dried, filtered, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (dichloromethane:methanol = 100:1, volume ratio) to obtain 145 mg of white solid, with a yield of 38%. 1 H NMR (400MHz, DMSO-d6) δ8.30–8.24(m,2H),8.11(dd,J=8.3,1.7Hz,3H),7.97–7.92(m,2H),7.73–7.65(m,2H),7.32(d,J=8 .2Hz,1H),3.89(d,J=23.2Hz,4H),3.66(d,J=24.8Hz,4H),2.73(s,1H),1.51(hd,J=7.4,3.9Hz,4H),0.83(t,J=7.4Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ182.35,168.59,147.24,139.56,134.29,133.44,132.85 ,130.76,128.79,127.57,126.01,124.93,119.39,109.69,58.74,26.85,11.03.

[0242] 4. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-isopropylpiperazine-1-thioamide (general formula I-25)

[0243] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was isopropylamine. After purification, 195 mg of white solid was obtained, with a yield of 54%. 1H NMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.13(d,J=8.0Hz,3H),8.00–7.9 2(m,2H),7.73–7.65(m,2H),7.43(d,J=7.7Hz,1H),4.52(dp,J=13.4,6.6Hz,

[0244] 1H),3.87(d,J=24.9Hz,4H),3.68(s,4H),1.15(d,J=6.6Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ181.01,168.57,147.28,139.55,134.32,133.49,

[0245] 132.89,132.89,130.81,128.79,127.62,126.05,125.00,119.41,109.73,47.72,22.49.

[0246] 5. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-neopentylpiperazine-1-thioamide (general formula I-26)

[0247] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was neopentylamine. After purification, 210 mg of white solid was obtained, with a yield of 56%. 1 H NMR(400MHz, DMSO-d6)δ8.35–8.29(m,2H),8.15(dd,J=6.6,1.8Hz,3H),8.02–7.94(m,2H),7.74–7.66(m, 2H),7.56(t,J=5.9Hz,1H),3.90(d,J=34.6Hz,4H),3.71–3.48(m,4H),3.17(d,J=5.2Hz,2H),0.88(s,9H). 13 C NMR(101MHz,DMSO-d6)δ183.60,162.51,147.31,139.59,134.34,133.52,13 2.92,130.81,128.80,127.64,126.07,125.03,109.75,56.33,33.29,28.10.

[0248] 6. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-(prop-2-en-1-yl)piperazine-1-thioamide (general formula I-27)

[0249] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was propargylamine. After purification, 201 mg of white solid was obtained, with a yield of 56%. 1 H NMR(400MHz,DMSO-d6)δ8.34–8.28(m,2H),8.17–8.12(m,3H),8.02–7.95(m,2H),7.7 1–7.65(m,2H),4.66(t,J=2.6Hz,2H),3.66(d,J=30.0Hz,4H),3.17(d,J=5.3Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ168.53,159.89,148.96,139.55,134.33,133.52,13 2.91,130.79,128.70,127.69,126.07,125.03,119.42,109.74,66.99,7.43.

[0250] 7. Preparation of N-allyl-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-thioamide (general formula I-28)

[0251] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was allylamine. After purification, 255 mg of white solid was obtained, with a yield of 71%. 1 H NMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.14(d,J=8.6Hz,3H),8.01–7.94 (m,3H),7.73–7.68(m,2H),5.89(ddt,J=17.2,10.5,5.4Hz,1H),5.14(dq,J=

[0252] 17.3,1.8Hz,1H),5.07(dq,J=10.3,1.6Hz,1H),4.20–4.12(m,2H),3.90(d,J=36.7Hz,4H),3.69(s,4H). 13 C NMR(101MHz,DMSO-d6)δ182.13,

[0253] 168.60,147.28,139.54,135.82,134.32,133.49,132.89,132.89,130.81,128.80,127.63,126.05,125.00,119.41,115.94,109.73,49.07,48.20.

[0254] 8. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-propylpiperazine-1-thioamide (general formula I-29)

[0255] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was propylamine. After purification, 224 mg of white solid was obtained, with a yield of 62%. 1 H NMR(400MHz, DMSO-d6)δ8.34–8.28(m,2H),8.14(d,J=8.0Hz,3H),8.00–7.95(m,2H),7.79(t,J=5.3Hz,1H),7 .73–7.68(m,2H),3.87(d,J=33.2Hz,4H),3.68(s,2H),3.46(s,4H),1.62–1.49(m,2H),0.85(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ181.98,168.59,147.29,139.55,134.32,133.50,132.90 ,130.81,128.79,127.63,126.05,125.01,119.41,109.73,47.62,22.34,11.83.

[0256] 9. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-(3-(diethylamino)propyl)piperazine-1-thioamide (general formula I-30)

[0257] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was 3-diethylaminopropylamine. After purification, 296 mg of white solid was obtained, with a yield of 71%. 1H NMR (400MHz, DMSO-d6) δ8.35–8.28(m,2H),8.19–8.07(m,4H),7.99–7.95(m,2H),7.74–7.67(m,2H), 3.91(d,J=35.4Hz,4H),3.74–3.53(m,4H),3.06(s,4H),1.93(d,J=8.3Hz,2H),1.19(t,J=7.2Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ168.60,147.30,139.53,133.52,132.91,128.80,127.66,

[0258] 126.06,125.03,119.41,109.75,48.67,46.48,42.82,36.26,31.24,8.93.

[0259] 10. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-(pyridin-3-yl)piperazine-1-thioamide (general formula I-31)

[0260] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was 3-aminopyridine. After purification, 266 mg of white solid was obtained, with a yield of 69%. 1 H NMR(400MHz, DMSO-d6)δ9.56(s,1H),8.50(d,J=2.5Hz,1H),8.36–8.27(m,3H),8.20–8.10(m,3H),8.02–7.91(m ,2H),7.74(dd,J=7.7,2.9Hz,3H),7.36(dd,J=8.2,4.7Hz,1H),4.05(d,J=39.4Hz,4H),3.66(d,J=103.2Hz,4H). 13 C NMR (101MHz, DMSO-d6) δ182.27,168.63,147.07,145.72,139.51,138.12,134.35,133. 51,133.34,132.92,130.88,128.84,127.67,126.07,125.02,123.41,119.41,109.75.

[0261] 11. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-methylpiperazine-1-thioamide (general formula I-32)

[0262] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was methylamine hydrochloride. After purification, 174 mg of white solid was obtained, with a yield of 51%. 1 H NMR(400MHz, DMSO-d6)δ8.33–8.28(m,2H),8.14(dd,J=6.6,1.8Hz,3H),8.00–7.95(m,2H),7.81 (q,J=4.1Hz,1H),7.73–7.68(m,2H),3.87(d,J=37.6Hz,4H),3.69(s,4H),2.93(d,J=4.1Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ182.72,168.59,147.29,139.56,134.35,134.35,133.51,132.91,130.82,

[0263] 128.79, 127.64, 126.06, 125.01, 119.41, 109.75, 33.07.

[0264] 12. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-cyclopropylpiperazine-1-thioamide (general formula I-33)

[0265] The preparation was carried out in the same manner as step 3 in Example 4, except that one of the raw materials was cyclopropylamine. After purification, 234 mg of white solid was obtained, with a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ8.35–8.28(m,2H),8.18–8.10(m,3H),8.02–7.94(m,2H),7.75(d,J=3.3Hz,1H),7.73–7.67(m, 2H),3.85(d,J=25.9Hz,4H),3.65(d,J=16.8Hz,4H),3.00(tt,J=7.1,3.6Hz,1H),0.73–0.64(m,2H),0.60–0.52(m,2H). 13 C NMR(101MHz,DMSO-d6)δ183.73,168.56,147.29,139.57,134.35,133.51,132.9 2,130.82,128.79,127.64,126.07,125.02,119.41,109.75,46.06,28.89,7.25.

[0266] Example 5: Preparation of imidazothiadiazole derivatives modified with urea groups on piperazine N

[0267] This embodiment aims to prepare imidazothiadiazole derivatives modified with urea groups on piperazine N in the compound of general formula (I), and the preparation route is shown in reaction formula I.

[0268] The structural formula of the imidazothiadiazole derivative modified with a urea group on piperazine N synthesized in this embodiment is as follows:

[0269]

[0270] R2, R4, and R5 are defined as above.

[0271] 1. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-(3-pentyl)piperazin-1-carboxamide (general formula I-34)

[0272] In a 25 mL round-bottom flask, an anhydrous N,N'-dimethylformamide (3 mL) solution of N,N'-carbonyldiimidazole (180 mg, 1.1 mmol) was added. The flask was cooled to approximately 0 °C in an ice bath under nitrogen protection. While stirring, an anhydrous N,N'-dimethylformamide (6 mL) solution of intermediate III-1 (0.3 g, 0.7 mmol) was slowly added. After the addition was complete, the temperature was raised to room temperature, and stirring was continued for 2 h. Subsequently, an anhydrous N,N'-dimethylformamide (3 mL) solution of 3-pentanylamine (126 mg, 1.4 mmol) and N,N'-diisopropylethylamine (378 μL, 2.2 mmol) were added, and the reaction was continued at 60 °C with stirring for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was extracted three times with water and ethyl acetate. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1, v / v) to obtain 145 mg of a white solid, with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.4Hz,2H),8.21–8.10(m,3H),8.00(d,J=8.4Hz,2H),7.71(d,J=8.2H z,2H),6.21(d,J=8.3Hz,1H),3.66(s,1H),3.48–3.36(m,8H),1.50–1.37(m,4H),0.85(t,J=7.4Hz,6H). 13C NMR(101MHz,DMSO-d6)δ168.49,157.93,139.76,134.33,133.49,132.91,132.90 ,130.71,128.70,127.64,126.06,125.00,119.40,109.75,53.32,27.60,11.08.

[0273] 2. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-isopropylpiperazin-1-carboxamide (general formula I-35)

[0274] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was isopropylamine. After purification, 276 mg of white solid was obtained, with a yield of 79%. 1 H NMR(400MHz, DMSO-d6)δ8.32–8.22(m,2H),8.11(dd,J=6.5,1.9Hz,3H),7.99–7.91(m,2H),7.70–7.62(m ,2H),6.31(d,J=7.5Hz,1H),3.77(dq,J=13.4,6.6Hz,1H),3.50(d,J=99.7Hz,8H),1.06(d,J=6.5Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ168.47,157.19,147.24,139.72,134.31,133.45,132 .87,130.70,128.68,127.61,126.02,124.94,119.39,109.70,42.33,23.39.

[0275] 3. Preparation of N-(sec-butyl)-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxamide (general formula I-36)

[0276] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was 2-aminobutane. After purification, 266 mg of white solid was obtained, with a yield of 76%. 1H NMR(400MHz, DMSO-d6)δ8.32–8.27(m,2H),8.12(t,J=4.2Hz,3H),8.00–7.95(m,2H),7.71–7.68(m,2H),7.06–7.01(m,1H), 3.77(tt,J=7.7,6.5Hz,1H),3.59(tt,J=13.9,6.0Hz,8H),1.59–1.49(m,2H),1.17(d,J=6.7Hz,3H),0.82(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.48,157.48,147.20,139.71,134.29,133.40,132.83,130.6 7,128.67,127.57,125.98,124.89,119.37,109.68,49.06,47.80,29.66,21.21,11.27.

[0277] 4. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-neopentylpiperazin-1-carboxamide (general formula I-37)

[0278] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was neopentylamine. After purification, 251 mg of white solid was obtained, with a yield of 68%. 1 H NMR(400MHz, DMSO-d6)δ8.36–8.26(m,2H),8.14(dd,J=6.2,2.2Hz,3H),8.02–7.94(m,2H),7.74–7 .62(m,2H),6.51(t,J=6.2Hz,1H),3.68–3.35(m,8H),2.90(d,J=6.0Hz,2H),0.82(d,J=2.8Hz,9H). 13 C NMR (101MHz, DMSO-d6) δ168.50,158.27,139.76,134.35,133.52,132.92,130.72,128.70,127.66,125.02,109.75,51.39,32.79,27.83.

[0279] 5. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-ethylpiperazine-1-carboxamide (general formula I-38)

[0280] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was ethylamine. After purification, 224 mg of white solid was obtained, with a yield of 66%. 1 H NMR(400MHz,DMSO-d6)δ8.32–8.26(m,2H),8.16–8.08(m,3H),8.00–7.92(m,2H),7.71–7.60(m ,2H),6.60(t,J=5.4Hz,1H),3.50(d,J=96.1Hz,8H),3.11–3.00(m,2H),1.02(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.48,157.68,147.27,139.71,134.33,133.48,132 .88,130.71,128.69,127.64,126.04,124.97,119.40,109.72,35.38,16.02.

[0281] 6. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-NN-(prop-2-en-1-yl)piperazin-1-carboxamide (general formula I-39)

[0282] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was propargylamine. After purification, 194 mg of white solid was obtained, with a yield of 56%. 1 H NMR(400MHz,DMSO-d6)δ8.32(d,J=8.1Hz,2H),8.20–8.07(m,3H),7.99(d,J=8.1Hz,2H),7.6 9(s,2H),7.12(t,J=5.6Hz,1H),4.19–3.94(m,2H),3.86–3.37(m,8H),3.05(t,J=2.5Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ168.52,157.24,139.68,133.52,132.91,132.91,1 30.74,128.70,127.68,125.03,109.74,83.06,72.89,56.49,38.53,30.02.

[0283] 7. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-allylpiperazin-1-carboxamide (general formula I-40)

[0284] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was allylamine. After purification, 247 mg of white solid was obtained, with a yield of 71%. 1 H NMR (400MHz, DMSO-d6) δ8.31–8.24(m,2H),8.17–8.07(m,3H),8.00–7.90(m,2H),7.71–7.61(m,2H),6.81(t,J=5.6Hz,1H),5.82(ddt,J=17 .2,10.3,5.2Hz,1H),5.10(dq,J=17.2,1.8Hz,1H),5.02(dq,J=10.2,1.7Hz,1H),3.68(ddt,J=5.5,3.8,1.7Hz,2H),3.54(d,J=73.4Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ168.50,157.57,147.27,139.71,137.22,134.32,133.48,132 .89,130.72,128.69,127.64,126.04,124.98,119.40,114.97,109.72,47.47,42.98.

[0285] 8. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-propylpiperazin-1-carboxamide (general formula I-41)

[0286] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was propylamine. After purification, 234 mg of white solid was obtained, with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=8.2Hz,2H),8.13(t,J=4.2Hz,3H),7.98(d,J=8.1Hz,2H),7.68(d,J=7.6Hz, 3H), 6.61 (t, J=5.5Hz, 1H), 3.62 (s, 8H), 3.06–2.88 (m, 2H), 1.42 (h, J=8.3, 7.9Hz, 2H), 0.83 (t, J=7.4Hz, 3H). 13 C NMR(101MHz,DMSO-d6)δ168.49,157.81,147.27,139.73,134.34,133.49,132.89 ,130.72,128.69,127.65,126.05,124.99,119.41,109.73,42.43,23.45,11.87.

[0287] 9. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-methylpiperazin-1-carboxamide (general formula I-42)

[0288] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was methylamine hydrochloride. After purification, 234 mg of white solid was obtained, with a yield of 71%. 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=8.4Hz,2H),8.12(dd,J=5.6,2.6Hz,3H),7.97(d,J=8 .5Hz,2H),7.72–7.62(m,2H),6.55(q,J=4.3Hz,1H),3.62(s,8H),2.59(d,J=4.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.49,158.31,147.26,139.71,134.32,133.48, 132.89,130.72,128.68,127.64,126.03,124.97,119.40,109.72,27.60.

[0289] 10. Preparation of 4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)-N-cyclopropylpiperazine-1-carboxamide (general formula I-43)

[0290] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was cyclopropane, and after purification, 206 mg of white solid was obtained, with a yield of 59%. 1 H NMR(400MHz, DMSO-d6)δ8.36–8.28(m,2H),8.13(dd,J=6.0,2.4Hz,3H),8.01–7.95(m,2H),7.71–7.63( m,2H),6.72(d,J=2.8Hz,1H),3.61(s,8H),2.53(s,1H),0.55(td,J=6.9,4.6Hz,2H),0.42–0.35(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.48,158.59,147.28,139.71,134.33,133.50,13 2.90,130.73,128.69,127.65,126.05,125.01,119.41,109.74,23.91,6.41.

[0291] Example 6: Preparation of imidazothiadiazole derivatives modified with phosphoryl groups on piperazine N

[0292] This embodiment aims to prepare imidazothiadiazole derivatives modified with phosphoryl groups on piperazine N in the compound of general formula (I), and the preparation route is shown in reaction formula I.

[0293] The structural formula of the imidazothiadiazole derivative modified with phosphoryl groups on piperazine N synthesized in this embodiment is as follows:

[0294]

[0295] R1 is selected from R2 and R4 are defined as above.

[0296] 1. Preparation of 4-(2-(4-(4-(2-oxo-1,3,2-dioxophosphazenecyclopentan-2-yl)piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-44)

[0297] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was 2-chloro-2-oxo-1,3,2-dioxophosphazenecyclopentane. After purification, 153 mg of a pale yellow solid was obtained, with a yield of 42%. 1 H NMR (400MHz, CDCl3) δ8.16–8.08(m,2H),8.05–7.97(m,2H),7.79–7.66(m,3H),7.62 –7.49(m,2H),4.56–4.41(m,2H),4.41–4.24(m,2H),3.88–3.40(m,4H),3.24(s,4H). 13 C NMR (101MHz, CDCl3) δ170.22,165.82,156.40,140.28,137.22,135.78,132.01,131.81,130.34,12 9.37,129.26,129.11,118.12,112.60,65.83,65.78,46.76,46.71,45.05,45.00.HRMS(ESI+):m / z calcd forC 24 H 22 N6O4PS: 521.1143 [M+H] + ;found:521.1155[M+H] + .

[0298] 2. Preparation of 4-(2-(4-(4-diisopropylphosphonopiperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-45)

[0299] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was diisopropylphosphonic chloride, and after purification, 186 mg of a pale yellow solid was obtained, with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.2Hz,2H),8.00(d,J=8.0Hz,2H),7.74(d,J=8.2Hz,3H),7.57(d,J= 8.0Hz,2H),4.64–4.51(m,2H),3.59(d,J=145.4Hz,4H),3.17(d,J=32.1Hz,4H),1.33–1.19(m,12H). 13 C NMR (101MHz, CDCl3) δ169.15,162.00,139.07,132.88,132.72,131.24,128.30,127.33,124.89,11 8.96,110.63,71.35(d,J=6.0Hz),45.10,42.49,29.79,23.90(t,J=4.4Hz),1.11.HRMS(ESI+):m / z calcd for C 28 H 32 N6O4PS: 579.1932 [M+H] + ;found:579.1938[M+H] + .

[0300] 3. Preparation of ethyl(4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazin-1-yl)ethyl phosphite (general formula I-46)

[0301] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was ethyl ethylphosphonochloride. After purification, 153 mg of a pale yellow solid was obtained, with a yield of 41%. 1H NMR (400MHz, CDCl3) δ8.14–8.06(m,2H),8.04–7.95(m,2H),7.77–7.69(m,3H),7.64–7.53(m,2H),4.24–3.87( m,2H),3.86–3.27(m,4H),3.20(s,4H),1.85–1.57(m,2H),1.30(t,J=7.1Hz,3H),1.14(dt,J=19.6,7.7Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.21,165.82,156.40,140.28,137.22,135.78,132.01,131.81,130.34,129.37,129.26,129.1 1,118.12,112.60,62.17,62.12,46.81,46.77,45.06,45.01,23.76,23.00,16.29,16.24,6.21,6.15.HRMS(ESI+):m / z calcd forC 26 H 25 N6O4PS: 535.1664 [M+H] + Found: 535.1653 [M+H] + .

[0302] 4. Preparation of 4-(2-(4-(4-(5,5-dimethyl-2-oxo-1,3,2-dioxophosphazenecyclopentan-2-yl)piperazin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula I-47)

[0303] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was 2-chloro-5,5-dimethyl-1,3,2-dioxophosphanecyclohexane-2-oxide. After purification, 169 mg of a pale yellow solid was obtained, with a yield of 43%. 1 H NMR (400MHz, CDCl3) δ8.16–8.08(m,2H),8.02–7.95(m,2H),7.79–7.71(m,3H),7.60–7.51(m,2H),4.73–4.15 (m,3H),3.80(dd,J=20.0,10.9Hz,2H),3.38(d,J=10.2Hz,1H),3.22–2.83(m,3H),2.10(s,2H),1.64(s,2H). 13C NMR (101MHz, CDCl3) δ167.82,160.93,138.34,131.75,130.00,126.97,126.15,123.77 ,117.84,109.52,47.96,37.12,30.88,30.22,28.66(d,J=3.7Hz),21.09,19.68,13.11.

[0304] Example 7: Preparation of imidazothiadiazole derivatives modified with acyl groups on the amino N-amino group of 4-aminopiperidine

[0305] This embodiment aims to prepare imidazothiadiazole derivatives with an acyl group modified on the amino N of 4-aminopiperidine in the compound of general formula (I), and the preparation route is shown in reaction formula II.

[0306] The structural formula of the imidazothiadiazole derivative with N-acyl modification of piperazine synthesized in this embodiment is as follows:

[0307]

[0308] R2, R3, R4, and R5 are defined as above.

[0309] 1. Preparation of tert-butyl-4-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperazine-1-carboxylate (Formula I-Y1)

[0310] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was 4-tert-butoxycarbonylaminopiperidine. After drying, 17.9 g of yellow solid was obtained and directly proceeded to the next reaction without purification. 1 H NMR (500MHz, CDCl3) δ8.03–7.98(m,2H),7.97–7.89(m,4H),7.88–7.82(m,2H),4.55(d,J =7.1Hz,1H),3.70–3.63(m,3H),3.25–3.21(m,2H),2.10–2.05(m,2H),1.79–1.75(m,2H). 13 C NMR (125MHz, CDCl3) δ171.22,167.75,160.05,157.33,137.82,135.64,136.58,134.25,13 2.76,130.08,128.25,127.72,127.35,117.15,113.55,80.38,48.01,44.88,32.12,29.31.

[0311]

[0312] 2. Preparation of tert-butyl(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)(methyl)carbamate (formula I-Y2)

[0313] The preparation was carried out in the same manner as step 1 in Example 2, except that one of the raw materials was tert-butyl methyl (piperidin-4-yl)carbamate. After drying, 18.3 g of yellow solid was obtained and directly proceeded to the next reaction without purification. 1 H NMR(500MHz, CDCl3)δ8.05–8.00(m,1H),7.95–7.87(m,2H),7.82–7.76(m,1H),3.78–3.6 4(m,2H),3.21–3.17(m,1H),2.80(d,J=1.4Hz,2H),2.21–2.16(m,1H),1.93–1.86(m,1H). 13 CNMR (125MHz, CDCl3) δ171.22,167.75,160.05,157.85,137.82,135.64,136.58,134.25,132.7 6,130.08,128.25,127.72,127.35,117.15,113.55,81.18,55.87,44.85,35.01,30.28,27.25.

[0314]

[0315] 3. Preparation of tert-butyl(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-fluorobenzoyl)piperidin-4-yl)carbamate (Formula I-Y3)

[0316] The preparation was carried out in the same manner as step 1 in Example 2, except that the two raw materials were intermediates II-3 and 4-tert-butoxycarbonylaminopiperidine. After drying, 18.7 g of yellow solid was obtained and directly proceeded to the next reaction without purification. 1 H NMR (500MHz, CDCl3) δ7.98–7.90(m,3H),7.99–7.83(m,2H),7.77(dd,J=7.3,2.2Hz,1H),7.64(dd,J=12.1,2. 1Hz,1H),4.50(d,J=7.1Hz,1H),3.71–3.65(m,3H),3.32–3.29(m,2H),2.14–2.11(m,2H),1.87–1.84(m,2H). 13C NMR (125MHz, CDCl3)δ

[0317] 168.35,166.31,167.05,164.93,162.43,159.44,157.45,157.33,137.61,134.58,135.08,133.03,132.10,129.11,131.06,127.72,129.62,127.59,127.28,125.95,123.83,120.23,118.06,117.09,113.57,80.38,48.00,44.85,32.08,29.32.

[0318]

[0319] 4. Preparation of 4-(2-(4-(4-aminopiperidin-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (intermediate V-1)

[0320] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-Y1. After purification, 7.0 g of yellow solid was obtained, with a two-step yield of 82%. 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.2Hz,2H),7.98(d,J=8.0Hz,2H),7.77–7.71(m,3H),7.56(d,J=7. 9Hz,2H),4.69–4.46(m,2H),3.71(s,2H),3.23–2.89(m,2H),1.97(s,2H),1.74(s,2H),1.43(s,9H). 13 C NMR (125MHz, CDCl3) δ169.55,165.39,166.55,163.78,161.25,160.25,158.87,136.56,137.23,136.21,132.09,131. 60,130.14,132.36,128.69,130.24,128.12,127.28,125.95,123.83,120.23,118.06,117.09,113.57,49.74,36.05.

[0321]

[0322] 5. Preparation of 4-(2-(4-(4-(4-methylamino-1-piperidinyl)-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (intermediate V-2)

[0323] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-Y2. After purification, 6.5 g of yellow solid was obtained, with a two-step yield of 74%. 1 H NMR (500MHz, CDCl3) δ8.07–7.02(m,2H),7.95–7.87(m,4H),7.80–7.75(m,2H),3.75(m,2H),3.34– 3.25(m,3H),2.87–2.84(m,1H),2.34–2.28(dd,J=4.8,1.6Hz,3H),2.06(m,2H),1.87–1.76(m,2H). 13 C NMR (125MHz, CDCl3) δ171.22,167.75,160.05,137.82,135.64,136.58,134.25,132 .76,130.08,128.25,127.72,127.35,117.15,113.55,57.65,45.01,34.36,32.84.

[0324]

[0325] 6. Preparation of 4-(2-(4-(4-aminopiperidin-1-carbonyl)-3-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (intermediate V-3)

[0326] The preparation was carried out in the same manner as step 8 in Example 2, except that one of the raw materials was compound I-Y3. After purification, 6.1 g of yellow solid was obtained, with a two-step yield of 68%. 1 H NMR (500MHz, CDCl3) δ7.96–7.88(m,3H),7.85–7.79(m,2H),7.73(dd,J=7.3,2.2Hz,1H),7.56(dd,J=12.2,2.2Hz, 1H),3.68–3.57(m,2H),3.29–3.21(m,2H),3.11–3.05(m,1H),2.06–2.01(m,2H),1.80–1.70(m,2H),1.40(s,2H). 13C NMR (125MHz, CDCl3) δ168.35,166.31,167.05,164.93,162.43,159.44,157.45,137.61,134.58,135.08,133.03,132.10, 129.11,131.06,127.72,129.62,127.59,127.28,125.95,123.83,120.23,118.06,117.09,113.57,49.74,44.92,35.05.

[0327]

[0328] 7. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)acetamide (general formula II-48)

[0329] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate compound V-1, which was purified to give 234 mg of white solid, with a yield of 71%. 1 H NMR (500MHz, CDCl3) δ8.13–8.02(m,2H),7.98–7.88(m,4H),7.84–7.78(m,2H),6.33(d,J=7 .7Hz,1H),3.61–3.48(m,3H),3.16(ddd,J=12.8,8.6,5.9Hz,2H),2.05(m,2H),1.73(m,2H).

[0330] 8. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-cyclopropylformamide (general formula II-49)

[0331] The preparation was carried out in the same manner as step 15 in Example 2, except that the raw materials were intermediate compound V-1 and cyclopropylformyl chloride. After purification, 271 mg of white solid was obtained, with a yield of 78%. 1H NMR (500MHz, CDCl3) δ8.13–8.06(m,2H),7.99–7.92(m,4H),7.88–7.83(m,2H),6.50(d,J=8.1Hz,1H),3.58–3.43(m,3H),3.18(ddd,J=12.8 ,8.6,5.9Hz,2H),2.18(p,J=5.5Hz,1H),2.06(dddd,J=13.1,8.6,6.0,4.5Hz,2H),1.79–1.69(m,2H),1.11–1.03(m,2H),0.94–0.83(m,2H).

[0332] 9. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-N-methylacetamide (general formula 2I-50)

[0333] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate compound V-2. After purification, 234 mg of white solid was obtained, with a yield of 69%. 1 H NMR (500MHz, CDCl3) δ8.24–8.13(m,2H),7.98–7.88(m,4H),7.79–7.75(m,2H),3.72(m,1H),3.54(ddd,J=12.1,8 .1,5.4Hz,2H),3.31(ddd,J=12.1,8.1,5.4Hz,2H),2.76(d,J=1.4Hz,3H),2.07–1.97(m,2H),1.80–1.70(m,2H).

[0334] 10. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-N-methylcyclopropylformamide (general formula II-51)

[0335] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate compound V-2. After purification, 268 mg of white solid was obtained, with a yield of 75%. 1H NMR (500MHz, CDCl3) δ8.13–8.06(m,2H),8.04–7.92(m,4H),7.90–7.84(m,2H),3.52(pq,J=6.0,1.5Hz,1H),3.48(ddd,J=12.1,8.1,5.4Hz,2H) ,3.19(ddd,J=12.1,8.1,5.4Hz,2H),2.80(d,J=1.5Hz,3H),2.20–2.11( m,2H),2.00(m,1H),1.83(s,2H),1.11–1.03(m,2H),0.89–0.76(m,2H).

[0336] 11. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)-2-fluorobenzoyl)piperidin-4-yl)acetamide (general formula II-52)

[0337] The preparation was carried out in the same manner as step 15 in Example 2, except that one of the raw materials was intermediate compound V-3, which was purified to give 222 mg of white solid, with a yield of 65%. 1 H NMR (500MHz, CDCl3) δ8.24–8.16(m,3H),8.01–7.91(m,2H),7.70(dd,J=7.3,2.2Hz,1H),7.51(dd,J=12.1,2.2H z,1H),6.48(d,J=7.7Hz,1H),3.65–3.49(m,3H),3.33(ddd,J=12.8,8.7,5.9Hz,2H),2.01(m,2H),1.95(m,2H).

[0338] Example 8: Preparation of imidazothiadiazole derivatives modified with sulfonyl groups on the amino N-group of 4-aminopiperidine

[0339] This embodiment aims to prepare imidazothiadiazole derivatives modified with sulfonyl groups on the amino N of 4-aminopiperidine in the compound of general formula (I), and the preparation route is shown in reaction formula II.

[0340] The structural formula of the imidazothiadiazole derivative modified with a sulfonyl group on the amino N-amino group of 4-aminopiperidine synthesized in this embodiment is as follows:

[0341]

[0342] R2, R3, R4, and R5 are defined as above.

[0343] 1. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)ethylsulfonamide (general formula II-53)

[0344] The preparation was carried out in the same manner as step 1 in Example 3, except that the raw materials were intermediate compound V-1 and ethyl sulfonyl chloride. After purification, 142 mg of a pale yellow solid was obtained, with a yield of 39%. 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.1Hz,2H),7.99(d,J=7.9Hz,2H),7.74(d,J=8.0Hz,3H),7.57(d,J=7.9Hz,2H) ,7.29(d,J=33.2Hz,1H),4.62(d,J=6.7Hz,1H),3.79–2.92(m,6H),2.03(s,2H),1.70(s,2H),1.07–0.58(m,3H). 13 C NMR (101MHz, CDCl3) δ172.08,170.25,161.08,136.87,136.64,135.62,133.28,131.82,131.1 3,129.21,128.75,128.32,118.12,112.60,48.53,48.30,43.61,30.97,7.59.HRMS(ESI+):m / z calcd for C 25 H 25 N6O3S2: 521.1410 [M+H] + ;found:521.1424[M+H] + .

[0345] 2. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-cyclopropylsulfonamide (general formula II-54)

[0346] The preparation was carried out in the same manner as step 1 in Example 3, except that the raw materials were intermediate compound V-1 and cyclopropylsulfonyl chloride. After purification, 153 mg of a pale yellow solid was obtained, with a yield of 41%. 1H NMR (400MHz, CDCl3) δ8.16–8.08(m,2H),8.03–7.96(m,2H),7.79–7.71(m,3H),7.61–7.54(m,2H),7.25(s,1H),4.55(d,J=7 .7Hz,1H),3.84–3.55(m,2H),3.10(q,J=7.3Hz,2H),2.44(s,1H),1.68(s,4H),1.02(d,J=8.1Hz,2H),0.86(t,J=6.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.08,170.25,161.08,136.87,136.64,135.62,133.28,131.82,131.13 ,129.21,128.75,128.32,118.12,112.60,47.94,43.61,37.37,30.98,10.18.HRMS(ESI+):m / z calcd for C 26 H 25 N6O3S2: 533.1411[M+H] + Found: 533.1424 [M+H] + .

[0347] 3. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)propylsulfonamide (general formula II-55)

[0348] The preparation was carried out in the same manner as step 1 in Example 3, except that the raw materials were intermediate compound V-1 and propylsulfonyl chloride. After purification, 183 mg of a pale yellow solid was obtained, with a yield of 49%. 1 H NMR (400MHz, CDCl3) δ8.16–8.09(m,2H),8.04–7.97(m,2H),7.79–7.72(m,3H),7.61–7.54(m,2H), 4.18(d,J=7.7Hz,1H),3.86–3.46(m,2H),3.28–2.93(m,5H),2.23–1.75(m,5H),0.93–0.79(m,3H). 13C NMR (101MHz, CDCl3) δ172.08,170.25,161.08,136.87,136.64,135.62,133.28,131.82,131.13,12 9.21,128.75,128.32,118.12,112.60,55.14,48.41,43.61,30.97,19.15,12.97.HRMS(ESI+):m / z calcd for C 26 H 27 N6O3S2: 535.1567 [M+H] + Found: 535.1581 [M+H] + .

[0349] 4. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-4-methylbenzenesulfonamide (general formula II-56)

[0350] The preparation was carried out in the same manner as step 1 in Example 3, except that the raw materials were intermediate compound V-1 and p-toluenesulfonyl chloride. After purification, 167 mg of a pale yellow solid was obtained, with a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ8.29 (ddd, J=7.8, 5.5, 2.2Hz, 2H), 8.11 (ddd, J=10.5 ,5.8,2.4Hz,3H),7.97(dt,J=8.7,2.8Hz,2H),7.80(d,J=6.9Hz,1H),7.76–7. 66(m,2H),7.58(dd,J=8.4,1.8Hz,1H),7.39(d,J=8.0Hz,1H),4.18(d,J=11. 2Hz,1H),3.13–2.94(m,2H),2.56(s,2H),2.38(s,3H),0.98(t,J=7.0Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ166.13,160.39,145.18,140.95,137.83,137.37,132.25,131.41,130.83,128.53,1 28.09,126.26,125.59,124.75,123.97,122.93,117.32,107.66,48.17,44.10,19.37,9.48.HRMS(ESI+):m / z calcd forC 30 H 27 N6O3S2: 583.1565 [M+H]+ ;found:583.1581[M+H] + .

[0351] 5. Preparation of N-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-N-methylmethanesulfonamide (general formula II-57)

[0352] The preparation was carried out in the same manner as step 1 in Example 3, except that one of the raw materials was intermediate compound V-2. After purification, 171 mg of a pale yellow solid was obtained, with a yield of 47%. 1 H NMR (400MHz, CDCl3) δ8.01–7.96(m,2H),7.94–7.86(m,4H),7.86–7.80(m,2H),3.68–3.55(m,3H),3.25(ddd,J=12.1,8.1,5 .4Hz,2H),2.75(d,J=1.4Hz,3H),2.71(s,3H),2.17(m,J=11.0,8.1,6.8,5.3Hz,2H),1.90(m,J=11.0,8.1,6.9,5.4Hz,2H). 13 C NMR (101MHz, CDCl3) δ172.08,170.25,161.08,136.87,136.64,135.62,133.28,131.82 ,131.13,129.21,128.75,128.32,118.12,112.60,54.78,43.66,37.92,33.38,29.14.

[0353] Example 9: Preparation of imidazothiadiazole derivatives modified with thiourea groups on the amino N-group of 4-aminopiperidine

[0354] This embodiment aims to prepare imidazothiadiazole derivatives modified with thiourea groups on the amino N of 4-aminopiperidine in the compound of general formula (I), and the preparation route is shown in reaction formula II.

[0355] The structural formula of the imidazothiadiazole derivative modified with a thiourea group on the amino N-amino group of 4-aminopiperidine synthesized in this embodiment is as follows:

[0356]

[0357] R2, R3, R4, and R5 are defined as above.

[0358] 1. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-ethylthiourea (general formula 2I-58)

[0359] The preparation was carried out in the same manner as step 1 in Example 4, except that one of the raw materials was intermediate compound V-1. After purification, 303 mg of white solid was obtained, with a yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ8.26–8.14(m,2H),8.10–7.99(m,3H),7.88(d,J=8.5Hz,2H),7.58(d,J=8.0Hz,2H),7.32(s,2H),4.29 (d,J=37.6Hz,2H),3.61–3.46(m,1H),3.21–3.09(m,1H),2.95(s,1H),2.04–1.74(m,2H),1.36(s,2H),1.02(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.27,162.41,147.20,140.06,134.25,133.40,132.82,13 0.57,128.35,127.61,125.98,124.88,119.38,109.67,46.48,32.31,31.59,14.91.

[0360] 2. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(4-methoxybenzyl)thiourea (general formula II-59)

[0361] The preparation was carried out in the same manner as step 1 in Example 4, except that the raw materials were intermediate compound V-1 and 4-methoxybenzyl isothiocyanate. After purification, 336 mg of white solid was obtained, with a yield of 79%. 1H NMR(400MHz, DMSO-d6)δ8.33–8.28(m,2H),8.13(dd,J=5.7,2.7Hz,3H),8.01–7.95(m,2H),7.86–7.68(m,1H),7.67–7.61(m,2H),7.47(s,1H) ),7.26–7.20(m,2H),6.92–6.86(m,2H),4.57(s,2H),3.73(s,3H),3.5 4(d,J=7.4Hz,2H),3.16(s,2H),2.08–1.80(m,2H),1.51–1.32(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.28,162.51,158.79,147.29,140.11,134.32,133.50,132 .92,130.61,129.26,128.38,127.69,126.06,125.02,119.41,114.18,109.75,55.55.

[0362] 3. Preparation of 1-(sec-butyl)-3-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)thiourea (general formula 2I-60)

[0363] The preparation was carried out in the same manner as step 1 in Example 4, except that the raw materials were intermediate compound V-1 and butane 2-isothiocyanate. After purification, 346 mg of white solid was obtained, with a yield of 91%. 1 H NMR(400MHz,DMSO-d6)δ8.33–8.26(m,2H),8.15–8.10(m,3H),8.00–7.94(m ,2H),7.68–7.61(m,2H),7.26–7.15(m,2H),3.54(d,J=13.5Hz,2H),3.17(d ,J=5.3Hz,2H),3.02(s,1H),2.07–1.81(m,2H),1.48(ddd,J=17.5,12.0,6. 9Hz, 2H), 1.30 (d, J = 61.7Hz, 2H), 1.10–1.01 (m, 3H), 0.84 (t, J = 7.4Hz, 3H). 13C NMR(101MHz,DMSO-d6)δ168.26,162.49,147.27,140.12,134.31,133.48,132.90,13 0.60,128.38,127.67,126.05,124.99,119.40,109.73,49.08,29.27,20.30,10.80.

[0364] 4. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-hexylthiourea (general formula II-61)

[0365] The preparation was carried out in the same manner as step 1 in Example 4, except that the raw materials were intermediate compound VII-1 and hexyl isothiocyanate. After purification, 324 mg of white solid was obtained, with a yield of 81%. 1 H NMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.17–8.10(m,3H),8.00–7.94(m,2H ),7.67–7.61(m,2H),7.32(s,2H),4.48–4.01(m,2H),3.69–3.40(m,2H),3.17(d ,J=5.2Hz,2H),2.98(d,J=16.7Hz,1H),2.45(d,J=22.6Hz,2H),2.06–1.78(m,2 H),1.52–1.44(m,2H),1.43–1.35(m,2H),1.27–1.21(m,4H),0.93–0.80(m,3H). 13 C NMR(101MHz,DMSO-d6)δ168.27,162.49,147.27,140.11,134.31,133.49,132.90,130.6 1,128.37,127.68,126.05,124.99,119.40,109.73,31.49,29.19,26.57,22.56,14.41.

[0366] 5. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(3-(diethylamino)propyl)thiourea (general formula 2I-62)

[0367] The preparation was carried out in the same manner as step 1 in Example 4, except that the raw materials were intermediate compound V-1 and hexyl isothiocyanate. After purification, 336 mg of white solid was obtained, with a yield of 80%. 1H NMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.17–8.11(m,3H),8.00–7.94(m, 2H),7.67–7.61(m,2H),7.41(d,J=30.4Hz,2H),4.32(d,J=40.1Hz,2H),3.54( s,2H),3.09(d,J=75.1Hz,2H),2.47(s,1H),2.38(t,J=7.0Hz,2H),2.05–1.8 1(m,3H),1.59(p,J=7.0Hz,2H),1.40(d,J=5.9Hz,2H),0.94(t,J=7.1Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ168.28,162.51,147.29,140.12,134.31,133.50,132.92 ,130.62,128.36,127.70,126.08,125.03,119.40,109.76,50.44,46.68,12.04.

[0368] 6. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(pyridin-3-yl)thiourea (general formula II-63)

[0369] The preparation was carried out in the same manner as step 1 in Example 4, except that the raw materials were intermediate compound V-1 and pyridine isothiocyanate. After purification, 312 mg of white solid was obtained, with a yield of 79%. 1 H NMR(400MHz, DMSO-d6)δ9.54(s,1H),8.55(d,J=2.6Hz,1H),8.35–8.26(m,3H),8.18–8.11(m,3H),8.04–7.91(m ,4H),7.68–7.61(m,2H),7.35(dd,J=8.2,4.7Hz,1H),3.18(s,2H),3.03(s,1H),2.10–1.95(m,2H),1.50(s,2H). 13 C NMR(101MHz,DMSO-d6)δ162.52,147.30,140.10,134.32,133.51,132.93, 130.65,128.38,127.72,126.09,125.05,123.66,119.41,109.77,55.39.

[0370] 7. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(pent-3-yl)thiourea (general formula 2I-64)

[0371] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and 3-aminopentane. After purification, 238 mg of white solid was obtained, with a yield of 61%. 1 H NMR(400MHz,DMSO-d6)δ8.32–8.26(m,2H),8.12(d,J=8.7Hz,3H),7.99–7.93 (m,2H),7.67–7.62(m,2H),7.18(dd,J=29.3,7.2Hz,2H),4.23(d,J=94.3Hz,2 H),3.55(d,J=13.2Hz,2H),3.05(d,J=15.9Hz,1H),2.74(d,J=0.6Hz,1H),2. 08–1.83(m,2H),1.57–1.46(m,2H),1.44–1.22(m,4H),0.83(t,J=7.4Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ168.27,162.48,147.25,140.12,134.29,133.46,132.89,130.59,128.37,127.66,

[0372] 126.04, 124.98, 119.39, 109.73, 46.42, 36.26, 26.84, 10.58.

[0373] 8. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-isopropylthiourea (general formula II-65)

[0374] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and isopropylamine. After purification, 330 mg of white solid was obtained, with a yield of 89%. 1H NMR (400MHz, DMSO-d6) δ8.32–8.26(m,2H),8.12(d,J=8.4Hz,3H),7.99–7.94(m,2H),7.67–7.62(m,2H),7.20(d,J=7.9Hz,2H),4.27(s,1H ),3.54(d,J=13.0Hz,2H),3.27–2.93(m,2H),2.73(d,J=0.6Hz,1H),1.94(d,J=44.9Hz,2H),1.40(d,J=7.9Hz,2H),1.10(d,J=6.5Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ168.26,162.48,147.26,140.11,134.29,133.47,132 .89,130.60,128.37,127.66,126.05,124.99,119.39,109.73,32.33,22.80.

[0375] 9. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-neopentylthiourea (general formula II-66)

[0376] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and neopentylamine. After purification, 211 mg of white solid was obtained, with a yield of 54%. 1 H NMR(400MHz, DMSO-d6)δ8.34–8.27(m,2H),8.13(dd,J=7.0,1.5Hz,3H),8.01–7.95(m,2H),7.69–7.61(m,2H),7.4 1(s,1H),7.25(s,1H),3.53(s,2H),3.27(s,2H),3.06(s,2H),2.08–1.88(m,2H),1.51–1.30(m,2H),0.88(s,9H). 13 C NMR(101MHz,DMSO-d6)δ168.29,162.54,147.28,140.12,

[0377] 134.27,133.50,132.90,130.60,128.39,127.68,126.06,125.02,119.41,109.75,55.39,49.08,32.34,27.77.

[0378] 10. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(prop-2-en-1-yl)thiourea (general formula diI-67)

[0379] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and propargylamine. After purification, 202 mg of white solid was obtained, with a yield of 55%. 1 H NMR(400MHz,DMSO-d6)δ8.34–8.26(m,2H),8.18–8.07(m,3H),8.00–7.91(m,2H),7.67–7.58(m,2H),4.59–4.30(m,2H) ,3.79(d,J=10.6Hz,2H),3.25–3.12(m,2H),3.07(d,J=13.5Hz,1H),2.73(s,1H),2.05–1.79(m,2H),1.42–1.27(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.36,162.56,

[0380] 147.30,134.21,133.50,132.87,130.60,128.35,127.71,126.06,125.05,119.41,109.73,31.27.

[0381] 11. Preparation of 1-allyl-3-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)thiourea (general formula 2I-68)

[0382] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and allylamine. After purification, 225 mg of white solid was obtained, with a yield of 61%. 1 H NMR(400MHz, DMSO-d6)δ8.34–8.26(m,2H),8.17–8.08(m,3H),8.01–7.93(m,2H),7.68–7.60(m,2H),7.48(s,2H),5.91–5.81(m,1H),5.7 6(s,1H),5.21–5.05(m,2H),4.36(s,1H),3.55(d,J=14.0Hz,2H),3.10(d,J=74.8Hz,2H),1.93(d,J=51.3Hz,2H),1.40(d,J=24.0Hz,2H). 13C NMR(101MHz,DMSO-d6)δ168.28,162.49,147.27,140.09,135.59,134.30,133.49,132 .89,130.60,128.37,127.68,126.04,124.99,119.41,115.97,109.72,55.39,31.54.

[0383] 12. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-propylthiourea (general formula II-69)

[0384] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and propylamine. After purification, 245 mg of white solid was obtained, with a yield of 66%. 1 H NMR (400MHz, DMSO-d6) δ8.32–8.25(m,2H),8.16–8.07(m,3H),7.99–7.90(m,2H),7.66–7.59(m,2H),7.35(d,J=24.4Hz,2H),4.32(d, J=38.0Hz,2H),3.31(s,2H),3.05–2.89(m,1H),1.91(d,J=55.1Hz,2H),1.49–1.41(m,2H),1.40–1.15(m,2H),0.84(q,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.34,162.53,147.28,140.04,134.19,133.47,132.86 ,130.59,128.35,127.69,126.05,125.02,119.40,109.72,40.45,22.47,11.82.

[0385] 13. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-methylthiourea (general formula 2I-70)

[0386] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and methylamine hydrochloride. After purification, 249 mg of white solid was obtained, with a yield of 71%. 1H NMR (400MHz, DMSO-d6) δ8.34–8.28(m,2H),8.17–8.10(m,3H),8.00–7.95(m,2H),7.67–7.60(m,2H),7.40(s,2 H),3.55(s,2H),3.18(s,2H),3.03–2.82(m,3H),2.77–2.53(m,1H),2.04–1.77(m,2H),1.42(d,J=6.5Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ168.31,162.53,147.30,

[0387] 140.08,134.27,133.50,132.90,130.62,128.35,127.71,126.07,125.03,119.42,109.74,55.46–55.28(m).

[0388] 14. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-cyclopropylthiourea (general formula II-71)

[0389] The preparation was carried out in the same manner as step 3 in Example 4, except that the raw materials were intermediate compound V-1 and cyclopropylamine. After purification, 240 mg of white solid was obtained, with a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ8.33–8.27(m,2H),8.17–8.10(m,3H),8.00–7.93(m,2H),7.84(s,1H),7.67–7.59(m,2H),7.25(d,J=8.1Hz,1H),4.12(q,J =5.2Hz,2H),3.63(d,J=54.6Hz,2H),3.04–2.85(m,1H),1.90(d,J=53.7H z,2H),1.69–1.34(m,2H),0.69(dd,J=6.9,2.0Hz,2H),0.55–0.39(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.26,162.48,147.27,140.11,134.32,133.48,13 2.90,130.63,128.33,127.71,126.05,124.99,119.40,109.73,49.08,7.36.

[0390] Example 10: Preparation of imidazothiadiazole derivatives modified with urea groups on the amino N-amino group of 4-aminopiperidine

[0391] This embodiment aims to prepare imidazothiadiazole derivatives modified with urea groups on the amino N of 4-aminopiperidine in the compound of general formula (I), and the preparation route is shown in reaction formula II.

[0392] The structural formula of the imidazothiadiazole derivative modified with a urea group on the amino N-amino group of 4-aminopiperidine synthesized in this embodiment is as follows:

[0393]

[0394] R2, R3, R4, and R5 are defined as above.

[0395] 1. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(pentan-3-yl)urea (general formula II-72)

[0396] The preparation was carried out in the same manner as step 1 in Example 5, except that one of the raw materials was intermediate compound V-1. After purification, 193 mg of white solid was obtained, with a yield of 51%. 1 H NMR(400MHz, DMSO-d6)δ8.33–8.28(m,2H),8.12(dd,J=5.9,2.6Hz,3H),7.99–7.95 (m,2H),7.66–7.61(m,2H),5.75(d,J=7.7Hz,1H),5.54(d,J=8.8Hz,1H),4.31(d,J= 17.2Hz,1H),3.72–3.45(m,2H),3.34–3.11(m,2H),3.04(s,1H),1.83(d,J=39.9Hz ,2H),1.40(ddd,J=13.0,7.4,5.5Hz,2H),1.33–1.20(m,4H),0.81(t,J=7.4Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ168.26,162.51,147.27,140.22,134.29,134.29,133.48,13 2.90,130.55,128.35,127.66,126.05,125.01,109.74,51.81,46.60,27.73,10.66.

[0397] 2. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-isopropylurea (general formula II-73)

[0398] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and isopropylamine. After purification, 298 mg of white solid was obtained, with a yield of 83%. 1 H NMR (400MHz, DMSO-d6) δ8.34–8.28(m,2H),8.19–8.08(m,3H),8.00–7.94(m,2H),7.67–7.59(m,2H),5.76(d,J=7.7Hz,1H),5.62(d,J=7.7Hz,1H ),4.29(s,1H),3.70–3.65(m,1H),3.63–3.37(m,2H),3.23–3.01(m,2H) ,1.81(d,J=40.9Hz,2H),1.25(d,J=20.8Hz,2H),1.02(d,J=6.5Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ168.24,162.51,140.22,133.49,132.93,130.56,128.35,127.67,125.03,119.40,119.40,109.75,46.50,41.26,23.71.

[0399] 3. Preparation of 1-(tert-butyl)-3-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)urea (general formula II-74)

[0400] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and 2-aminobutane. After purification, 299 mg of white solid was obtained, with a yield of 81%. 1H NMR(400MHz,DMSO-d6)δ8.33–8.27(m,2H),8.15–8.08(m,3H),7.99–7.94(m,2H),7.66–7 .61(m,2H),5.77(d,J=7.7Hz,1H),5.60(d,J=8.2Hz,1H),4.32(dd,J=22.7,10.0Hz,1H), 3.66(d,J=7.0Hz,1H),3.57–3.40(m,2H),3.11(d,J=52.8Hz,2H),1.82(d,J=39.4Hz,2H) ,1.35(d,J=7.2Hz,2H),1.31–1.18(m,2H),0.99(d,J=6.5Hz,3H),0.82(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.25,162.51,147.27,140.22,134.29,133.48,132.90,132.9 0,130.55,128.34,127.66,125.00,119.40,109.74,46.54,46.49,30.03,21.33,10.78.

[0401] 4. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-neopentylurea (general formula II-75)

[0402] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and neopentylamine. After purification, 209 mg of white solid was obtained, with a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ8.34–8.27(m,2H),8.17–8.09(m,3H),8.01–7.95(m,2H),7.67–7.60(m,2H),5.94(d,J=7.7Hz,1H),5.85(t,J=6.1Hz,1H) ,4.37–4.20(m,1H),3.73–3.44(m,2H),3.13(dd,J=44.1,12.8Hz,2H),2 .81(d,J=6.1Hz,2H),1.94–1.71(m,2H),1.39–1.25(m,2H),0.81(s,9H). 13C NMR(101MHz,DMSO-d6)δ168.25,162.51,140.23,134.33,133.50,132.92,130.5 5,128.36,127.67,126.05,125.01,119.41,109.73,50.95,46.56,32.33,27.58.

[0403] 5. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-ethylurea (general formula 2I-76)

[0404] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and ethylamine. After purification, 150 mg of white solid was obtained, with a yield of 43%. 1 H NMR (400MHz, DMSO-d6) δ8.34–8.29(m,2H),8.13(dd,J=7.0,1.5Hz,3H),8.01–7.96(m,2H),7.67–7.61(m,2H),5.86(d,J=7.7Hz,1H),5.74(t,J=5.6H z,1H),4.32(dd,J=12.8,7.7Hz,1H),3.74–3.44(m,2H),3.16(s,2H),3.03 –2.97(m,2H),1.92–1.69(m,2H),1.35–1.22(m,2H),0.98(t,J=7.1Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ168.24,157.71,140.23,134.33,133.52,130.58,128.35,127.69,126.07,125.04,119.79,119.42,46.60,34.45,16.16.

[0405] 6. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazol[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-(prop-2-en-1-yl)urea (general formula diI-77)

[0406] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and propargylamine. After purification, 75 mg of white solid was obtained, with a yield of 21%. 1H NMR (400MHz, DMSO-d6) δ8.35–8.27(m,2H),8.17–8.09(m,3H),8.01–7.94(m,2H),7.68–7.60(m,2H),6.16(t,J=5.8Hz,1H),6.11(d,J=7.7Hz,1H ),4.30(d,J=13.2Hz,1H),3.79(dd,J=5.8,2.5Hz,2H),3.73–3.43(m,2H ),3.33–3.10(m,2H),3.05(s,1H),1.92–1.69(m,2H),1.41–1.28(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.25,162.53,140.20,134.34,133.51,132.93,132.9 3,130.58,128.35,127.69,125.02,119.42,109.74,83.01,73.05,46.76,29.19.

[0407] 7. Preparation of 1-allyl-3-(1-(4-(5-(4-cyanophenyl)imidazol[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)urea (general formula II-78)

[0408] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and allylamine. After purification, 165 mg of white solid was obtained, with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=8.2Hz,2H),8.13(d,J=7.4Hz,3H),7.98(d,J=8.3Hz,2H),7.6 4(d,J=7.9Hz,2H),6.11(d,J=7.7Hz,1H),6.02(t,J=5.8Hz,1H),5.81(ddt,J=17.3,10.3,5.1Hz ,1H),5.10(dq,J=17.3,2.0Hz,1H),5.05–4.95(m,1H),3.64(d,J=5.7Hz,2H),3.61(d,J=1.9Hz, 1H),3.51(d,J=13.2Hz,2H),3.12(d,J=43.3Hz,2H),1.81(d,J=48.4Hz,2H),1.44–1.27(m,2H). 13CNMR(101MHz,DMSO-d6)δ168.24,162.52,140.22,137.30,133.51,132.92,130.56,128.35,127.68,126.06,125.02,114.77,109.74,42.05.

[0409] 8. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazolium[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-propylurea (general formula II-79)

[0410] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and propylamine. After purification, 234 mg of white solid was obtained, with a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=8.2Hz,2H),8.13(d,J=7.3Hz,3H),7.98(d, J=8.2Hz,2H),7.64(d,J=8.0Hz,2H),5.85(d,J=7.6Hz,1H),5.79(t,J=5.8Hz,1 H),3.66(s,1H),3.49(s,2H),3.13–2.99(m,2H),2.94(q,J=6.6Hz,2H),1.94– 1.66(m,2H),1.43–1.35(m,2H),1.26(d,J=20.8Hz,2H),0.83(t,J=7.4Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ140.22,133.51,130.57,128.35,127.68,125.02,109.75,49.07,46.61,41.46,23.68,11.83.

[0411] 9. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-methylurea (general formula 2I-80)

[0412] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and methylamine hydrochloride. After purification, 207 mg of white solid was obtained, with a yield of 61%. 1H NMR (400MHz, DMSO-d6) δ8.35–8.27(m,2H),8.13(d,J=7.7Hz,3H),8.02–7.92(m,2H),7.66–7.58(m,2H),6.03(d,J=7.8Hz,1H),5.75(q,J=4.7H z,1H),4.29(d,J=13.0Hz,1H),3.59(dd,J=62.4,10.5Hz,2H),3.26–2.95(m,2H),2.54(d,J=4.7Hz,3H),1.92–1.66(m,2H),1.40–1.27(m,2H). 13 C NMR (101MHz, DMSO-d6) δ168.23,158.45,140.22,134.33,133.51,132.92,130.56,128.34,127.68,126.05,125.01,109.74,46.64,26.74.

[0413] 10. Preparation of 1-(1-(4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)-3-cyclopropylurea (general formula II-81)

[0414] The preparation was carried out in the same manner as step 1 in Example 5, except that the raw materials were intermediate compound V-1 and methylamine hydrochloride. After purification, 251 mg of white solid was obtained, with a yield of 70%. 1 H NMR(400MHz, DMSO-d6)δ8.29(d,J=8.2Hz,2H),8.18–8.06(m,3H),7.97(d,J=8.3Hz, 2H),7.63(d,J=8.0Hz,2H),6.09(d,J=2.8Hz,1H),5.82(d,J=7.8Hz,1H),3.68(dp,J= 14.7,5.2,3.7Hz,1H),3.50(s,2H),3.17(s,2H),2.40(tq,J=6.8,3.4Hz,1H),1.95– 1.66(m,2H),1.37(d,J=28.1Hz,2H),0.55(dt,J=6.6,3.2Hz,2H),0.38–0.27(m,2H). 13 C NMR(101MHz,DMSO-d6)δ168.23,158.43,147.26,140.20,134.31,133.47,132.89,

[0415] 132.89,130.56,128.33,127.66,126.04,124.97,119.40,109.72,46.67,22.81,6.98.

[0416] Example 11: Preparation of imidazothiadiazole derivatives modified with phosphoryl groups on the amino N-group of 4-aminopiperidine

[0417] This embodiment aims to prepare imidazothiadiazole derivatives modified with phosphoryl groups on the amino N of 4-aminopiperidine in the compound of general formula (I), and the preparation route is shown in reaction formula II.

[0418] The structural formula of the imidazothiadiazole derivative modified with a phosphoryl group on the amino N-amino group of 4-aminopiperidine synthesized in this embodiment is as follows:

[0419]

[0420] R1 is selected from R2, R3, and R4 are defined as above.

[0421] 1. Preparation of 4-(2-(4-(4-((2-oxo-1,3,2-dioxophosphazenecyclopentan-2-yl)amino)piperidine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula II-82)

[0422] The preparation was carried out in the same manner as step 1 in Example 3, except that the starting materials were intermediate compound V-1 and 2-chloro-2-oxo-1,3,2-dioxophosphazenecyclopentane. After purification, 157 mg of a pale yellow solid was obtained, with a yield of 42%. 1 HNMR (500MHz, CDCl3) δ8.01–7.96(m,2H),7.94–7.86(m,4H),7.86–7.80(m,2H),4.23(d,J=8.4Hz,4H),4.01(d,J=9.0 Hz,1H),3.64(ddd,J=12.8,8.3,5.6Hz,2H),3.31–3.22(m,3H),2.10(ddt,J=12.9,8.4,5.4Hz,2H),1.87–1.77(m,2H). 13C NMR (101MHz, CDCl3) δ170.39,165.82,156.40,140.28,137.14,135.78,132.01,131.81,130.34,1 29.37,129.24,129.11,118.12,112.60,64.83,64.78,48.62,48.57,44.11,44.09,31.97,31.92.

[0423] 2. Preparation of diisopropyl(1-(4-(5-(4-cyanophenyl)imidazol[2,1-b][1,3,4]thiadiazol-2-yl)benzoyl)piperidin-4-yl)phosphamide (general formula 2I-83)

[0424] The preparation was carried out in the same manner as step 1 in Example 3, except that the raw materials were intermediate compound V-1 and ethyl ethylphosphonochloride. After purification, 199 mg of a pale yellow solid was obtained, with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ8.10–8.02(m,2H),7.93(d,J=8.1Hz,2H),7.72–7.64(m,3H),7.53(d,J=8.0Hz,2H),4.55(ddq,J=14.0,12.4,6.0H z,2H),3.69–3.59(m,1H),3.30–2.94(m,3H),2.79(t,J=9.0Hz,1H),2.16–1.82(m,2H),1.56–1.36(m,2H),1.27(dd,J=6.3,4.1Hz,12H). 13 C NMR (101MHz, CDCl3) δ168.86,161.99,147.09,133.06,132.80,132.67,131.00 ,128.06,126.37,124.79,118.91,110.52,74.23(d,J=6.6Hz),73.03,71.10(d ,J=5.8Hz),69.01,50.57,48.89,46.56,45.33,41.27,34.69(d,J=102.2Hz),3 1.97, 29.71 (d, J = 4.3Hz), 23.94 (dd, J = 8.4, 4.7Hz), 22.74, 14.18, 8.57, 1.07.

[0425] 3. Preparation of 4-(2-(4-(4-((5,5-dimethyl-2-oxo-1,3,2-dioxophosphazenecyclopentan-2-yl)amino)piperidine-1-carbonyl)phenyl)imidazolium[2,1-b][1,3,4]thiadiazol-5-yl)benzonitrile (general formula II-84)

[0426] The preparation was carried out in the same manner as step 1 in Example 3, except that the starting materials were intermediate compound VII-1 and 2-chloro-5,5-dimethyl-1,3,2-dioxophosphanecyclohexane-2-oxide. After purification, 174 mg of a pale yellow solid was obtained, with a yield of 43%. 1 H NMR (400MHz, CDCl3) δ8.16–8.08(m,2H),8.02–7.95(m,2H),7.79–7.71(m,3H),7.60–7.51(m,2H),4.73–4.15 (m,3H),3.80(dd,J=20.0,10.9Hz,2H),3.38(d,J=10.2Hz,1H),3.22–2.83(m,3H),2.10(s,2H),1.64(s,2H). 13 C NMR (101MHz, CDCl3) δ167.82,160.93,138.34,131.75,130.00,126.97,126.15,123.77 ,117.84,109.52,47.96,37.12,30.88,30.22,28.66(d,J=3.7Hz),21.09,19.68,13.11.

[0427] Example 12: Inhibitory effect of the 3,5-substituted imidazothiadiazole heterocyclic derivative of the present invention on the expression of p-eIF4E in cells.

[0428] In this embodiment, the 3,5-substituted imidazothiadiazole heterocyclic derivative obtained above was selected, and the inhibitory effect of the compound on p-eIF4E expression was evaluated by Western blot. eFT508 (Shanghai Yuanye Biotechnology Co., Ltd.) and 2A (WO2023 / 093700A1, Imidazotiadiazole Derivatives and Their Preparation Methods and Applications) were used as positive controls in this experiment. The experimental procedure was as follows: the concentration of the test compound was 3 μM or 0.3 μM, and it was applied to 3T3-L1 mouse embryonic fibroblasts (Wuhan Pronosei Life Science Co., Ltd.) for 2 h. After that, the cells were collected and the protein was extracted. The phosphorylation level of eIF4E in the protein was tested by Western blot. The positive controls were eFT508 (concentration 1 μM) or 2A (concentration 0.3 μM). The lighter the color of the p-eIF4E band in the obtained Western blot results, the stronger the inhibitory effect on eIF4E phosphorylation. Figure 1 .

[0429] Example 13: Cytotoxicity of the 3,5-substituted imidazothiadiazole heterocyclic derivative of the present invention on normal cells.

[0430] In this embodiment, the 3,5-substituted imidazothiadiazole heterocyclic derivatives synthesized above were selected to evaluate their inhibitory activity on the proliferation of two types of human normal cells and two types of mouse normal cells. The screening concentration was 100 μM. Cell lines (all from Wuhan Pronosei Life Science Technology Co., Ltd.) included human embryonic kidney cells HEK-293T, human renal cortical proximal tubular epithelial cells HK-2, mouse embryonic fibroblasts 3T3-L1, and mouse normal hepatocytes AML12. The evaluation method was the MTT assay. Four compounds (patent numbers 12, 14, 17, and 41) from the applicant's patent application (WO2023 / 093700A1, Imidazothiadiazole Derivatives and Their Preparation Methods and Applications) were selected as positive controls. Cell viability results are shown in Table 1. The evaluation results show that the cell viability of these four types of normal cells treated with the compounds of this invention was between 80% and 100%, which is higher than the cell viability (between 60% and 80%) treated with the previously applied patent compounds, exhibiting lower cytotoxicity and demonstrating higher safety in the treatment of related diseases.

[0431] Table 13. Cytotoxicity of 5-position substituted imidazothiadiazole heterocyclic derivatives to four types of normal cell lines.

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] The applicant tested the effects of the above compounds on different mouse disease models, which are illustrated below with specific examples.

[0438] Example 14: Effects of compound I-48 on liver lesions and weight loss in obese mice fed a high-fat diet.

[0439] Male C57BL / 6J mice (purchased from Vital River) were fed with high-fat diets (containing 60 kcal%) and low-fat diets (containing 10 kcal%) (both purchased from Synergistic Biotech). After 16 weeks, the obesity model was successfully established (the weight of mice fed high-fat diets was 20% higher than that of mice fed low-fat diets). The subjects were divided into the following groups: normal diet control group (CD-B group, given solvent, 0.5% sodium carboxymethyl cellulose solution), high-fat diet model group (HFD-B group, given solvent, 0.5% sodium carboxymethyl cellulose solution), positive control drug orlistat group (HFD-O-50 group, 50 mg / kg), positive control drug fenofibrate group (HFD-F-50 group, 50 mg / kg), and I-48 very low, low, medium, and high dose groups (HFD-I-48-3 group, 3 mg / kg; HFD-I-48-10 group, 10 mg / kg; HFD-I-48-30 group, 30 mg / kg; HFD-I-48-100 group, 100 mg / kg). Mice were administered the drug via gavage every morning for 24 consecutive days. During this period, their food intake and body weight changes were measured periodically. Results showed that after 24 days, the body weight of the administered group and the I-48 very low, low, medium, and high dose groups decreased in a dose-dependent manner, while food intake did not decrease (see...). Figure 2 In addition, liver tissue was dissected and extracted from mice 24 days after drug administration for sectioning and analysis of liver condition using Oil Red O staining and H&E staining. The results showed that Oil Red O staining indicated fatty liver in mice in the HFD-B group. Compared with the HFD-B group, the amount of lipid droplet deposition in the liver of mice treated with I-48 was significantly reduced, and the HFD-I-48-100 group showed the best treatment effect (see...). Figure 3 H&E staining results showed that numerous lipid vacuoles of varying sizes appeared in the cytoplasm of hepatocytes in HFD-B mice, and the hepatocyte volume increased; after I-48 treatment, the number of lipid vacuoles in hepatocytes was significantly reduced, and most hepatocytes returned to normal size and morphology, and were arranged in a tight and orderly manner (see...). Figure 4 ).

[0440] Example 15: Effect of compound I-12 on LPS-induced acute kidney and spleen injury in mice.

[0441] Male C57BL / 6J mice were selected and acclimatized for one week. They were then administered different concentrations of I-12 via gavage for 16 days using 0.5% sodium carboxymethyl cellulose solution as the solvent. Two hours after the last administration, 10 mg / kg of LPS (lipopolysaccharide) was injected intraperitoneally. Twenty-four hours later, the mice were dissected, and kidney, spleen, and liver indices were calculated. Serum renal function-related indicators, urea and creatinine, were measured. Serum levels of inflammatory cytokines TNF-α, IL-6, IL-1β, and MCP-1 were also measured. The release of large amounts of inflammatory factors into the circulatory system is the main response to LPS-induced inflammation. The results showed that I-12 significantly reduced the increase in LPS-induced serum inflammatory factors (see...). Figure 5 Organ indexes indicate that different concentrations of I-12 can significantly improve LPS-induced acute kidney and spleen injury, and serum renal function-related biochemical indicators also show significant improvement (see...). Figure 6 PAS staining of kidney tissue was used to observe the extent of damage. I-12 could alleviate LPS-induced renal tubular dilation, brush border necrosis, cell vacuolation, and structural loss (see...). Figure 7 H&E sections of the spleen showed that I-12 could alleviate LPS-induced splenic cell nuclear swelling, cell edema, inflammatory cell infiltration, and microcirculatory disturbances (see [link to article]). Figure 8 The above results indicate that I-12 can improve tissue damage caused by inflammation.

[0442] Example 16: Effect of Compound I-1 on Deep Vein Thrombosis in Mice

[0443] Male BALB / c mice were selected and, after one week of acclimatization, were divided into four groups: I-1 IV 0.1 mg / kg² group, I-1 IV 0.5 mg / kg² group, I-1 IV 2.5 mg / kg² group, blank Vehicle group, and positive control group (Enoxaparin). After tail vein injection, the mice were anesthetized with isoflurane and placed in a supine position. Abdominal hair was removed to expose the skin, which was then disinfected with iodine-soaked cotton balls. An incision was made along the midline of the abdomen to access the abdominal cavity. The small intestine was wrapped and protected with a piece of gauze soaked in physiological saline and placed in the right abdominal cavity, exposing the inferior vena cava and its main tributaries. The inferior vena cava and its branches were ligated below the confluence of the right renal vein and the inferior vena cava. The intestine was then inserted and the skin sutured. The animals were injected with physiological saline and kept at 25-28°C until awakening. Six hours after ligation, a second dose was administered. Twelve hours later, the mice were sacrificed, and the thrombus was collected for dry weight, wet weight, and length measurements. Experimental results show that I-1 can reduce thrombus size in this model in a dose-dependent manner (see...). Figure 9 ).

[0444] The above experimental results demonstrate that the compounds of this invention exhibit good inhibitory effects on p-eIF4E expression and show virtually no cytotoxicity to normal cells, demonstrating excellent safety. For example, compound I-48 significantly reduced body weight and improved metabolic diseases such as fatty liver in obese mouse models; compound I-12 significantly improved inflammation and tissue damage caused by acute kidney and spleen injury; and compound I-1 treats thrombotic diseases by inhibiting platelet production and exhibiting antiplatelet activity, showing promising prospects for drug development and application.

[0445] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. 3,5-substituted imidazothiadiazole heterocyclic derivatives, or pharmaceutically acceptable salts, characterized in that, The 3,5-substituted imidazothiadiazole heterocyclic derivative has the structure shown in formula (I): Equation (I) Formula (I) includes general formula I and general formula II, where R1 is selected from one of the following groups: , , , , , , , , R5 is optionally selected from H, an unsubstituted C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkoxide, amino, C1-C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, an unsubstituted 3- to 6-membered heterocycle, a C1-C6 alkyl group substituted with one or more C1-C6 alkyl, halogen, hydroxyl, alkynyl, alkenyl, methoxy, cyano, nitro, C1-C6 alkoxycarbonyl, C1-C6 alkynyl, C1-C6 alkoxyenyl, C1-C6 alkoxide, C1-C6 alkoxide, C1-C6 alkyloxide, C1-C6 alkylmetall, C1-C6 alkylene, C1-C6 alkoxide, C 1-C6 alkoxy, amino, C1-C6 alkylamine, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic, aryl, heteroaryl substituted 3- to 6-membered heterocycle, unsubstituted aryl or heteroaryl, aryl or heteroaryl substituted with one or more C1-C6 alkyl, halogen, hydroxyl, alkynyl, alkenyl, methoxy, cyano, nitro, C1-C6 alkylcarbonyl, C1-C6 alkynyl, C1-C6 alkenyl, C1-C6 alkthiol, C1-C6 alkoxy, amino, C1-C6 alkylamine, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic, aryl, heteroaryl substituted aryl or heteroaryl; R2 can be selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkylcarbonyl, hydroxy-substituted C1-C6 alkyl, halogen, hydroxyl, cyano, nitro, amino, carbonyl; R3 is selected from H, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with one or more alkynyl, alkenyl, cyano, C1-C6 alkoxy, C1-C6 alkylthiol, amino, C1-C6 alkylamine, halogen, nitro, carbonyl, sulfonyl, phosphoryl, 3- to 6-membered heterocyclic, aryl, heteroaryl, carbonyl substituted with C1-C6 alkyl; R4 is selected from any one of H, halogen, methoxy, hydroxyl, cyano, nitro, carbonyl, amino, N,N-dimethylamino, trifluoromethyl, and trifluoromethoxy. The aryl group is selected from monocyclic or polycyclic aryl groups containing 6-12 carbon atoms; the heteroaryl group is selected from 5- to 6-membered heteroaryl groups, which refers to a heteroaryl system having a cyclic carbon atom and 1-3 cyclic heteroatoms, wherein each cyclic heteroatom is independently selected from nitrogen, oxygen, and sulfur.

2. The 3,5-substituted imidazothiadiazole heterocyclic derivative or pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically acceptable salt refers to the salt formed by the reaction of a compound with the structure shown in formula (I) with an inorganic acid, an organic acid, an alkali metal, or an alkaline earth metal.

3. A method for preparing the 3,5-substituted imidazothiadiazole heterocyclic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 2, characterized in that, include: The specific steps for synthesizing Formula 1 are as follows: First, compound (II) undergoes an ester-amine exchange reaction with piperazine-1-carboxylic acid tert-butyl ester to obtain compound (IX). Then, under trifluoroacetic acid conditions, the tert-butyloxycarbonyl group is removed to generate compound (III). Finally, compound (III) undergoes a condensation reaction with the corresponding acyl chloride compound, the corresponding amine compound, or the corresponding isothiocyanate compound to obtain the compound. R1, R2, R4, and R5 are defined as above. The specific steps for synthesizing Formula 2 are as follows: First, the compound of formula (II) undergoes an ester-amine exchange reaction with a 4-N-substituted 4-N-tert-butoxycarbonylaminopiperidine to obtain the compound of formula (IY). Then, the tert-butoxycarbonyl group is removed under trifluoroacetic acid conditions to generate the compound of formula (V). Finally, the compound of formula (V) undergoes a condensation reaction with the corresponding acyl chloride compound, the corresponding amine compound, or the corresponding isothiocyanate compound to obtain the compound of general formula (I), wherein R1, R2, R3, R4, and R5 are defined as above.

4. The preparation method according to claim 3, characterized in that, The intermediate compound of formula (II) is prepared by the following method: Starting with aminothiourea and compound (i), a nucleophilic addition reaction is carried out to obtain Schiff base intermediate compound (ii). Subsequently, an intramolecular cyclization reaction is carried out under ferric chloride conditions to generate intermediate compound (iii). Intermediate compound (iii) undergoes a cycloaddition reaction with 2-bromo-1,1-diethoxyethane to obtain intermediate compound (iv). Under NBS conditions, a bromination reaction is carried out to obtain intermediate compound (v). Then, intermediate compound (v) undergoes a Suzuki coupling reaction with the corresponding 4-substituted phenylboronic acid to obtain intermediate compound (vi). Subsequently, a hydrolysis reaction is carried out under lithium hydroxide conditions to obtain intermediate compound (vii). Finally, a condensation reaction is carried out with N-hydroxysuccinimide to obtain compound (II), wherein R2 and R4 are defined as above.

5. The use of the 3,5-substituted imidazothiadiazole heterocyclic derivative or pharmaceutically acceptable salt of any one of claims 1 to 2 in the preparation of a medicament for inhibiting eIF4E phosphorylation and reducing p-eIF4E formation.

6. The use of the 3,5-substituted imidazothiadiazole heterocyclic derivative or pharmaceutically acceptable salt of any one of claims 1 to 2 in the preparation of medicaments for the prevention and / or treatment of metabolic diseases, thrombotic diseases, septic acute kidney injury, MASLD and its severe stage MASH associated with dysregulation of eIF4E phosphorylation levels.

7. A pharmaceutical composition, characterized in that, It comprises a 3,5-substituted imidazothiadiazole heterocyclic derivative or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 2.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition also includes other treatments for diseases associated with dysregulation of eIF4E phosphorylation levels.

9. A formulation, characterized in that, It comprises the pharmaceutical composition of claim 7, or the active ingredient is a 3,5-substituted imidazothiadiazole heterocyclic derivative of claim 1, or a pharmaceutically acceptable salt.

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