Imidazothiazole derivatives, their preparation and use

Abstract

Imidazothiazole derivatives having the structure represented by formula (I) and methods for their preparation and use are disclosed. [Solution] R1 and R3 are each independently selected from 5- to 6-membered heterocyclic groups containing 1-2 nitrogen atoms which may be optionally substituted, and R2 and R4 are each independently selected from aryl or heteroaryl groups which may be optionally substituted. The imidazothiazole derivative has good MNK inhibitory activity, excellent selectivity and excellent blood glucose lowering effect in the body, and has a wide range of medicinal background.

Description

[Technical Field]

[0001] Technical Field The present invention is in the field of medicinal chemistry, and specifically relates to imidazothiazole derivatives and their preparation and use. [Background technology]

[0002] Background technology Metabolic syndrome is a clinical syndrome characterized by the combined presence of multiple metabolic diseases, such as obesity and type 2 diabetes (T2D), which are determined by a set of both genetic and environmental factors, and can further lead to dyslipidemia, hypertension, non-alcoholic fatty liver disease, gout, etc. With socio-economic development and changes in people's lifestyles (increased energy intake, decreased exercise, etc.), the incidence of metabolic syndrome is increasing year by year around the world, and has already become a global public health challenge. Nonalcoholic fatty liver disease (NAFLD) is a genetic, environmental, metabolic, and stress-related liver disease characterized by hepatic parenchymal steatosis and fat accumulation. Clinically, it includes three types: simple steatosis, steatohepatitis (NASH), and fatty cirrhosis. MNK (mitogen-activated protein kinase-interacting kinase) includes two subtypes, MNK1 and MNK2. It has now been demonstrated that MNK regulates protein synthesis in vivo by phosphorylating eIF4E. Studies have shown that regulating MNK activity can regulate body weight, glucose tolerance, insulin sensitivity, energy expenditure, liver fat accumulation, and inflammation in animal fat. These findings suggest that MNK may be a potential drug target for metabolic diseases such as diabetes, obesity, and NAFLD. In this field, there is a strong demand for more small molecule compounds that can inhibit MNK activity more effectively. Summary of the Invention [Problem to be solved by the invention]

[0003] Summary of the Invention In order to solve the above technical problems, a series of imidazothiazole or imidazothiadiazole derivative compounds have been invented, which can regulate the activity of MNK protein kinase, thereby achieving changes such as blood sugar regulation, weight gain reduction, and fat accumulation in the body, thereby improving the conditions of patients with diabetes and other metabolic diseases. [Means for solving the problem]

[0004] The present invention provides an imidazothiazole derivative, a stereoisomer, a tautomer, a geometric isomer, or a pharmaceutically acceptable salt thereof, characterized in that it has a structure represented by formula (I): [ka] (Formula (I) includes general formula 1 and general formula 2, wherein R1 and R3 are each independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms which may be optionally substituted with one or more groups such as a halogen atom, a hydroxy group, a cyano group, a nitro group, an amino group, or a carbonyl group; or R1 is selected from a hydroxy group, a halogen atom, an amino group, a dimethylamino group, or a C1-C6 alkoxy group which may be optionally substituted with one or more groups such as a hydroxy group, a halogen atom, an amino group, a dimethylamino group, or a 5- to 6-membered heterocyclic group. R1 is selected from a C1-C6 alkylthio group optionally substituted with one or more heterocyclic rings, R1 is selected from a hydroxy group, a halogen, an amino group, a dimethylamino group, and a C1-C6 alkylamino group optionally substituted with one or more 5- to 6-membered heterocyclic rings, and R2 and R4 are each independently selected from an aryl group or heteroaryl group optionally substituted with one or more groups such as a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a hydroxy-substituted C1-C6 alkyl group, a halogen, a hydroxy group, a cyano group, a nitro group, an amino group, or a carbonyl group.

[0005] The C1-C6 alkyl group according to the present invention is a linear or branched monovalent saturated hydrocarbon group containing 1, 2, 3, 4, 5 or 6 carbon atoms, representative examples of which include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. The C1-C6 alkyl group may suitably be a C1-C3 alkyl group. The C1-C6 haloalkyl group according to the present invention is a C1-C6 alkyl group defined above in which one or more hydrogen atoms have been replaced with the same or different halogen atoms. The C1-C6 haloalkyl group may suitably be a C1-C3 haloalkyl group. Representative examples include, but are not limited to, a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a trichloromethyl group, a 1,1,1-trifluoroethyl group, a pentafluoroethyl group, etc. The C1-C6 alkylamino group according to the present invention refers to an amino group (-NH2) in which one or two hydrogen atoms are substituted with the same or different "C1-C6 alkyl group" defined above, i.e., -NR 1 R 2 It can also be expressed as R 1 , R 2 are each independently selected from H and a C1-C6 alkyl group, and R 1 , R 2 and cannot be H at the same time.

[0006] The C1-C6 alkoxy group described in the present invention is -OR 3 So, here, R 3 is selected from C1-C6 alkyl groups, and the C1-C6 alkoxy group may be preferably a C1-C3 alkoxy group, more preferably a methoxy group, an ethoxy group, or the like. The C1-C6 alkoxycarbonyl group described in the present invention is —C(O)R 4 So, here, R 4 is selected from C1-C6 alkoxy groups. The 5- or 6-membered heterocyclic ring according to the present invention has a ring carbon atom and 1 to 4 ring heteroatoms (preferably 1, 2, or 3 ring heteroatoms) in the ring system, where each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur, and in heterocyclic groups containing one or more nitrogen atoms, the bonding site may be a carbon or nitrogen atom as long as the valence allows. More preferred examples include a piperazine ring, a morpholine ring, a piperidine ring, a hexahydropyran ring, a tetrahydropyran ring, a tetrahydrothiene ring, a pyrrole ring, and a tetrahydropyrrole ring. The aryl group described in the present invention is preferably a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms, with phenyl and naphthyl being preferred. The heteroaryl group is preferably a 5- to 6-membered heteroaryl group, which has ring carbon atoms and 1 to 4 ring heteroatoms (preferably 1, 2, or 3 ring heteroatoms) in the heteroaryl system, where each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur. More preferred are furyl, thienyl, pyridyl, thiazolyl, and imidazolyl groups.

[0007] The halogen atom or halogen according to the present invention is preferably fluorine, chlorine, bromine or iodine. The imidazothiazole derivative of the above formula (I) structure is preferably Compound 1-55, or a stereoisomer, tautomer, geometric isomer, or a pharmaceutically acceptable salt thereof.

[0008] [ka] [ka] [ka] [ka]

[0009] Another embodiment of the present invention provides a method for preparing an imidazothiazole derivative of the above formula (I), comprising the steps of: Synthesis of General Formula 1: [ka] Suzuki condensation of the compound of formula (II) with the corresponding boric acid derivative (B(OH)R) to obtain a compound of general formula 1 (wherein R and R are as defined above, and X is a halogen, preferably chlorine, bromine, or iodine); Synthesis of General Formula 2: [ka] Compounds of formula (III) and corresponding ethyne derivatives [ka] is reacted under basic conditions to obtain a compound of general formula 2 (wherein R3 and R4 are defined as above). Another embodiment of the present invention provides a method for preparing an imidazothiazole derivative of the above formula (I), comprising the steps of:

[0010] The synthesis method of general formula 1 comprises the steps of preparing a compound of formula (II) from a compound of formula (IV): [ka] (wherein R1 is as defined above, and X is a halogen, preferably chlorine, bromine, or iodine); The synthesis method of general formula 2 includes the steps of preparing a compound of formula (III) from a compound of formula (V): [ka] (However, the definition of R3 is as above.) Another embodiment of the present invention provides a method for preparing an imidazothiazole derivative having the above formula (I), wherein the imidazothiazole derivative having the formula (I) is selected from general formula 1 in which R2 is a 4-cyanophenyl group and is represented by compound N, and the method comprises the following steps: [ka] Compound M and R1H are subjected to a condensation reaction to obtain compound N (R1 is defined as above).

[0011] Another embodiment of the present invention provides an intermediate for producing an imidazothiazole derivative of formula (I), characterized in that the intermediate has a structure represented by formula (II): [ka] (wherein R1 is defined as above, and X is a halogen, preferably chlorine, bromine, or iodine.) Another embodiment of the present invention provides an intermediate for producing an imidazothiazole derivative of formula (I), characterized in that the intermediate has a structure represented by formula (III): [ka] (However, the definition of R3 is as above.) Another embodiment of the present invention provides an intermediate for preparing formula (II), characterized in that the intermediate has a structure represented by formula (IV): [ka] (wherein X is a halogen, preferably chlorine, bromine, or iodine.)

[0012] Another embodiment of the present invention provides an intermediate for preparing formula (III), characterized in that the intermediate has a structure represented by formula (V): [ka] Another embodiment of the present invention provides an intermediate for preparing the imidazothiazole derivative of formula (I), characterized in that the intermediate has the following structure: [ka]

[0013] Another embodiment of the present invention provides the use of a compound of formula (II), (III), (IV) or (V) in the preparation of an imidazothiazole derivative of formula (I). Another embodiment of the present invention provides use of an imidazothiazole derivative having the above formula (I) structure, its stereoisomer, tautomer, geometric isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for inhibiting the kinase activity of MNK1 or MNK2 or a variant thereof, or for preventing and / or treating cancer caused by abnormalities in MNK1 and / or MNK2 levels. Another embodiment of the present invention provides use of an imidazothiazole derivative having the above formula (I), its stereoisomer, tautomer, geometric isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating a metabolic disease associated with MNK activity, the metabolic disease being selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, and complications and associated diseases thereof.

[0014] Another embodiment of the present invention provides use of an imidazothiazole derivative having the structure of the above formula (I), a stereoisomer, a tautomer, a geometric isomer, or a pharmaceutically acceptable salt thereof in the manufacture of an MNK1 and / or MNK2 inhibitor. Another embodiment of the present invention provides a pharmaceutical composition comprising an imidazothiazole derivative of the above formula (I), its stereoisomer, tautomer, geometric isomer, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant. The pharmaceutical composition may further comprise another MNK1 and / or MNK2 inhibitor (a commercially available therapeutic agent). The dosage form may be a solid, liquid, or semisolid formulation, preferably a tablet, capsule, or injection. The methods and techniques of the present invention are generally carried out by conventional methods known in the art unless otherwise specified. Terms used in the present invention are named in accordance with chemistry, biology, and pharmacology, and experimental methods and techniques are known and commonly used in the art. Standard techniques are used in chemical synthesis, chemical analysis, pharmaceutical manufacturing and preparation, and patient treatment. Unless otherwise specified, scientific and technical terms used in the present invention have the ordinary meanings understood by those skilled in the art. However, the following terms have the following definitions:

[0015] Unless otherwise stated, all compounds described herein include all possible optical isomers, e.g., a single chiral compound or a mixture of various different chiral compounds (i.e., a racemate). In all compounds of the present invention, each chiral carbon atom may optionally be in the R or S configuration, or a mixture of the two configurations. Specific examples of diabetes and its complications include impaired glucose tolerance, diabetic gangrene, diabetic joint lesions, diabetic osteopenia, diabetic glomerulosclerosis, diabetic kidney lesions, diabetic skin lesions, diabetic nerve lesions, diabetic cataracts, diabetic retinal lesions, diabetic macular lesions, diabetic foot syndrome, diabetic coma, hyperosmolar coma, hypoglycemic coma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis, intracapillary glomerular kidney disease, diabetic muscle atrophy, diabetic autonomic nerve lesions, diabetic mononeuropathy, diabetic polyneuropathy, diabetic vascular disease, diabetic peripheral vascular disease, diabetic ulcers, diabetic joint lesions, and diabetic obesity. Specific examples of hyperlipidemia and its complications include hypercholesterolemia, familial hypercholesterolemia, Fredrickson's hyperlipoproteinemia, hyperbetalipoproteinemia, hyperlipidemia, low-density lipoprotein hyperlipoproteinemia, pure hypertriglyceridemia, endogenous hypertriglyceridemia, and cardiovascular disease, including hypertension, ischemia, varicose veins, retinal vein occlusion, atherosclerosis, angina pectoris, myocardial infarction, stenosis, pulmonary hypertension, congestive heart failure, glomerulopathy, tubulointerstitial disorders, renal failure, vascular stenosis, and cerebrovascular disease (stroke).

[0016] Fatty liver diseases include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the progressive fibrosis and cirrhosis caused by chronic inflammation caused thereby. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the changes in blood glucose levels in each group of mice during the experiment. [Figure 2] FIG. 2 shows the changes in glucose tolerance and insulin tolerance in each administration group. [Figure 3] FIG. 3 is an illustration of changes in each relevant index in the serum of each administration group. [Figure 4] FIG. 4 is an illustration of an insulin loading experiment in each group of db / db mice. [Figure 5] FIG. 5 is an illustration of changes in various indices related to liver function in db / db experimental mice. [Figure 6] FIG. 6 is an illustration of changes in each relevant index in the serum of db / db experimental mice.

[0018] Specific Embodiments Common synthesis methods for compounds Synthesis of General Formula 1: [ka] Starting from commercially available 5-bromo-2-amino-1,3,4-thiadiazole, chloroacetaldehyde or 2-bromo-1,1-diethoxyethane is refluxed in an alcohol solution (e.g., ethanol, n-butanol, etc.) for 1-2 days to give cyclized product A, which is then subjected to Suzuki condensation with 4-methoxycarbonylphenylboronic acid to give compound B, which is then subjected to nucleophilic substitution with NBS (or NIS) in dichloromethane to give compound C, which is then condensed under basic conditions (e.g., lithium hydroxide, sodium hydroxide, or potassium hydroxide) to give compound C. After hydrolysis in a mixed solution of ethanol, water, tetrahydrofuran, and alcohol, and adjusting to acidity (the acid can be an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, formic acid, etc.), a carboxylic acid structure compound D is obtained, which is then subjected to an amidation reaction with an amino compound R1H under amide condensation reagent conditions (for example, a combination of EDCI and NHS, EDCI and Hobt, or EDCI and Hoat, etc.) to obtain compound E, and finally subjected to Suzuki condensation reaction with a boronic acid compound B(OH)2R2 to obtain the final compound F (general formula 1), where R1 and R2 are as defined above.

[0019] The intermediate C obtained in the above reaction is subjected to Suzuki condensation with 4-cyanophenylboronic acid to obtain compound L, which is then hydrolyzed under basic conditions (for example, in a mixed solution of lithium hydroxide, sodium hydroxide, or potassium hydroxide in water, tetrahydrofuran, and alcohol) and acidified (the acid can be an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, formic acid, etc.) to obtain compound M with a carboxylic acid structure, which is then subjected to condensation with R1H (an amino compound, an alcohol compound, a thiol compound) under condensation reagent conditions (for example, a combination of EDCI and NHS, EDCI and Hobt, or EDCI and Hoat, etc.) to obtain the final compound N (general formula 1 when R2 is a 4-cyanophenyl group), where R1 is as defined above.

[0020] Synthesis of General Formula 2: [ka] Starting from commercially available methyl 4-acetylbenzoate, compound G is refluxed in NBS, p-toluenesulfonic acid, and acetonitrile solution to obtain compound G, which is then refluxed in alcohol solution for 6 hours to obtain compound H. Compound H is then hydrolyzed under basic conditions (for example, in a mixture of lithium hydroxide, sodium hydroxide, or potassium hydroxide in water, tetrahydrofuran, and alcohol) and acidified (the acid can be an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, formic acid, etc.) to obtain compound I with a carboxylic acid structure. Compound J is then amidated with amino compound R3H under amide condensation reagent conditions (for example, a combination of EDCI and NHS, EDCI and Hobt, or EDCI and Hoat, etc.). Finally, compound K (general formula 2) is obtained by reacting with phenylacetylene compound R4CCH in DMF solution using potassium t-butoxide as a base at room temperature for 6 hours, where R3 and R4 refer to the description in the claims. Specific Embodiments Hereinafter, the present invention will be described in detail through specific manufacturing examples and examples. However, the uses and purposes of these exemplary embodiments are merely illustrative of the present invention and do not limit the actual scope of protection of the present invention, nor do they limit the scope of protection of the present invention to these.

[0021] Example 1: 2-Bromoimidazo[2,1-b][1,3,4]thiadiazole (Compound A) [ka] 5-Bromo-2-amino-1,3,4-thiadiazole was reacted with chloroacetaldehyde in ethanol under reflux to give compound A in 17.6% yield. 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.36 (s, 1H).

[0022] Example 2: Methyl 4-(imidazo[2,1-b][1,3,4]thiadiazolyl)benzoate (Compound B) [ka] 300 mg (1.47 mmol) of 2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Compound A) was subjected to a Suzuki condensation reaction with 317 mg (1.76 mmol) of 4-methoxycarbonylphenylboronic acid under the action of a catalyst, and then the reaction mixture was subjected to silica gel column chromatography (PE:EA=10:1) to obtain 93.2 mg of a white solid (i.e., Compound B), with a yield of 24.3%. 1 H NMR (500 MHz, CDCl3) δ 8.19 - 8.15 (m, 2H), 7.97 - 7.93 (m, 2H), 7.81 (d, J = 1.4 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 3.97 (s, 3H).

[0023] Example 3: Methyl 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazolyl-2-yl)benzoate (Compound C) [ka] 350 mg (1.35 mmol) of methyl 4-(imidazo[2,1-b][1,3,4]thiadiazolyl)benzoate was reacted with 286 mg (1.62 mmol) of N-bromosuccinimide, followed by silica gel column chromatography to give 340 mg of a pale green solid (i.e., Compound C), with a yield of 74.7%. 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 3.98 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 165.9, 161.5, 144.2, 133.8, 133.7, 133.1, 130.5, 126.9, 96.3, 52.5.

[0024] Example 4: 4-(5-Bromoimidazo[2,1-b][1,3,4]thiadiazolyl-2-yl)benzoic acid (Compound D) [ka] 340 mg (1 mmol) of methyl 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazolyl-2-yl)benzoate was mixed with 424 mg (10 mmol) of lithium hydroxide monohydrate in 30 mL of THF / HO (V:V=1:1) solution. After the reaction was completed, the mixture was purified to obtain 320 mg of a white solid, i.e., Compound D, in a yield of 98%.

[0025] Example 5: Methyl 4-(2-bromoacetyl)benzoate (Compound G) [ka] Methyl 4-acetylbenzoate (5 g, 28 mmol) was dissolved in acetonitrile (100 mL), and NBS (6.0 g, 33.6 mmol) and TsOH (482 mg, 2.8 mmol) were added to the solution. The resulting mixture was then purified by column chromatography (PE:EA=10:1) to give 4.6 g of a white solid (i.e., Compound G) in a 63.9% yield. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 4.46 (s, 2H), 3.94 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 190.84, 165.95, 137.16, 134.62, 130.01, 128.87, 52.58, 30.71.

[0026] Example 6: Methyl 4-(2-(2-amino-1,3,4-thiadiazolyl)acetyl)benzoate (Compound H) [ka] A 250 mL eggplant-shaped flask was charged with methyl 4-(2-bromoacetyl)benzoate (4 g, 15.6 mmol), 2-amino-1,3,4-thiadiazole (1.6 g, 16 mmol), and ethanol (100 mL). The mixture was refluxed at 80 °C for 6 h with magnetic stirring. TLC indicated complete reaction of the starting materials. The flask was cooled to room temperature, suction filtered, and the cake was washed three times with ethanol to give 3.2 g of a white solid (i.e., Compound H) in 74% yield. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.1 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.67 (s, 1H), 5.41 (s, 2H), 3.96 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 192.06, 166.05, 161.55, 137.93, 134.56, 133.53, 130.03, 128.07, 53.71, 52.55.

[0027] Example 7: 4-(Imidazo[2,1-b][1,3,4]thiadiazolyl)benzoic acid (Compound I) [ka] A 100 mL eggplant-shaped flask was charged with methyl 4-(2-(2-amino-1,3,4-thiadiazolyl)acetyl)benzoate (3 g, 10.8 mmol) and 2N hydrochloric acid (60 mL) and refluxed at 100°C for 6 h. TLC confirmed complete reaction of the starting materials. The flask was cooled to room temperature, and the pH was adjusted to 9-10 with 1N sodium hydroxide in an ice bath. Ethyl acetate was added, and the mixture was transferred to a separatory funnel. The mixture was shaken evenly and allowed to stand. The aqueous layer was separated and adjusted to a pH of 2-3 with 1N hydrochloric acid to obtain a yellowish-earth solid. This solid was filtered under suction to obtain 2.2 g of the solid (i.e., Compound I) in 83% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.87 (s, 1H), 7.98 - 7.92 (m, 4H);13 C NMR (100 MHz, DMSO-d6) δ 167.62, 151.69, 145.50, 145.26, 138.49, 130.38, 129.83, 125.12, 112.39.

[0028] Example 8: Methyl 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazolyl-2-yl)benzoate (Compound L) A 100 mL eggplant-shaped flask was charged with compound C (50 mg, 0.12 mmol), 4-cyanophenylboronic acid (35.2 mg, 0.24 mmol), Pd(PPh3)4 (28 mg, 0.025 mmol), CsF (51 mg, 0.24 mmol), dioxane (40 mmol), and water (10 mL). The mixture was incubated at 100 °C for 6 h under N2 protection. After TLC showed complete reaction, the mixture was cooled to room temperature and filtered to give 16 mg of a yellow solid (i.e., compound L) in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (m, 9H), 3.91 (s, 3H).

[0029] Example 9: 4-(5-Bromoimidazo[2,1-b][1,3,4]thiadiazolyl)-2-benzoylmorpholine (Intermediate 1) [ka] Compound D (2 g, 6.2 mmol), EDCI (2.4 g, 12.4 mmol), NHS (1.4 g, 12.4 mmol), and morpholine (2.7 g, 31 mmol) were dissolved in DMF (50 mL) and reacted at room temperature until the starting materials were completely reacted as detected by TLC. After removing the DMF by rotary evaporation, the mixture was purified by column chromatography (CH2Cl2:CH3OH=50:1) to give 1.8 g of a white solid (i.e., Intermediate 1) in a 75% yield. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.39 (s, 1H), 3.61 (s, 4H), 3.51 (s, 2H), 3.30 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 168.95, 161.56, 144.10, 138.68, 133.74, 131.25, 128.14, 127.24, 96.26, 66.82, 48.17, 42.65.

[0030] Example 10: 4-(5-Bromoimidazo[2,1-B][1,3,4]thiadiazolyl)-2-(4-dimethylaminobenzoylaminopiperidine) (Intermediate 2) [ka] Compound D (2 g, 6.2 mmol), EDCI (2.4 g, 12.4 mmol), NHS (1.4 g, 12.4 mmol), and 4-dimethylaminopiperidine (1.6 g, 12.4 mmol) were dissolved in DMF (50 mL) and reacted at room temperature until the starting materials were completely reacted as detected by TLC. After removing the DMF by rotary evaporation, the mixture was purified by column chromatography (CHCl:CHOH=50:1) to give 1.6 g of a white solid (i.e., intermediate 2) in a 59.3% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.46 (s, 1H), 4.45 (d, J = 13.1 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 3.06 (t, J = 12.9 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.47 - 2.37 (m, 1H), 2.21 (s, 6H), 1.86 (d, J = 12.9 Hz, 1H), 1.70 (d, J = 12.6 Hz, 1H), 1.39 (q, J = 13.5 Hz, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 168.13, 162.63, 144.34, 140.26, 133.98, 130.48, 128.44, 127.58, 96.51, 61.73, 46.71, 41.78, 28.74, 28.10.

[0031] Example 11: (N-methylpiperazine)-4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Intermediate 3) [ka] Compound D (8 mg, 0.18 mmol), (1-ethyl-3(3-dimethylpropylamino)carbodiimide) (69 mg, 0.36 mmol), and N-hydroxysuccinimide (42 mg, 0.36 mmol) were mixed in 10 mL of DMF and reacted at room temperature with stirring for 10 hours. Then, 99 μL of N-methylpiperazine was added and stirred for 1 hour. After that, the mixture was washed with water, extracted with chloroform, and subjected to column chromatography to obtain 50 mg of a yellow solid (i.e., intermediate 3). The yield was 68%. 1H NMR (400 MHz, CDCl3) δ 7.97 - 7.93 (m, 1H), 7.57 - 7.52 (m, 2H), 7.25 (s, 1H), 3.84 - 3.77 (m, 2H), 3.52 - 3.34 (m, 2H), 2.57 - 2.45 (m, 2H), 2.35 (s, 2H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.8, 161.7, 144.1, 139.2, 133.7, 131.0, 128.1, 127.2, 96.2, 55.2, 54.6, 47.6, 46.0, 42.1.

[0032] Example 12: 6-(4-morpholylcarbonylphenyl)imidazo[2,1-b][1,3,4]thiadiazole (Intermediate 4) [ka] Compound I (2 g, 8.2 mmol), EDCI (3.2 g, 16.4 mmol), NHS (1.9 g, 16.4 mmol), and morpholine (3.6 g, 41 mmol) were dissolved in DMF (50 mL) and reacted at room temperature until the starting materials were completely reacted as detected by TLC. After removing the DMF by rotary evaporation, the mixture was purified by column chromatography (CHCl:CHOH=50:1) to give 1.8 g of a white solid (i.e., intermediate 4) in 69.8% yield. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.72 (s, 6H), 3.56 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.22, 147.03, 146.49, 144.67, 135.43, 134.24, 127.80, 125.18, 110.13, 66.89, 48.27, 42.68.

[0033] Example 13: 6-(4-(N-methylpiperazinylcarbonylphenyl)imidazo[2,1-b][1,3,4]thiadiazole (Intermediate 5) [ka] Compound I (2 g, 8.2 mmol) and N-methylpiperazine (1.6 g, 16.4 mmol) were synthesized according to the method for synthesizing Intermediate 4 to give a white solid (1.6 g) in 59.6% yield. 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 3.82 (s, 2H), 3.51 (s, 2H), 2.50 (s, 2H), 2.39 (s, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.13, 146.80, 146.70, 144.61, 135.22, 134.82, 127.76, 125.15, 110.08, 55.18, 47.73, 46.04, 42.15.

[0034] Example 14: 6-(4-(4-dimethylamino)piperidinylcarbonylphenyl)imidazo[2,1-b][1,3,4]thiadiazole (Intermediate 6) [ka] Starting from compound I (2 g, 8.2 mmol) and 4-dimethylaminopiperidine (2.1 g, 16.4 mmol), a white solid (1.5 g) was obtained in 51.5% yield according to the synthesis method of intermediate 4. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.76 (s, 1H), 3.92 (s, 1H), 3.06 (s, 1H), 2.82 (s, 1H), 2.53 (ddt, J = 11.4, 7.5, 3.6 Hz, 1H), 2.35 (s, 6H), 1.87 (s, 2H), 1.52(s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.52, 147.55, 146.49, 144.95, 135.26, 134.73, 127.62, 125.29, 110.34, 62.19, 47.17, 41.66, 41.27, 28.78, 27.63.

[0035] Example 15: 6-(4-morpholylpiperidinylcarbonylphenyl)imidazo[2,1-b][1,3,4]thiadiazole (Intermediate 7) [ka] Starting from compound I (2 g, 8.2 mmol) and 4-morpholylpiperidine hydrochloride (3.4 g, 16.4 mmol), a white solid (900 mg) was obtained in 27.6% yield according to the synthesis method of Intermediate 4. 1 H NMR (400 MHz, CDCl3-CD3OD) δ 8.59 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.67 (s, 1H), 3.85 (s, 1H), 3.71 (t, J = 4.7 Hz, 4H), 3.01 (s, 1H), 2.75 (s, 1H), 2.59 (t, J = 4.8 Hz, 4H), 2.52 (s, 1H),1.97(s,1H), 1.83 (s,1H), 1.46 (s, 2H); 13C NMR (100 MHz, CDCl3-CD3OD) δ 172.74, 170.12, 147.22, 146.08, 144.60, 134.86, 134.34, 127.27, 124.95, 109.98, 66.36, 61.72, 49.24, 46.70, 41.26, 25.06.

[0036] Example 16: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (Intermediate 8) Compound L (340 mg, 1.01 mmol) and LiOH·HO (420 mg, 10 mmol) were mixed in 30 ml THF / HO (V:V=1:1) and stirred at room temperature for 12 h. After adjusting the pH to 2-3 with HCl, the mixture was filtered to give compound M (i.e., intermediate 8) as a white solid, which could be used in the next step without further purification.

[0037] Example 17: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 1) A 100 mL eggplant-shaped flask was charged with 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazolyl)-2-benzoylmorpholine (Intermediate 1) (200 mg, 0.5 mmol), 4-cyanophenylboronic acid (150 mg, 1 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), CsF (380 mg, 2.5 mmol), dioxane (40 mmol), and water (10 mL), and the mixture was reacted at 100 °C for 6 h under N2 protection. TLC showed that the raw materials had completely reacted. Dioxane was removed by distillation under reduced pressure, and dichloromethane and water were added. The mixture was transferred to a separatory funnel, shaken evenly, and allowed to stand. The organic layer was separated, the aqueous layer was extracted twice with dichloromethane, the organic layers were combined, the organic layers were washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, the filtrate was rotary evaporated, and purified by column chromatography (CH2Cl2:CH3OH=50:1) to obtain 40 mg of a white solid, with a yield of 19.2%. 1 H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 6.9 Hz, 2H), 8.02 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 7.8 Hz, 3H), 7.62 (d, J = 7.3 Hz, 2H), 3.82 (s, 4H), 3.68 (s, 2H), 3.48 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 168.85, 162.00, 146.97, 138.84, 132.76, 132.52, 132.06, 131.13, 128.58, 128.25, 127.21, 124.83, 118.78, 110.66, 66.81, 48.18, 42.62; HRMS (C 22 H 18 O2N5S + H) + Calculated value 416.1176, measured value 416.1168.

[0038] Example 18: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 2) A 100 mL eggplant-shaped flask was charged with 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazolyl)-2-benzoylmorpholine (Intermediate 1) (200 mg, 0.5 mmol), 4-fluorophenylboronic acid (140 mg, 1 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), CsF (380 mmol, 2.5 mmol), dioxane (40 mmol), and water (10 mL), and the mixture was reacted at 100 °C for 6 h under N2 protection. TLC showed that the raw materials were completely reacted. Dioxane was removed by rotary evaporation, and dichloromethane and water were added. The mixture was transferred to a separatory funnel, shaken evenly, and allowed to stand. The organic layer was separated, the aqueous layer was extracted twice with dichloromethane, the organic layers were combined, the organic layers were washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, the filtrate was rotary evaporated, and purified by column chromatography (CH2Cl2:CH3OH=50:1) to obtain 56 mg of a white solid, with a yield of 27.5%. 1 H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 6.4 Hz, 2H), 7.98 - 7.94 (m, 2H), 7.59 (d, J = 6.4 Hz, 3H), 7.20 (t, J = 7.8 Hz, 2H), 3.82 (s, 4H), 3.68 (s, 2H), 3.48 (s, 2H); 13 C NMR (125 MHz, CDCl3) δ 168.92, 163.29, 161.50, 144.92, 138.62, 135.70, 131.33, 129.69, 128.17, 127.16, 126.99, 124.36, 116.08, 114.45, 66.82, 48.12, 42.64; HRMS (C 21 H 18 O2N4FS + H) + Calculated value 409.1129, measured value 409.1119.

[0039] Example 19: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-hydroxyphenyl) (Compound 3) A 100 mL eggplant-shaped flask was charged with 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazolyl)-2-benzoylmorpholine (Intermediate 1) (200 mg, 0.5 mmol), 4-hydroxyphenylboronic acid (140 mg, 1 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), CsF (380 mmol, 2.5 mmol), dioxane (40 mmol), and water (10 mL), and the mixture was reacted at 100 °C for 6 h under N2 protection. TLC showed that the raw materials were completely reacted. Dioxane was removed by rotary evaporation, and dichloromethane and water were added. The mixture was transferred to a separatory funnel, shaken evenly, and allowed to stand. The organic layer was separated, the aqueous layer was extracted twice with dichloromethane, the organic layers were combined, the organic layers were washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, the filtrate was rotary evaporated, and purified by column chromatography (CH2Cl2:CH3OH=50:1) to obtain 60 mg of a white solid, with a yield of 29.5%. 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.08 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 3H), 6.91 (d, J = 8.8 Hz, 2H), 3.65 (s, 4H), 3.57 (s, 2H), 3.36 (s, 2H); 13 C NMR (125 MHz, DMSO-d6) δ 168.41,161.20, 157.55, 139.21, 131.02, 129.93, 128.65, 128.05, 127.47, 126.71, 119.54, 116.22, 66.48, 48.08, 42.48; HRMS (C 21 H 19 O3N4S + H) + Calculated value 407.1172, Measured value 407.1172.

[0040] Example 20: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methoxycarbonylphenyl) (Compound 4) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 4-methoxycarbonylphenylboronic acid (180 mg, 1 mmol), 78 mg of a white solid was obtained in 34.8% yield according to the synthesis method for Compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 3H), 8.08 (d, J = 8.6 Hz, 3H), 8.02 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 4H), 3.66 (s, 2H), 3.48 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 169.02, 166.77, 161.97, 146.13, 138.83, 133.72, 132.34, 131.25, 130.40, 129.11, 128.79, 128.35, 127.36, 124.63, 66.93, 52.37, 48.28, 42.75; HRMS (C 23 H 21 O4N4S + H) + Calculated value 499.1278, measured value 499.1269.

[0041] Example 21: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 5) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 4-trifluoromethylphenylboronic acid (190 mg, 1 mmol), 80 mg of a white solid was obtained in 34.9% yield according to the synthesis method for Compound 1. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 3H), 7.59 (d, J = 8.2 Hz, 2H), 3.82 (s, 4H), 3.66 (s, 2H), 3.48 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 168.98, 161.50, 146.46, 138.67, 132.29, 131.80, 131.41, 129.44, 128.24, 127.20, 125.92, 124.85, 122.76, 66.85, 48.22, 42.77; HRMS (C 22 H 18 O2N4F3S + H) + Calculated value 459.1097, measured value 459.1086.

[0042] Example 22: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-chlorophenyl) (Compound 6) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 4-chlorophenyl ronic acid (160 mg, 1 mmol), 76 mg of a white solid was obtained in 35.8% yield according to the synthesis method of Compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 3.80 (s, 4H), 3.67 (s, 2H), 3.51 (s, 2H), 3.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 169.02, 161.15, 145.70, 138.53, 133.34, 131.54, 131.23, 129.14, 128.20, 127.17, 126.94, 126.18, 66.85, 48.23, 42.58; HRMS (C 21 H 18 O2N4ClS + H) + Calculated value 425.0834, measured value 425.0823.

[0043] Example 23: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methylphenyl) (Compound 7) Compound 1 was synthesized using intermediate 1 (200 mg, 0.5 mmol) and 4-methylphenylboronic acid (140 mg, 1 mmol) as starting materials, and 64 mg of a white solid was obtained in a yield of 31.7% according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.58 (m, 3H), 7.30 (d, J = 7.9 Hz, 3H), 3.80 (s, 4H), 3.67 (s, 2H), 3.50 (s, 2H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 169.11, 160.63, 145.06, 138.33, 137.64, 131.79, 130.55, 129.59, 128.33, 128.13, 127.14, 125.63, 125.09, 66.86, 48.14, 42.67, 21.36; HRMS (C 22 H 21 O2N4S + H) + Calculated value 405.1380, measured value 405.1374.

[0044] Example 24: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-hydroxymethylphenyl) (Compound 8) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 4-hydroxymethylphenylboronic acid (152 mg, 1 mmol), 54 mg of a white solid was obtained in 25.7% yield according to the synthesis method for Compound 1. 1 H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 5.1 Hz, 4H), 7.58 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.74 (s, 2H), 3.81 (s, 4H), 3.65 (s, 2H), 3.46 (s, 2H), 2.40 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 169.19, 161.00, 145.43, 140.62, 138.36, 131.65, 130.86, 128.21, 128.01, 127.58, 127.19, 125.19, 66.92, 65.02, 48.31, 42.72; HRMS (C 22 H 21 O3N4S + H) + Calculated value 421.1329, measured value 421.1322.

[0045] Example 25: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-trifluoromethylphenyl) (Compound 9) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 3-fluoro-4-trifluoromethylphenylboronic acid (208 mg, 1 mmol), 78 mg of a white solid was obtained in 32.8% yield according to the synthesis method for Compound 1. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.2 Hz, 2H), 7.92 (dd, J = 11.8, 1.6 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 3.81 (s, 4H), 3.67 (s, 2H), 3.47 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 168.91, 161.95, 147.00, 138.85, 134.21, 133.03, 131.18, 128.29, 127.80, 127.24, 125.74, 119.84, 112.71, 66.84, 48.24, 42.67; HRMS (C 22 H 17 O2N4F4S + H) + Calculated value 477.1003, measured value 477.0989.

[0046] Example 26: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-hydroxyphenyl) (Compound 10) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 3-fluoro-4-hydroxyphenylboronic acid (156 mg, 1 mmol), 98 mg of a white solid was obtained in 46.2% yield according to the synthesis method for Compound 1. 1 H NMR (400 MHz, CDCl3-CD3OD) δ 7.94 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 12.2, 2.1 Hz, 1H), 7.51 (dd, J = 8.6, 2.5 Hz, 3H), 7.41 (s, 1H), 6.98 (t, J = 8.7 Hz, 1H), 3.75 (s, 4H), 3.60 (s, 2H), 3.42 (s, 2H); 13C NMR (100 MHz, CDCl3-CD3OD) δ 169.60, 161.23, 152.93, 150.54, 144.95, 138.31, 131.76, 129.74, 128.24, 127.41, 121.70, 120.44, 118.34, 113.07, 66.91, 42.84; HRMS (C 21 H 18 O3N4FS + H) + Calculated value 425.1078, measured value 425.1066.

[0047] Example 27: 2-(4-(benzoylmorpholyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3,4-difluorophenyl) (Compound 11) Starting from Intermediate 1 (200 mg, 0.5 mmol) and 3,4-difluorophenyl ronic acid (160 mg, 1 mmol), 68 mg of a white solid was obtained in 31.9% yield according to the synthesis method of Compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H), 7.87 (ddd, J = 11.6, 7.5, 2.2 Hz, 1H), 7.68 (dddd, J = 8.7, 3.9, 2.2, 1.4 Hz, 1H), 7.59 (m, 3H), 7.26 (dt, J = 10.1, 8.5 Hz, 1H), 3.80 (s, 4H), 3.67 (s, 2H), 3.48 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 169.00, 161.50, 151.90, 150.99, 149.43, 148.50, 145.76, 138.63, 131.38, 128.23, 127.20, 126.29, 125.49, 121.11, 118.03, 114.14, 66.84, 48.21, 42.69; 21 H 17 O2N4F2S + H) + Calculated value 427.1035, measured value 427.1024.

[0048] Example 28: 2-(4-(4-dimethylaminopiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 12) Starting from intermediate 2 (300 mg, 0.7 mmol) and 4-cyanophenylboronic acid (200 mg, 1.4 mmol), 50 mg of a white solid was obtained in 15.6% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 7.9 Hz, 2H), 7.80 - 7.73 (m, 3H), 7.60 (d, J = 7.9 Hz, 2H), 4.82 (s, 1H), 3.86 (s, 1H), 3.12 (s, 1H), 2.80 (m, 1H), 2.71 (s, 1H), 2.50 (s, 6H), 2.06 (s, 2H) 1.62 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 168.82, 161.88, 147.05, 139.18, 133.01, 132.78, 132.64, 131.13, 130.45, 128.06, 127.20, 126.58, HRMS (C 25 H 25 ON6S + H) + Calculated value 457.1805, measured value 457.1792.

[0049] Example 29: 2-(4-(4-dimethylaminopiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 13) Starting from intermediate 2 (300 mg, 0.7 mmol) and 4-fluorophenylboronic acid (200 mg, 1.4 mmol), 40 mg of a white solid was obtained in 12.7% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (m, 4H), 7.82 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 4.46 (s, 1H), 3.56 (s, 1H), 3.06 (s, 1H), 2.83 (s, 1H), 2.26 (s, 6H), 1.89 (s, 1H), 1.74 (s, 1H), 1.41 (s, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 168.29, 161.80, 160.64, 145.44, 139.58, 131.69, 130.92, 128.45, 127.57, 127.18, 126.78, 125.23, 116.59, 116.37, 62.21, 55.06, 29.51, 26.30; HRMS (C 24 H 25 ON5FS + H) + Calculated value 450.1758, measured value 450.1750.

[0050] Example 30: 2-(4-(4-dimethylaminopiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-hydroxyphenyl) (Compound 14) Starting from intermediate 2 (300 mg, 0.7 mmol) and 4-hydroxyphenylboronic acid (190 mg, 1.4 mmol), 50 mg of a white solid was obtained in 15.9% yield according to the synthesis method for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.46 (s, 1H), 3.53 (s, 1H), 3.03 (s, 1H), 2.82 (s, 1H), 2.51 (m, 1H), 2.24 (s, 6H), 1.84 (s, 1H), 1.69 (s, 1H), 1.38 (s, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 168.17, 161.26, 157.60, 144.25, 139.90, 130.85, 129.92, 128.34, 128.06, 127.45, 126.71, 119.54, 116.25, 61.73, 46.60, 41.54, 41.05, 28.54, 27.89; 24 H 26 O2N5S + H) + Calculated value 448.1802, measured value 448.1798.

[0051] Example 31: 2-(4-(4-dimethylaminopiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methoxyphenyl) (Compound 15) Compound 1 was synthesized using intermediate 2 (300 mg, 0.7 mmol) and 4-methoxyphenylboronic acid (210 mg, 1.4 mmol) as starting materials, and 40 mg of a pale yellow solid was obtained in a yield of 12.4% according to the synthesis method for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.51 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.78 (s, 1H), 3.87 (s, 4H), 2.85 (s, 1H), 2.70 (m, 1H), 2.44 (s, 6H), 2.00 (s, 2H), 1.54 (s, 2H); 13 C NMR (101 MHz, CDCl3) δ 169.05, 160.73, 159.24, 144.76, 138.81, 132.58, 131.70, 129.93, 127.98, 127.14, 126.65, 121.23, 114.40, 62.37, 55.47, 41.11, 29.80; HRMS (C 25 H 28 O2N5S + H) + Calculated value 462.1958, measured value 462.1947.

[0052] Example 32: 2-(4-(4-dimethylaminopiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 16) Compound 1 was synthesized using intermediate 2 (300 mg, 0.7 mmol) and 4-trifluoromethylphenylboronic acid (260 mg, 1.4 mmol) as starting materials, and 32 mg of a white solid was obtained in a 9.2% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 9.7 Hz, 3H), 7.57 (d, J = 8.6 Hz, 2H), 4.76 (s, 1H), 3.80 (s, 1H), 3.07 (s, 2H), 2.58 (m, 1H), 2.39 (s, 6H), 2.00 (s, 2H), 1.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.87, 161.55, 146.44, 139.10, 132.24, 131.79, 131.28, 128.01, 127.15, 126.83, 125.94, 124.84, 62.31, 46.67, 41.04, 31.93, 29.71, 29.37; HRMS (C 25 H 25 ON5F3S + H) + Calculated value 500.1726, measured value 500.1718.

[0053] Example 33: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 17) Starting from intermediate 3 (200 mg, 0.5 mmol) and 4-cyanophenylboronic acid (150 mg, 1 mmol), 45 mg of a white solid was obtained in 21% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 8.3 Hz, 3H), 7.59 (d, J = 8.0 Hz, 2H), 3.83 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.36 (s, 2H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.78, 161.94, 147.06, 139.34, 133.01, 132.77, 132.65, 131.01, 128.20, 127.15, 126.37, 124.79, 118.85, 110.55, 55.23, 54.64, 47.65, 46.02, 42.18; 23 H 21 ON6S + H) + Calculated value 429.1492, measured value 429.1485.

[0054] Example 34: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 18) Starting from intermediate 3 (200 mg, 0.5 mmol) and 4-fluorophenylboronic acid (140 mg, 1 mmol), 60 mg of a white solid was obtained in 28.6% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 7.97 (m, 4H), 7.56 (m, 3H), 7.17 (m, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.52 (s, 2H), 2.37 (s, 2H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.99, 163.51, 161.27, 161.05, 145.36, 139.06, 131.43, 130.65, 128.20, 127.42, 127.17, 126.94, 124.77, 116.17, 115.95, 55.32, 54.71, 47.70, 46.12, 42.18; 22 H 21 ON5FS + H) + Calculated value 422.1445, measured value 422.1437.

[0055] Example 35: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methoxycarbonylphenyl) (Compound 19) Compound 1 was synthesized using intermediate 3 (200 mg, 0.5 mmol) and 4-methoxycarbonylphenylboronic acid (180 mg, 1 mmol) as starting materials, and 46 mg of a white solid was obtained in a 20% yield according to the synthesis method for compound 1. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 3.94 (s, 3H), 3.83 (s, 2H), 3.46 (s, 2H), 2.52 (s, 2H), 2.38 (s, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.95, 166.83, 161.54, 146.61, 139.20, 132.73, 132.56, 131.30, 130.37, 128.81, 128.24, 127.27, 127.22, 124.42, 55.33, 52.33, 47.73, 46.15, 42.25, 29.80; 24 H 24 O3N5S + H) + Calculated value 462.1594, measured value 462.1582.

[0056] Example 36: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-pyridine) (Compound 20) Starting from intermediate 3 (200 mg, 0.5 mmol) and pyridine-4-boronic acid (120 mg, 1 mmol), 50 mg of a white solid was obtained in 24.7% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 6.3 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 6.3 Hz, 2H), 7.81 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.36 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.86, 162.03, 150.51, 147.41, 139.33, 135.55, 133.49, 131.07, 128.27, 127.23, 125.53, 118.44, 55.30, 54.68, 47.69, 46.11, 42.20; HRMS (C 21 H 20 ON6S + H) + Calculated value 405.1458, measured value 405.1465.

[0057] Example 37: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 21) Starting from Intermediate 3 (200 mg, 0.5 mmol) and 4-trifluoromethylphenylboronic acid (190 mg, 1 mmol), 54 mg of a white solid was obtained in 23% yield according to the synthesis method for Compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.7 Hz, 3H), 7.57 (d, J = 8.4 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.36 (s, 2H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.93, 161.71, 146.51, 139.25, 132.25, 131.83, 131.23, 128.25, 127.21, 126.88, 125.99, 124.91, 55.34, 54.72, 47.74, 46.15, 42.24; HRMS (C 23 H 21 ON5F3S + H) + Calculated value 472.1413, measured value 472.1407.

[0058] Example 38: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-chlorophenyl) (Compound 22) Starting from intermediate 3 (200 mg, 0.5 mmol) and 4-chlorophenyl ronic acid (160 mg, 1 mmol), 56 mg of a white solid was obtained in 25.6% yield according to the synthesis method of compound 1. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 3.83 (s, 2H), 3.46 (s, 2H), 2.52 (s, 2H), 2.38 (s, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.99, 161.37, 145.83, 139.18, 133.42, 131.43, 131.30, 129.24, 128.23, 127.26, 127.20, 127.07, 126.28, 55.38, 54.78, 47.78, 46.17, 42.30; HRMS (C 22 H 21 ON5ClS + H) + Calculated value 438.1150, measured value 438.1145.

[0059] Example 39: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-trifluoromethylphenyl) (Compound 23) Starting from intermediate 3 (200 mg, 0.5 mmol) and 3-fluoro-4-trifluoromethylphenylboronic acid (210 mg, 1 mmol), 78 mg of a white solid was obtained in 31.8% yield according to the synthesis method for compound 1. 1H NMR (600 MHz, CDCl3) δ 8.00 - 7.89 (m, 3H), 7.83 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.57 (m, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.37 (m, 2H), 2.33 (m, 3H); 13 C NMR (150 MHz, CDCl3) δ 168.86, 162.14, 147.09, 139.44, 134.28, 133.77, 133.07, 131.06, 128.29, 128.16, 127.25, 119.95, 112.59, 55.31, 54.72, 47.70, 46.09, 42.22; HRMS (C 23 H 20 ON5F4S + H) + Calculated value 490.1319, measured value 490.1307.

[0060] Example 40: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-cyanophenyl) (Compound 24) Starting from intermediate 3 (200 mg, 0.5 mmol) and 3-fluoro-4-cyanophenylboronic acid (160 mg, 1 mmol), 66 mg of a white solid was obtained in 29.6% yield according to the synthesis method for compound 1. 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.96 (dd, J = 10.4, 1.6 Hz, 1H), 7.85 (dd, J = 8.1, 1.6 Hz, 1H), 7.78 (s, 1H), 7.69 (dd, J = 8.2, 6.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.37 (s, 2H), 2.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.79, 162.50, 147.71, 139.60, 135.22, 134.00, 130.87, 128.34, 127.28, 120.44, 114.11, 111.73, 55.33, 54.71, 47.70, 46.10, 42.22; HRMS (C 23 H 20 ON6FS + H) + Calculated value 477.1398, measured value 477.1400.

[0061] Example 41: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-nitrophenyl) (Compound 25) Starting from intermediate 3 (200 mg, 0.5 mmol) and 4-nitrophenylboronic acid (170 mg, 1 mmol), 88 mg of a white solid was obtained in 39.3% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.83 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 3.84 (s, 2H), 3.48 (s, 2H), 2.53 (s, 2H), 2.39 (s, 2H), 2.35 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 167.43, 160.80, 146.13, 145.11, 138.12, 133.23, 132.28, 129.64, 126.91, 125.86, 124.84, 123.44, 123.17, 53.92, 53.37, 46.36, 44.72, 40.83; HRMS (C 22 H 21 O3N6S + H) + Calculated value 449.1390, measured value 449.1386.

[0062] Example 42: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(2,4-difluorophenyl) (Compound 26) Starting from intermediate 3 (200 mg, 0.5 mmol) and 3,4-difluoro-phenylboronic acid (160 mg, 1 mmol), 78 mg of a white solid was obtained in 35.6% yield according to the synthesis method for compound 1. 1 H NMR (400 MHz, CDCl3) δ 8.39 - 7.90 (m, 3H), 7.75 - 7.50 (m, 3H), 7.25 (s, 1H) 7.09 - 6.92 (m, 1H), 3.81 (s, 2H), 3.44 (s, 2H), 2.50 (s, 2H), 2.36 (s, 3H), 2.32 (d, J = 1.0 Hz, 5H); 13 C NMR (100 MHz, CDCl3) δ 168.86, 161.68, 161.11, 144.13, 139.23, 139.09, 134.16, 133.71, 131.31, 131.05, 128.09, 127.17, 111.78, 104.67, 55.23, 54.67, 47.64, 46.03, 42.18; 22 H 20 ON5F2S + H) + Calculated value 440.1351, measured value 440.1348.

[0063] Example 43: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyano-3-pyridine) (Compound 27) Starting from Intermediate 3 (200 mg, 0.5 mmol) and 2-cyano-5-pyridineboronic acid (150 mg, 1 mmol), 76 mg of a white solid was obtained in 35% yield according to the synthesis method for Compound 1. 1H NMR (400 MHz, CDCl3) δ 9.40 (d, J = 2.3 Hz, 1H), 8.46 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.82 - 7.76 (m, 2H), 7.59 (d, J = 8.6 Hz, 2H), 3.83 (s, 2H), 3.46 (s, 2H), 2.52 (s, 2H), 2.38 (s, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.70, 162.68, 147.88, 146.78, 139.59, 133.72, 131.37, 130.72, 128.62, 128.27, 127.80, 127.20, 123.53, 117.34, 55.20, 54.60, 47.63, 46.01, 42.15; 22 H 20 ON7S + H) + Calculated value 430.1445, measured value 430.1435.

[0064] Example 44: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-fluoro-3-pyridine) (Compound 28) Starting from intermediate 3 (200 mg, 0.5 mmol) and 2-fluoro-5-pyridineboronic acid (140 mg, 1 mmol), 65 mg of a white solid was obtained in 30.8% yield according to the synthesis method for compound 1. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 2.5 Hz, 1H), 8.36 (ddd, J = 8.6, 7.5, 2.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.07 (ddd, J = 8.6, 3.1, 0.7 Hz, 1H), 3.83 (s, 2H), 3.46 (s, 2H), 2.50 (d, J = 5.9 Hz, 2H), 2.38 (s, 2H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.83, 163.91, 161.87, 161.52, 146.18, 144.13, 139.25, 137.46, 131.39, 131.09, 128.18, 127.12, HRMS (C 21 H 20 ON6FS + H) + Calculated value 423.1398, measured value 423.1393.

[0065] Example 45: 2-(4-(N-methylpiperidinylcarbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethyl-3-pyridine) (Compound 29) Compound 1 was synthesized using intermediate 3 (200 mg, 0.5 mmol) and 2-(trifluoromethyl)pyridine-5-boronic acid (190 mg, 1 mmol) as starting materials, to give 75 mg of a white solid in 31.8% yield. 1H NMR (400 MHz, CDCl3) δ 9.35 (dd, J = 2.3, 0.9 Hz, 1H), 8.45 (dd, J = 8.2, 2.3 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.83 (s, 1H), 7.78 (dd, J = 8.2, 0.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 2H), 2.51 (s, 2H), 2.38 (s, 2H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.75, 162.34, 147.31, 145.88, 139.48, 132.99, 132.37, 130.88, 128.22, 127.46, 127.14, 123.86, 120.66, 55.26, 54.61, 47.64, 46.03, 42.16; HRMS (C 22 H 20 ON6F3S + H) + Calculated value 473.1366, measured value 473.1355.

[0066] Example 46: 4-(2-(4-pyrrolidyl-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 30) A mixture of intermediate 8 (65 mg, 0.18 mmol), EDCI (60 mg, 0.36 mmol), and NHS (42 mg, 0.36 mmol) in 10 mL of DMF was stirred at room temperature for 10 h. Pyrrolizidine (65 μL, 0.9 mmol) was then added and the reaction was continued for an additional 1 h. After TLC showed complete reaction of the starting material, the mixture was quenched with water and extracted three times with DCM. The organic layer was washed three times with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, and the filtrate was rotary evaporated. The product was purified by column chromatography (DCM:MeOH = 15:1) to give a white solid (50 mg) in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.3 Hz, 2H), 8.08 - 8.02 (m, 3H), 7.91 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3.37 (t, J = 6.2 Hz, 2H), 1.89-1.76 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 167.5, 162.5, 147.3, 141.0, 134.3, 133.5, 132.8, 130.8, 128.7, 127.4, 126.1, 124.9, 119.4, 109.7, 49.3, 46.6, 26.5, 24.5. HRMS (M+H)+ calculated 400.1227, found 400.1217.

[0067] Example 47: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(2-(pyrrolidyl)ethyl)benzoyl ester (Compound 31) Starting from 1-(2-hydroxyethyl)pyrrolidine (104 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a white solid was obtained in 60% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ, 8.29 (d, J = 8.2 Hz, 2H), 8.16 - 8.09 (m, 3H), 8.05 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 4.42 (dd, J = 12.5, 6.3 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), 2.51 - 2.47 (m, 4H), 1.64 - 1.74 (m, 4H). HRMS (M+H)+ Calculated value 443.1449, Actual value 443.1452.

[0068] Example 48: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(n-pentyl)benzoyl ester (Compound 32) Starting from n-pentanethiol (91.8 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 53% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 9.7 Hz, 3H), 8.01 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 3.53 (t, J = 5.1 Hz, 1H), 1.97 (dd, J = 11.5, 6.1 Hz, 2H), 1.82 - 1..77 (m, 4H), 1.32 (p, J = 6.5 Hz, 2H),0.8 (p, J = 6.5 Hz, 2H). HRMS (M+H)+ calculated 432.1176, found 432.1163.

[0069] Example 49: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(3-(morpholyl)propyl)benzoyl ester (Compound 33) Compound 30 was synthesized from N-(3-hydroxypropyl)morpholine (131 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) according to the method for preparing compound 30, to give a yellow solid in 45% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.4 Hz, 2H), 8.03 - 8.09 (m, 3H), 7.82 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 3.50 (t, J = 4.3 Hz, 4H), 3.35 - 3.30 (m, 2H), 2.41 - 2.31 (m, 2H), 1.72 (p, J = 7.0 Hz, 2H). HRMS (M+H)+ Calculated value 473.1528, Actual value 473.1542

[0070] Example 50: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(5-hydroxypentyl)benzoyl ester (Compound 34) Starting from 1,5-pentanediol (94 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained according to the synthesis method of compound 30 in 45% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 9.5 Hz, 3H), 7.96 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 3.21 (t, J = 5.1 Hz, 2H), 3.41 (dd, J = 11.6, 6.3 Hz, 2H), 1.69 (dd, J = 12.9, 6.7 Hz, 2H), 1.31 - 1.22 (m, 2H), 1.06 (m, 2H). HRMS (M+H)+ Calculated value 432.1347, Actual value 432.1356.

[0071] Example 51: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(2-hydroxyethyl)benzoyl thioester (Compound 35) Starting from 2-mercaptoethanol (70.2 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), the synthesis of compound 30 was followed to give a yellow solid in 35% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.4 Hz, 2H), 8.10–8.01 (m, 3H), 7.90 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 4.80 (t, J = 5.6 Hz, 1H), 3.66 (q, J = 6.0 Hz, 2H), 3.28 (dd, J = 11.7, 5.8 Hz, 2H). HRMS (M+H)+ calculated 406.0622, found 406.0635.

[0072] Example 52: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(2-(dimethylamino)ethyl)benzamide (Compound 36) Starting from N,N-dimethyl-1,2-ethylenediamine (80 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 35% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.26 (d, J = 7.8 Hz, 2H), 8.10 (d, J = 10.0 Hz, 3H), 8.03 (d, J = 7.5 Hz, 2H), 7.94 (d, J = 7.8 Hz, 2H), 3.37 (t, J = 4.0 Hz, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.20 (s, 6H). 13C NMR (100 MHz, DMSO-d6) δ 162.5, 147.4, 138.1, 134.4, 133.5, 132.9, 132.1, 128.9, 127.5, 126.1, 125.1, 119.5, 109.8, 100.00, 58.6, 45.8, 38.1. HRMS (M+H)+ calculated 417.1492, found 417.1488.

[0073] Example 53: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(3-(morpholyl)propyl)benzamide (Compound 37) Compound 30 was synthesized from N-(3-aminopropyl)morpholine (130 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) to give a yellow solid in 47% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 5.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 8.08 - 8.14 (m, 3H), 8.04 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 3.58 (t, J = 4.3 Hz, 4H), 3.35 - 3.30 (m, 2H), 2.41 - 2.31 (m, 6H), 1.72 (p, J = 7.0 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 165.5, 162.4, 147.3, 138.1, 134.3, 133.4, 132.8, 131.9, 128.7, 127.4, 126.0, 124.9, 119.4, 109.7, 66.7, 56.5, 53.8, 38.4, 26.4. HRMS (M+H)+ calculated 473.1730, found 473.1742.

[0074] Example 54: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(2-(pyrrolidyl)ethyl)benzamide (Compound 38) Starting from 1-(2-aminoethyl)pyrrolidine (102 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a white solid was obtained in 62% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.2 Hz, 1H), 8.29 (d, J = 8.2 Hz, 2H), 8.16 - 8.09 (m, 3H), 8.05 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 3.42 (dd, J = 12.5, 6.3 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.51 - 2.47 (m, 4H), 1.64 - 1.74 (m, 4H). 13 C NMR (100 MHz, DMSO-d₆) δ 165.5, 162.4, 147.2, 138.0, 134.4, 133.5, 132.9, 132.0, 128.8, 127.4, 126.1, 125.0, 119.4, 109.7, 55.3, 54.2, 23.6. HRMS (M+H)+ calculated 443.1649, found 473.1642.

[0075] Example 55: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(3-hydroxypropyl)benzamide (Compound 39) Starting from 3-aminopropanol (68 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 28% yield according to the synthesis method for compound 30. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 5.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 2H), 8.12 (d, J = 9.7 Hz, 3H), 8.05 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 4.53 (t, J = 5.1 Hz, 1H), 3.50 (dd, J = 11.5, 6.1 Hz, 2H), 3.40 - 3.35 (m, 2H), 1.72 (p, J = 6.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 165.5, 162.3, 147.2, 138.1, 134.3, 133.4, 132.8, 131.9, 128.7, 127.3, 126.0, 124.9, 119.4, 109.7, 59.1, 37.3, 32.8. HRMS (M+H)+ calculated 404.1176, found 404.1173.

[0076] Example 56: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(2-hydroxyethyl)benzamide (Compound 40) Starting from ethanolamine (55 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 36% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.5 Hz, 1H), 8.28 (d, J = 8.4 Hz, 2H), 8.15 - 8.10 (m, 3H), 8.07 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 4.80 (t, J = 5.6 Hz, 1H), 3.56 (q, J = 6.0 Hz, 2H), 3.38 (dd, J = 11.7, 5.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 165.7, 162.4, 147.3, 138.0, 134.3, 133.5, 132.9, 131.9, 128.8, 127.3, 126.0, 124.9, 119.4, 109.7, 60.1, 42.8. HRMS (M+H)+ calculated 390.1019, found 390.1018.

[0077] Example 57: 4-(2-(4-methylpiperidinyl-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 41) Starting from 2-methylpiperidine (89 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 46% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.5 Hz, 2H), 8.09 (d, J = 8.6 Hz, 3H), 7.96 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 5.03 - 3.59 (m, 2H), 2.99 (d, J = 37.9 Hz, 1H), 1.75 - 1.33 (m, 6H), 1.22 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d₆) δ 168.4, 162.5, 147.2, 140.9, 134.3, 133.4, 132.9, 130.3, 127.8, 127.7, 126.0, 124.9, 119.4, 109.7, 30.2, 25.9, 18.9. HRMS (M+H)+ calculated 428.1540, found 428.1533.

[0078] Example 58: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(5-hydroxypentyl)benzamide (Compound 42) Starting from 5-amino-1-pentanol (93 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol), a yellow solid was obtained in 48% yield according to the synthesis method for compound 30. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 5.4 Hz, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 9.5 Hz, 3H), 8.06 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 4.39 (t, J = 5.1 Hz, 1H), 3.41 (dd, J = 11.6, 6.3 Hz, 2H), 3.29 (dd, J = 12.9, 6.7 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.46 (dd, J = 13.9, 6.8 Hz, 2H), 1.40 - 1.31 (m, 2H). 13 C NMR (100 MHz, DMSO-d₆) δ 165.4, 162.4, 147.3, 138.2, 134.3, 133.5, 132.8, 131.9, 128.8, 127.4, 126.0, 125.0, 119.4, 109.7, 61.1, 32.7, 29.5, 23.6. HRMS (M+H)+ calculated 432.1489, found 432.1479.

[0079] Example 59: 6-(4-morpholylcarbonylphenyl)-3-(4-cyanophenyl)imidazo[2,1-b]thiazole (Compound 43) A 50 mL eggplant-shaped flask was charged with intermediate 4 (500 mg, 1.6 mmol), 4-cyanophenylacetylene (240 mg, 1.9 mmol), potassium t-butoxide (540 mg, 4.8 mmol), and DMF (40 mL). The mixture was allowed to react at room temperature with magnetic stirring for 6 h. TLC indicated complete reaction of the starting materials. The reaction bottle was charged with dichloromethane and water, transferred to a separatory funnel, and shaken evenly. The organic layer was separated, extracted twice with dichloromethane, combined, washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, and the filtrate was rotary evaporated. The mixture was purified by column chromatography (CHCl2:CH3OH=50:1) to give a white solid (200 mg) in 30.2% yield. 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7. 89 (m, 1H), 7.87 (m, 3H), 7.81 (m, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.98 (s, 1H), 3.76 (s, 6H), 3.52 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.29, 150.45, 147.16, 135.21, 134.26, 133.86, 133.28, 130.78, 127.84, 127.29, 125.39, 117.98, 113.43, 111.64, 107.75, 66.91, 48.08, 42.57; 23 H 19 O2N6S + H) + Calculated value 415.1223, measured value 415.1226.

[0080] Example 60: 6-(4-morpholylcarbonylphenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 44) Compound 30 was synthesized from intermediate 4 (500 mg, 1.6 mmol) and 4-fluorophenylacetylene (230 mg, 1.9 mmol) according to the method for synthesizing compound 30, to give a white solid (170 mg) in 26% yield. 1 H NMR (400 MHz, CDCl3) δ 7.88 (m, 3H), 7.65 (dd, J = 8.8, 5.1 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.24 (m, 2H), 6.77 (s, 1H), 3.75 (s, 6H), 3.51 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.36, 164.64, 162.14, 150.41, 146.96, 135.73, 133.99, 131.57, 129.04, 128.96, 127.78, 126.03, HRMS (C 22 H 19 O2N3FS + H) + Calculated value 408.1177, measured value 408.1178.

[0081] Example 61: 6-(4-morpholylcarbonylphenyl)-3-(4-methoxyphenyl)imidazo[2,1-b]thiazole (Compound 45) Compound 30 was synthesized from intermediate 4 (500 mg, 1.6 mmol) and 4-methoxyphenylacetylene (250 mg, 1.9 mmol) according to the method for synthesizing compound 30, to give a white solid (280 mg) in 41.7% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 1.2 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H), 3.73 - 3.47 (m, 8H); 13 C NMR (100 MHz, DMSO-d6) δ 169.53, 162.85, 161.52, 160.58, 149.93, 146.21, 135.86, 134.35, 132.17, 128.84, 128.07, 125.20, HRMS (C 23 H 22 O3N3S + H) + Calculated value 420.1376, measured value 420.1370.

[0082] Example 62: 6-(4-morpholylcarbonylphenyl)-3-(4-trifluoromethylphenyl)imidazo[2,1-b]thiazole (Compound 46) Compound 30 was synthesized from intermediate 4 (500 mg, 1.6 mmol) and 4-trifluoromethylphenylacetylene (320 mg, 1.9 mmol) according to the method for synthesizing compound 30, to give a white solid (220 mg) in a yield of 30.1%. 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.82 (m, 4H), 7.46 (d, J = 8.3 Hz, 2H), 6.93 (s, 1H), 3.76 (s, 6H), 3.52 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 170.31, 150.45, 147.19, 135.53, 134.15, 133.22, 131.19, 127.81, 127.22, 126.53, 125.30, 110.52, 107.73, 66.93, 48.32, 42.60; HRMS (C 23 H 19 O2N3S + H) + Calculated value 458.1145, measured value 458.1144.

[0083] Example 63: 6-(4-morpholylcarbonylphenyl)-3-(4-chlorophenyl)imidazo[2,1-b]thiazole (Compound 47) Compound 30 was synthesized from intermediate 4 (500 mg, 1.6 mmol) and 4-chlorophenylacetylene (260 mg, 1.9 mmol) according to the method for synthesizing compound 30, to give a white solid (265 mg) in a 39.1% yield. 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 4.4 Hz, 2H), 7.85 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 3.73 (s, 6H), 3.51 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.32, 150.40, 146.95, 135.77, 135.66, 134.01, 131.44, 129.71, 128.17, 127.78, 125.24, 109.22, 107.80, 66.92, 48.30, 42.71; HRMS (C 22 H 19 O2N3ClS + H) + Calculated value 424.0881, measured value 424.0870.

[0084] Example 64: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-cyanophenyl)imidazo[2,1-b]thiazole (Compound 48) Compound 30 was synthesized from intermediate 5 (500 mg, 1.5 mmol) and 4-cyanophenylacetylene (230 mg, 1.8 mmol) according to the synthesis method for compound 30, to give a white solid (280 mg) in 43.7% yield. 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.88 - 7.84 (m, 4H), 7.80 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 6.97 (s, 1H), 3.80 (s, 2H), 3.49 (s, 2H), 2.48 (s, 2H), 2.36 (s, 2H), 2.32 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.15, 150.41, 147.48, 135.24, 134.71, 133.99, 133.26, 130.77, 127.77, 127.26, 125.26, 118.00, 113.37, 111.39, 107.63, 55.05, 47.56, 45.96, 41.99; 24 H 22 ON5S + H) + Calculated value 428.1540, measured value 428.1535.

[0085] Example 65: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 49) Compound 30 was synthesized from intermediate 5 (500 mg, 1.5 mmol) and 4-fluorophenylacetylene (220 mg, 1.8 mmol) according to the method for synthesizing compound 30, to give a white solid (220 mg) in 34.9% yield. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 3H), 7.64 (dd, J = 8.8, 5.1 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.79 (s, 2H), 3.49 (s, 2H), 2.48 (s, 2H), 2.35 (s, 2H), 2.31 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.24, 164.61, 162.11, 150.35, 147.03, 135.51, 134.48, 131.55, 129.02, 127.71, 126.04, 125.17, 116.51,108.65,107.65,55.21,54.82,47.70,46.02,42.15; 23 H 22 ON4FS + H) + Calculated value 421.1493, measured value 421.1490.

[0086] Example 66: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-trifluoromethylphenyl)imidazo[2,1-b]thiazole (Compound 50) Compound 30 was synthesized from intermediate 5 (500 mg, 1.5 mmol) and 4-trifluoromethylphenylacetylene (310 mg, 1.8 mmol) according to the method for synthesizing compound 30, to give a white solid (300 mg) in 42.5% yield. 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.80 (m, 4H), 7.44 (d, J = 8.6 Hz, 2H), 6.91 (s, 1H), 3.79 (s, 2H), 3.49 (s, 2H), 2.47 (s, 2H), 2.36 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.66, 148.87, 145.72, 133.82, 133.04, 131.68, 129.63, 126.19, 125.66, 124.97, 123.68, 108.92, 106.15, 53.55, 46.07, 44.43, 40.52; HRMS (C 24 H 22 ON4F3S + H) + Calculated value 471.1461, measured value 471.1452.

[0087] Example 67: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-chlorophenyl)imidazo[2,1-b]thiazole (Compound 51) Compound 30 was synthesized from intermediate 5 (500 mg, 1.5 mmol) and 4-chlorophenylacetylene (245 mg, 1.8 mmol) according to the method for synthesizing compound 30, to give a white solid (264 mg) in a 40.3% yield. 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 6.78 (s, 1H), 3.78 (s, 2H), 3.48 (s, 2H), 2.46 (s, 2H), 2.35 (s, 2H),2.30 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 170.22, 150.37, 147.04, 135.77, 135.45, 134.47, 131.44, 129.70, 128.23, 128.17, 127.70, 125.17, 109.15, 107.72, 55.18, 54.86, 47.68, 46.00, 42.09; 23 H 22 ON4ClS + H) + Calculated value 437.1197, Measured value 437.1197.

[0088] Example 68: 6-(4-(4-morpholylpiperidinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 52) Compound 30 was synthesized from intermediate 6 (500 mg, 1.3 mmol) and 4-fluorophenylacetylene (190 mg, 1.6 mmol) according to the method for synthesizing compound 30, to give a white solid (280 mg) in a 43.9% yield. 1 H NMR (400 MHz, CDCl3) δ 7.85 (m, 3H), 7.64 (dd, J = 8.8, 5.1 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.7 Hz,2H), 6.75 (s, 1H), 4.71 (s, 1H), 3.88 (s, 1H), 3.71 (t, J = 4.6 Hz, 4H), 3.02 (s, 1H), 2.81 (s, 1H), 2.55 (t, J = 4.6 Hz, 4H), 2.43 (m, 1H), 1.96 (s, 1H), 1.82(s, 1H), 1.58(s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.19, 164.62, 162.13, 150.36, 147.07, 135.44, 134.75, 131.56, 129.03, 128.95, 127.53, 126.02, HRMS (C 27 H 28 O2N4FS + H) + Calculated value 491.1912, measured value 491.1908.

[0089] Example 69: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 53) Compound 30 was synthesized from intermediate 7 (500 mg, 1.4 mmol) and 4-fluorophenylacetylene (200 mg, 1.7 mmol) according to the method for synthesizing compound 30, to give a white solid (215 mg) in a 34.2% yield. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 9.1 Hz, 3H), 7.64 (dd, J = 8.8, 5.1 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.73 (s, 1H), 3.87 (s, 1H), 3.01 (s, 1H), 2.80 (s, 1H), 2.48 (m, 1H), 2.34 (s, 6H), 2.03 - 1.78 (m, 2H), 1.48 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.22, 164.61, 162.12, 150.35, 147.05, 135.47, 134.69, 131.56, 129.02, 128.94, 127.54, 126.04, HRMS (C 25 H 26 ON4FS + H) + Calculated value 499.1806, measured value 499.1795.

[0090] Example 70: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-trifluoromethylphenyl)imidazo[2,1-b]thiazole (Compound 54) Compound 30 was synthesized from intermediate 7 (500 mg, 1.4 mmol) and 4-trifluoromethylphenylacetylene (290 mg, 1.7 mmol) according to the method for synthesizing compound 30, to give a white solid (284 mg) in a 40.7% yield. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.79 (m, 4H), 7.42 (d, J = 8.3 Hz, 2H), 6.91 (s, 1H), 4.73 (s, 1H), 3.87 (s, 1H), 3.01 (s, 1H), 2.80 (s, 1H), 2.49 (m, 1H), 2.34 (s, 6H), 1.97 (s, 2H), 1.49 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.17, 150.40, 147.25, 135.31, 134.81, 133.22, 131.17, 127.56, 127.20, 126.50, 125.22, 122.33, 110.49, 107.72, 62.26, 46.96, 41.36, 28.88, 27.77; 26 H 26 ON4F3S + H) + Calculated value 499.1774, measured value 499.1783.

[0091] Example 71: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-chlorophenyl)imidazo[2,1-b]thiazole (Compound 55) Compound 30 was synthesized from intermediate 7 (500 mg, 1.4 mmol) and 4-chlorophenylacetylene (230 mg, 1.7 mmol) according to the method for synthesizing compound 30, to give a white solid (254 mg) in 39% yield. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 1H), 3.88 (s, 1H), 3.01 (s, 1H), 2.79 (s, 1H), 2.52 (m, 1H), 2.35 (s, 6H), 1.88 (s, 2H), 1.49 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.21, 150.38, 147.08, 135.79, 135.44, 134.66, 131.46, 129.72, 128.25, 128.18, 127.55, 125.19, 109.13, 107.71, 62.29, 46.89, 41.27, 28.70, 27.68; HRMS (C 25 H 26 ON4ClS + H) + The calculated value is 465.1510, and the measured value is 465.1501.

[0092] Example 72: Production of compound 56-61

change

[0093] N-(3-(dimethylamine)-2,2-dimethylpropyl)-4-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Compound 56) A round-bottom flask was charged with Q2 (0.5 mmol), EDCI (1 mmol), NHS (1 mmol), and N,N,2,2-tetramethyl-1,3-propanediamine (2.5 mmol), followed by DMF, and the mixture was stirred at room temperature for 12 h. After the reaction was judged complete by thin-layer chromatography (TLC), the reaction mixture was diluted with water and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography (DCM:MeOH = 10:1) to give compound 51 as a white solid in 45% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.08 (s, 4H), 7.90 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 3.30 (s, 2H), 3.01 (s, 2H), 2.88 (s, 6H), 1.07 (s, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 166.9, 161.1, 159.1, 158.8, 158.5, 158.1, 145.9, 145.0, 137.3, 133.7, 132.4, 129.1 (d, J = 3.4 Hz), 128.0, 127.0, 125.2, 118.8, 116.5, 114.2, 111.9, 111.2, 65.6, 47.2, 46.7, 36.3, 24.2. HRMS (M+H) + Calculated value 434.2009, measured value 434.2010.

[0094] 4-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(3-(tetrahydropyrrolyl)propyl)benzamide (Compound 57) Using Q2 and 1-(3-aminopropyl)tetrahydropyrrole as starting materials, compound 52 was obtained as a white solid in 49% yield according to the synthesis method for compound 51. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 - 8.77 (m, 2H), 8.05 (q, J = 8.4 Hz, 4H), 7.91 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 3.37 - 3.34 (m, 2H), 2.81 (d, J = 86.5 Hz, 6H), 1.83 (s, 6H). 13C NMR (125 MHz, DMSO-d6) δ 165.8, 160.9, 146.3, 145.02, 137.5, 134.1, 132.3, 129.2, 128.8, 127.9, 127.1, 125.2, 111.1, 53.9, 52.9, 37.4, 26.9, 23.2. HRMS (M+H) + Calculated value 432.1853, measured value 432.1855.

[0095] 4-(6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (Compound 58) Using Q1 and 4-(2-aminoethyl)pyridine as starting materials, compound 53 was obtained as a white solid in 31% yield according to the synthesis method for compound 51. 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (t, J = 5.6 Hz, 1H), 8.77 (s, 1H), 8.47 (d, J = 5.9 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.96 - 7.91 (m, 2H), 7.27 (dd, J = 15.5, 6.7 Hz, 4H), 3.57 (dd, J = 12.9, 6.9 Hz, 2H), 2.90 (dd, J = 11.9, 4.7 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 165.6, 162.1 (d, J = 244.2 Hz), 160.9, 149.8, 148.9, 145.2 (d, J = 29.8 Hz), 137.6, 132.2, 130.7 (d, J = 2.8 Hz), 128.7, 127.2 (d, J = 6.9 Hz), 124.7, 116.1 (d, J = 21.6 Hz), 111.0, 109.9, 40.56, 34.57. HRMS (M+H) + Calculated value 444.1289, measured value 444.1291.

[0096] N-(2-hydroxyethyl)-4-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Compound 59) Using Q2 and ethanolamine as raw materials, the compound 54 was obtained as a white solid in 51% yield according to the synthesis method of compound 51. 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.66 (t, J = 5.5 Hz, 1H), 8.05 (s, 4H), 7.91 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 4.76 (s, 1H), 3.53 (t, J = 6.2 Hz, 2H), 3.36 (d, J = 5.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 165.7, 160.9, 146.2, 145.0, 137.7, 134.1, 132.2, 129.2, 128.8, 127.9, 127.0, 125.2, 111.2, 60.1, 42.8. HRMS (M+H) + Calculated value 365.1067, measured value 365.1065.

[0097] 4-(2-(4-(tetrahydropyrrolyl-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)cyanobenzene (Compound 60) Compound 55 was obtained as a white solid in 51% yield using Q3 and tetrahydropyrrole according to the synthesis method for compound 51. 1 H NMR (400 MHz, TFA-d1) δ 8.47 (s, 1H), 8.19 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 8.8 Hz, 4H), 7.86 (d, J = 7.9 Hz, 2H), 3.93 (s, 2H), 3.70 (s, 2H), 2.18 (d, J = 6.3 Hz, 2H), 2.10 (d, J = 5.9 Hz, 2H). 13C NMR (400 MHz, TFA-d1) 166.4, 145.3, 137.6, 133.5, 131.1, 130.2, 128.6, 128.1, 126.6, 51.8, 49.3, 24.8, 23.5.

[0098] 4-(2-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)cyanobenzene (Compound 61) Compound 56 was obtained as a green solid in 63% yield according to the synthesis method for compound 51 using Q3 and N-methylpiperazine as starting materials. 1 H NMR (400 MHz, TFA-d1) δ 8.47 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.96 - 7.89 (m, 4H), 7.73 (d, J = 8.1 Hz, 2H), 5.04 (d, J = 14.5 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.73 (d, J = 12.0 Hz, 1H), 3.57 (t, J = 13.0 Hz, 1H), 3.32 (dt, J = 37.8, 11.3 Hz, 2H), 3.11 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.2, 161.9, 145.8, 144.3, 139.7, 138.7, 133.3, 130.7, 128.6, 127.5, 125.7, 119.5, 113.4, 109.9, 55.0, 46.0.

[0099] Example 73: Inhibitory activity test of the compounds of the present invention against MNK protein kinase The inhibitory activity of MNK1 and MNK2 kinases was tested using the LANCE Ultra kinase activity assay technology developed and developed by PerkinElmer. Staurosporine (STSP) served as the positive control for this assay. The assay procedure involved incubating 1.00 ng MNK1 or 0.05 ng MNK2 at 25°C with different concentrations of test compound (10,000, 1,000, 100, 10, and 1 nM) in a total volume of 10 μL (MNK1: 12.5 nM CREB, 450 μM ATP, 2 mM DTT, 1x buffer; MNK2: 12.5 nM CREB, 100 μM ATP, 2 mM DTT, 1x buffer) for 60 min. The reaction was then stopped by adding 5 μL EDTA / detection buffer and 5 μL Eu-CREB / detection buffer. After 60 min of incubation, the ratio of HTRF signals at 615 nm to 665 nm was measured. First, 1000 nM of the test compound was measured, and the inhibition rate was calculated. Inhibition rates of >75%, 50%, and 25% were graded as +++, ++, and +, respectively (see Table 1). Then, five concentrations (10,000, 1,000, 100, 10, and 1 nM) of the test compound were measured, and the IC was calculated by fitting a curve based on the inhibition rate. 50 The IC values ​​of the test compounds against MNK1 / 2 in vitro were calculated. 50 The results are shown in Table 2, where IC 50 <0.05uM(****), 0.05-0.2uM(***), 0.2-0.8uM(**), and 0.8-1.5uM(*).

[0100] [Table 1] [Table 2] The above compounds were tested for their effects on different mouse disease models, and compound 12 will be described below as a specific example.

[0101] Example 74: Weight loss test in a high-fat-fed obese model Male C57BL / 6J mice were fed a high-fat (60 kcal) or low-fat (10 kcal) diet for 16 weeks, and an obese model was successfully constructed after 16 weeks (high-fat diet weight was 20% higher than low-fat diet weight). The mice were divided into groups: blank, high-dose (100 mg / kg), low-dose (50 mg / kg), and orlistat (50 mg / kg). Orlistat was administered intragastrically every afternoon for 4 consecutive weeks. The blank group was administered saline as a control. The mice's food intake and body weight were measured periodically over the period. After 1 month, the treated groups showed a significant decrease in body weight, but no decrease in food intake.

[0102] Example 75: Blood glucose lowering test in STZ + high-fat fed diabetic mouse model Fifty male Kunming mice were housed in a constant temperature environment at 25°C and allowed to eat and drink water ad libitum. After five days of adaptation, they were first divided into two groups: the first group consisted of 10 mice, the blank group (C) which was given normal feed, and the remaining group (40 mice) was given a 60% high-fat diet to induce the high-fat model. They were then allowed to drink water ad libitum and housed for four weeks. At the fifth week, the second group of mice was injected with streptozocin (STZ) to induce a type 2 diabetes model. The injections were given three times, every other day, for a total dose of 150 mg / kg. The animals were kept in the same condition. One week later, the mice's fasting blood glucose levels were measured using a blood glucose meter and disposable blood glucose test strips. Mice with blood glucose levels higher than 11 mmol / L were type 2 diabetic mice. The mice were then divided into a second group of 10 mice each: model group (M, distilled water), metformin group (Meft, 225 mg / kg / d), low-dose compound 12 group (2A-L, 50 mg / kg / d), and high-dose compound 12 group (2A-H, 100 mg / kg / d). In the M group, distilled water was administered intragastrically at the doses of 225 mg / kg Meft, 50 mg / kg 2A-L, and 100 mg / kg 2A-H. The dose was 0.2 mL / g for 8 weeks, and the body weight and fasting blood glucose levels of the mice were measured periodically during this period. The results (Figure 1) showed that compound 12 significantly lowered blood glucose levels in mice at both low (50 mg / kg) and high (100 mg / kg) doses. The low dose group showed comparable blood glucose reduction to the positive control (metformin, 225 mg / kg), while the high dose group showed better blood glucose reduction than the positive control. Compound 12 has the effect of improving glucose tolerance (Figure 2). The results of the insulin tolerance experiment showed that after intraperitoneal injection of insulin, blood glucose gradually decreased and reached its lowest value 55 minutes later. Compared with the model group, the low-dose and high-dose groups of compound 12 both had lower insulin sensitivity than the model group, indicating that compound 12 can restore insulin sensitivity in mice. This demonstrates that compound 12 has the effect of lowering blood glucose and restoring insulin sensitivity. Compound 12 significantly reduced serum AST levels (Figure 3). Compared with the model group, both serum TG and TC levels in the compound 12-treated group were significantly reduced, indicating that compound 12 has some lipid-lowering effects. Compound 12's TG-lowering effect was similar to that of metformin, and its TC-lowering effect was even better than metformin's. Higher than normal blood creatinine levels indicate kidney damage. Compared with the control group, CREA significantly increased in the model group, indicating kidney damage in the model. After administration, CREA significantly decreased, indicating that compound 12 can repair diabetic kidney damage.

[0103] Example 76: Insulin tolerance and liver function improvement test in male db / db mice model Six-week-old male db / db mice were randomly divided into six groups (12 mice per group): model group (M, distilled water), metformin group (Meft, 200 mg / kg / d), lovastatin group (6 mg / kg), low-dose group of Compound 12 (20 mg / kg / d), medium-dose group of Compound 12 (40 mg / kg / d), and high-dose group of Compound 12 (80 mg / kg / d). They were housed in a constant temperature environment of 25°C and allowed to eat and drink freely. A 0.2 mL / g intragastric administration was administered for 6 weeks, and the mice's weight and fasting blood glucose were measured periodically during the period. In the insulin tolerance experiment (ITT), mice were given 1.0 U / ml saline at a dose of 1.0 U / kg. After a 4-h fast in the morning, they were allowed to drink normally. In the afternoon, the mice were weighed and blood glucose was measured before insulin injection. The insulin injection dose was calculated based on body weight, and blood glucose was measured at 15, 30, 45, and 60 min. After the experiment, each cage was replenished with food. As observed by insulin tolerance analysis (Figure 4), all drug treatments in each group significantly improved insulin sensitivity in db / db mice, with the 12-high dose group showing the greatest improvement.

[0104] Among the serum biochemical indicators of liver function (Fig. 5), ALT, AST, and total bile acid contents were significantly decreased in the high-dose group compared with the model group, indicating that the drug can alleviate liver injury and alleviate liver inflammatory responses in db / db mice. Among serum active protein indicators (Figure 6), insulin INS content significantly increased after high-dose administration, indicating that this compound promotes insulin secretion from pancreatic islet cells. Blood levels of brain-gut peptides such as GLP-1 increased, demonstrating the drug's beneficial therapeutic effects. At the same time, plasma BNP, an indicator of heart failure, and inflammatory factors TNF and IL-6 significantly decreased after low-dose administration, further demonstrating the drug's effective anti-inflammatory effect in vivo in mice. From the above test results, it can be seen that the compounds of the present invention have good inhibitory effect on MNK1 / 2 protein kinase, and show good safety in cells.In diabetic mouse model and obese mouse model, such compounds as example compound 12 show significant blood glucose control, weight loss, improvement of various blood biochemical indexes, and protection of vital organs such as liver, and have good prospects for drug development. The present invention has been introduced in detail above, and specific examples have been used herein to explain the principles and embodiments of the present invention. However, these examples are merely intended to help understand the method and spirit of the present invention, including the best mode, and to enable anyone skilled in the art to practice the present invention, including manufacturing and using any device or system, and implementing any combination of methods. It should be noted that those skilled in the art may make some improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications are also within the scope of protection of the claims of the present invention. The patent protection scope of the present invention is limited by the claims and may include other embodiments that may occur to those skilled in the art. If these other embodiments have elements that are not different from those described in the claims, or contain equivalent elements that are substantially different from those described in the claims, these other embodiments are also within the scope of the claims.

Claims

1. An imidazothiazole derivative, its stereoisomer, tautomer, geometric isomer, or pharmaceutically acceptable salt thereof, characterized by being represented by general formula 1 or 2: 【Chemistry 1】 (R １ R3 is independently selected from a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms, which may be optionally substituted with one or more groups: a halogen atom, a hydroxy group, a cyano group, a nitro group, an amino group, and a carbonyl group; or R １ is selected from a C1-C6 alkoxy group optionally substituted with one or more of a hydroxy group, a halogen, an amino group, a dimethylamino group, and a 5- to 6-membered heterocycle; R １ is selected from a C1-C6 alkylthio group optionally substituted with one or more of a hydroxy group, a halogen, an amino group, a dimethylamino group, and a 5- to 6-membered heterocyclic ring; R １ is selected from a C1-C6 alkylamino group optionally substituted with one or more of a hydroxy group, a halogen, an amino group, a dimethylamino group, and a 5- to 6-membered heterocyclic ring; R ２ , R ４ are each independently selected from an aryl group or heteroaryl group optionally substituted with one or more groups such as a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a hydroxy-substituted C1-C6 alkyl group, a halogen, a hydroxy group, a cyano group, a nitro group, an amino group, or a carbonyl group.

2. The imidazothiazole derivative, its stereoisomer, tautomer, geometric isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein the 5- to 6-membered heterocyclic group is selected from the group consisting of a piperazine ring group, a morpholine ring group, a piperidine ring group, a hexahydropyran ring group, a tetrahydrofuran ring group, a tetrahydrothiophene ring group, a pyrrolyl group, and a tetrahydropyrrolyl group.

3. The imidazothiazole derivative, its stereoisomer, tautomer, geometric isomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 and 2, characterized in that the aryl group is selected from a phenyl group and a naphthyl group, and the heteroaryl group is selected from a furyl group, a thienyl group, a pyridyl group, a thiazolyl group, and an imidazolyl group.

4. The C1-C6 alkylamino group is an amino group (—NH ２ ) in which one or two hydrogen atoms are substituted with the same or different "C1-C6 alkyl group", i.e., -NR １ R ２ may be expressed as R １ , R ２ are each independently selected from H and a C1-C6 alkyl group, and R １ , R ２ and the imidazothiazole derivative, its stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein

5. An imidazothiazole derivative or a stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the imidazothiazole derivative is selected from compounds 1-55 shown in the table below. Table 1 Table 2 Table 3 Table 4

6. A method for producing the imidazothiazole derivative according to claim 1, comprising the following steps: Synthesis method of general formula 1: 【Chemistry 2】 Compounds of formula (II) and the corresponding boric acid derivatives (B(OH) ２ R ２ ) is subjected to Suzuki condensation reaction to obtain a compound of general formula 1 (wherein R １ , R ２ The definitions are the same as in any one of claims 1 to 5, and X is a halogen, preferably chlorine, bromine or iodine; Synthesis method of general formula 2: 【Chemistry 3-1】 Compounds of formula (III) and corresponding ethyne derivatives 【Chemistry 3-2】 under basic conditions to obtain a compound of general formula 2 (wherein R ３ , R ４ The definitions are the same as in claim 1.

7. 7. The method of claim 6, comprising the steps of: The synthesis method of general formula 1 includes the steps of preparing a compound of formula (II) from a compound of formula (IV); 【Chemistry 4】 The synthesis method of general formula 2 includes the step of preparing a compound of formula (III) from a compound of formula (V). 【Transformation 5】

8. The method for producing the imidazothiazole derivative according to claim 1, wherein the imidazothiazole derivative is R ２ is a 4-cyanophenyl group, and is represented by compound N, and the method comprises the steps of: 【Transformation 6】 Compounds M and R １ H is subjected to a condensation reaction to obtain compound N (R １ The definition of is the same as in any one of claims 1-5.

9. An intermediate for producing the imidazothiazole derivative according to claim 1, characterized in that the intermediate is represented by formula (II), formula (III), formula (IV) or formula (V): 【Transformation 7】 (R １ , R ３ The definitions are the same as in claim 1, and X is a halogen, preferably chlorine, bromine, or iodine.

10. An intermediate for producing the imidazothiazole derivative of claim 1, characterized in that it is represented by the following structure: 【Transformation 8】

11. Use of a compound of formula (II), (III), (IV), or (V) as defined in claim 9 or an intermediate as defined in claim 10 in the preparation of an imidazothiazole derivative as defined in claim 1.

12. Use of the imidazothiazole derivative according to claim 1, its stereoisomer, tautomer, geometric isomer or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing and / or treating a metabolic disease associated with MNK activity.

13. The use according to claim 12, characterized in that the metabolic disease associated with MNK activity is selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, and complications and associated diseases thereof.

14. Use of the imidazothiazole derivative, its stereoisomer, tautomer, geometric isomer or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a drug for preventing and / or treating cancer caused by abnormalities in MNK1 and / or MNK2 levels.

15. Use of the imidazothiazole derivative according to claim 1, its stereoisomer, tautomer, geometric isomer or a pharmaceutically acceptable salt thereof in the manufacture of an MNK1 and / or MNK2 inhibitor.

16. A pharmaceutical composition comprising the imidazothiazole derivative according to claim 1, its stereoisomer, tautomer, geometric isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

17. 17. The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable adjuvant.

18. The pharmaceutical composition according to any one of claims 16-17, which may further comprise other MNK1 and / or MNK2 inhibitors.

19. The pharmaceutical composition according to any one of claims 16-17, characterized in that the dosage form may be a solid formulation, a liquid formulation or a semi-solid formulation.

Images