Imidazolothiazole derivatives and their preparation methods and applications

Abstract

Disclosed are imidazothiazole derivatives, their preparation methods, and uses. The imidazothiazole derivatives have a structure represented by formula (I): R1 and R3 are each independently selected from an optionally substituted 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms, and R2 and R4 are each independently selected from an optionally substituted aryl or heteroaryl group. The imidazothiazole derivatives have good MNK inhibitory activity, excellent selectivity, and superior in vivo hypoglycemic effects, and have broad medicinal prospects.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to imidazothiazole derivatives and preparation methods and applications thereof. Background Art

[0002] Metabolic syndrome is a clinical syndrome characterized by the coexistence of multiple metabolic diseases, such as obesity and type 2 diabetes (T2D), and is determined by both genetic and environmental factors. This syndrome can further lead to dyslipidemia, hypertension, non-alcoholic fatty liver disease, gout, and other conditions. With socioeconomic development and changes in lifestyle (such as increased energy intake and decreased physical activity), the incidence of metabolic syndrome has been increasing annually worldwide, posing a global public health challenge.

[0003] Non-alcoholic fatty liver disease (NAFLD) is a liver disease characterized by genetic, environmental, metabolic, and stress-related factors, characterized by fatty degeneration and fat accumulation in hepatocytes. Clinically, it can be divided into three types: simple fatty liver, steatohepatitis (NASH), and fatty liver cirrhosis.

[0004] MNK (mitogen-activated protein kinase-interacting enzyme), comprising two isoforms, MNK1 and MNK2, has been shown to phosphorylate eIF4E in vivo, thereby regulating protein synthesis. 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, suggesting that MNK may serve as a potential drug development target for metabolic diseases such as diabetes, obesity, and NAFLD.

[0005] There is an urgent need in this field for more types of small molecule compounds that can better inhibit MNK activity. Summary of the Invention

[0006] To solve the above technical problems, we invented a series of imidazothiazole or imidazothiadiazole derivative compounds, which can regulate blood sugar, reduce weight gain, alleviate fat accumulation and other changes in the body by regulating the activity of MNK protease, thereby improving the conditions of diabetic patients and patients with other metabolic diseases.

[0007] The present invention provides an imidazothiazole derivative, its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof, characterized in that the imidazothiazole derivative has a structure represented by formula (I):

[0008]

[0009] Formula (I) includes Formula 1 and Formula 2, R1 and R3 are each independently selected from the group optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, 5-membered to 6-membered heterocycle, halogen, hydroxyl, cyano, nitro, amino, carbonyl and the like.

[0010] 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms, or R1 is selected from one or more hydroxyl, halogen, amino, dimethylamino, 5-

[0011] C1-C6 alkoxy substituted with 5- to 6-membered heterocyclic ring, R1 is selected from the group consisting of one or more hydroxyl groups, halogen groups, amino groups, dimethylamino groups, 5- to 6-membered heterocyclic rings,

[0012] C1-C6 alkylthio substituted with a 5-membered to 6-membered heterocyclic ring, R1 is selected from the group consisting of one or more hydroxyl groups, halogen, amino, dimethylamino, 5-membered to 6-membered heterocyclic rings

[0013] substituted C1-C6 alkylamino, R2, R4 are each independently selected from optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6

[0014] Alkylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, hydroxy-substituted C1-C6 alkyl, halogen, hydroxy, cyano, nitro, amino

[0015] an aryl or heteroaryl group substituted by a group such as an alkyl or carbonyl group.

[0016] The C1-C6 alkyl group herein refers to a linear or branched saturated monovalent hydrocarbon group containing 1, 2, 3, 4, 5, or 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. The C1-C6 alkyl group may further preferably be a C1-C3 alkyl group.

[0017] The C1-C6 haloalkyl group herein refers to a group in which one or more hydrogen atoms in the "C1-C6 alkyl" group defined above are replaced by the same or different halogen atoms. The C1-C6 haloalkyl group may further preferably be a C1-C3 haloalkyl group. Representative examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, and the like.

[0018] The C1-C6 alkylamino group of the present invention refers to an amino group (-NH2) in which one or two hydrogen atoms are replaced by the same or different "C1-C6 alkyl" as defined above; it can be represented as -NR 1 R 2 , R 1 、R 2 are each independently selected from H, C1-C6 alkyl, and R 1 、R2 Cannot be H at the same time.

[0019] The C1-C6 alkoxy group of the present invention refers to -OR 3 , where R 3 Selected from C1-C6 alkyl; C1-C6 alkoxy may further preferably be C1-C3 alkoxy, further preferably methoxy, ethoxy, etc.

[0020] The C1-C6 alkoxycarbonyl group of the present invention refers to -C(O)R 4 , where R 4 Selected from C1-C6 alkoxy.

[0021] The 5- to 6-membered heterocyclic rings of the present invention refer to ring systems containing ring carbon atoms and 1-4 ring heteroatoms (preferably 1, 2, or 3 ring heteroatoms), wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as valence permits. Further preferred rings include piperazine, morpholine, piperidine, hexahydropyran, tetrahydrofuran, tetrahydrothiophene, pyrrole, and tetrahydropyrrole.

[0022] The aryl group of the present invention is preferably a monocyclic or polycyclic aromatic group containing 6-12 carbon atoms, preferably phenyl, naphthyl, etc.; the heteroaryl group is preferably a 5- to 6-membered heteroaryl group, which refers to a heteroaryl system having ring carbon atoms and 1-4 ring heteroatoms (preferably 1, 2, or 3 ring heteroatoms), wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur. Further preferred are furyl, thienyl, pyridyl, thiazolyl, imidazolyl, etc.

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

[0024] The imidazothiazole derivative of the above formula (I) is preferably compound 1-55 or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof.

[0025]

[0026]

[0027]

[0028]

[0029] Another embodiment of the present invention provides a method for preparing the imidazothiazole derivative of the above-mentioned formula (I), characterized by comprising the following steps: Synthesis method of general formula 1:

[0030]

[0031] The compound of formula (II) undergoes Suzuki condensation reaction with the corresponding boronic acid derivative (B(OH)2R2) to obtain a compound of formula 1, wherein R1 and R2 are as defined above, and X is a halogen, preferably chlorine, bromine, or iodine;

[0032] Synthesis method of general formula 2:

[0033]

[0034] The compound of formula (III) and the corresponding acetylene derivative The reaction is carried out under alkaline conditions to obtain a compound of the general formula 2, wherein R3 and R4 are as defined above.

[0035] Another embodiment of the present invention provides a method for preparing the imidazothiazole derivative of the above formula (I), characterized by comprising the following steps:

[0036] The synthesis method of general formula 1 comprises the steps of preparing a compound of formula (II) from a compound of formula (IV):

[0037] Wherein R1 is as defined above, X is halogen, preferably chlorine, bromine, or iodine;

[0038] The synthesis method of general formula 2 comprises the steps of preparing a compound of formula (III) from a compound of formula (V):

[0039] Wherein R3 is as defined above.

[0040] Another embodiment of the present invention provides a method for preparing the imidazothiazole derivative of the above-mentioned formula (I), characterized in that the imidazothiazole derivative of the formula (I) is selected from the general formula 1 in which R2 is 4-cyanophenyl, represented by compound N, comprising the following steps:

[0041]

[0042] Compound M undergoes a condensation reaction with R1H to obtain compound N, where R1 has the same definition as above.

[0043] Another embodiment of the present invention provides an intermediate for preparing an imidazothiazole derivative of formula (I), characterized in that the intermediate has a structure shown in formula (II):

[0044] wherein R1 is as defined above, and X is halogen, preferably chlorine, bromine or iodine.

[0045] Another embodiment of the present invention provides an intermediate for preparing an imidazothiazole derivative of formula (I), characterized in that the intermediate has a structure shown in formula (III):

[0046] wherein R3 is as defined above.

[0047] Another embodiment of the present invention provides an intermediate for preparing formula (II), characterized in that the intermediate has a structure shown in formula (IV):

[0048] Wherein X is halogen, preferably chlorine, bromine or iodine.

[0049] Another embodiment of the present invention provides an intermediate for preparing formula (III), characterized in that the intermediate has a structure shown in formula (V):

[0050]

[0051] Another embodiment of the present invention provides an intermediate for preparing the imidazothiazole derivative of formula (I), characterized in that the intermediate

[0052] The intermediate has the following structure:

[0053]

[0054] Another embodiment of the present invention provides the use of compounds of formula (II), formula (III), formula (IV), and formula (V) in the preparation of imidazothiazole derivatives of formula (I).

[0055] Another embodiment of the present invention provides the use of the imidazothiazole derivatives of the structure of the above formula (I), their stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof in inhibiting the kinase activity of MNK1 or MNK2 or their variants; or in the preparation of drugs for preventing and / or treating cancers caused by abnormal levels of MNK1 and / or MNK2.

[0056] Another embodiment of the present invention provides the use of the imidazothiazole derivatives of the structure of formula (I), stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for preventing and / or treating metabolic diseases associated with MNK activity. The metabolic diseases associated with MNK activity are selected from type 1 diabetes, type 2 diabetes, hyperlipidemia, obesity, fatty liver disease, and their complications and related conditions.

[0057] Another embodiment of the present invention provides the use of the imidazothiazole derivative of the above formula (I), its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof in the preparation of MNK1 and / or MNK2 inhibitors.

[0058] Another embodiment of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises an imidazothiazole derivative of the structure of the above-mentioned formula (I), its stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts thereof as an active ingredient. The pharmaceutical composition may also include pharmaceutically acceptable excipients. The pharmaceutical composition may also include other MNK1 and / or MNK2 inhibitors (marketed therapeutic drugs). The dosage form may be a solid preparation, a liquid preparation, or a semisolid preparation, preferably a tablet, a capsule, an injection, or the like.

[0059] The methods and techniques of the present invention are generally implemented according to conventional methods known in the art, unless otherwise specified. The terms described in the present invention are named according to chemistry, biology, and pharmacology, and the experimental methods and techniques are known and commonly used in the art. Chemical synthesis, chemical analysis, pharmaceutical preparation and formulation, and patient treatment all use standard techniques. Unless otherwise specified, the scientific and technical terms used in the present invention should have the meanings commonly understood by those of ordinary skill in the art. However, the following terms have the following definitions:

[0060] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the two configurations.

[0061] Diabetes and its complications are specifically described as impaired glucose tolerance, diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataracts, diabetic retinopathy, diabetic maculopathy, diabetic foot syndrome, diabetic coma, diabetic hyperosmolar coma, hypoglycemic coma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis, intracapillary glomerulonephropathy, diabetic amyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy, diabetic polyneuropathy, diabetic angiopathy, diabetic peripheral vascular disease, diabetic ulcers, diabetic arthropathy, and diabetic obesity.

[0062] Hyperlipidemia and its complications specifically include: hypercholesterolemia, familial hypercholesterolemia, Freund's hyperlipoproteinemia, hyperbetalipoproteinemia, hyperlipidemia, low-density lipoprotein hyperlipoproteinemia, pure hyperglyceridemia, endogenous hyperglyceridemia, isolated hypercholesterolemia, isolated hypertriglyceridemia, and cardiovascular disease. Cardiovascular disease includes: hypertension, ischemia, varicose veins, retinal vein occlusion, atherosclerosis, angina pectoris, myocardial infarction, angina pectoris, pulmonary hypertension, congestive heart failure, glomerulopathy, tubulointerstitial disease, renal failure, vascular stenosis, or cerebrovascular disease (stroke).

[0063] Fatty liver disease includes but is not limited to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and the chronic inflammation caused by them, leading to progressive fibrosis, cirrhosis, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 This is a graph showing changes in blood sugar levels in each group of mice during the experiment;

[0065] Figure 2 is a graph showing changes in glucose tolerance and insulin tolerance in each drug-treated group;

[0066] Figure 3 This is an example diagram of the changes in serum related indicators in each drug-dosing group;

[0067] Figure 4 This is an example diagram of the insulin tolerance experiment in db / db mice.

[0068] Figure 5 This is an example diagram of the changes in various related indicators of liver function in db / db experimental mice;

[0069] Figure 6 This is an example diagram of the changes in various related indicators in the serum of db / db experimental mice. DETAILED DESCRIPTION

[0070] General synthetic methods for compounds

[0071] Synthesis method of general formula 1:

[0072]

[0073]

[0074] Commercially available 5-bromo-2-amino-1,3,4-thiadiazole is used as a raw material, and chloroacetaldehyde or 2-bromo-1,1-diethoxyethane is refluxed in an alcohol solution (such as ethanol, n-butanol, etc.) for 1-2 days to obtain a cyclization product A, which is then subjected to a Suzuki condensation reaction with 4-methylphenylboronic acid to obtain compound B, which is then subjected to a nucleophilic substitution reaction with NBS (or NIS) in a dichloromethane solution to obtain C, and is then subjected to an alkaline condition (such as lithium hydroxide, sodium hydroxide, or potassium hydroxide aqueous solution, the solution can be water, tetrahydrofuran, etc.). The compound D is hydrolyzed in a mixed solution of furan and alcohol, and after acid adjustment (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 amidated 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 undergoes a Suzuki condensation reaction with a boronic acid compound B(OH)2R2 to obtain the final compound F (general formula 1), wherein R1 and R2 are as defined above.

[0075] The intermediate C obtained by the above reaction undergoes a Suzuki condensation reaction with 4-cyanophenylboronic acid to obtain compound L, which is then hydrolyzed under alkaline conditions (for example, in an aqueous solution of lithium hydroxide, sodium hydroxide, or potassium hydroxide, which can be a mixed solution of water, tetrahydrofuran, or alcohol). After acid adjustment (the acid can be an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, formic acid, etc.), a compound M with a carboxylic acid structure is obtained. Subsequently, a condensation reaction with R1H (an amino compound, an alcohol compound, or a thiol compound) is carried out under condensation reagent conditions (for example, a combination of EDCI and NHS, EDCI and Hobt, or EDCI and Hoat) to obtain the final compound N (general formula 1 when R2 is 4-cyanophenyl), where R1 is as defined above.

[0076] Synthesis method of general formula 2:

[0077]

[0078] Commercially available methyl 4-acetylbenzoate is used as a raw material, and is reacted with NBS in a p-toluenesulfonic acid and acetonitrile solution under reflux to obtain compound G, which is then reacted with 2-amino-1,3,4-thiadiazole in an alcohol solution under reflux for 6 hours to obtain compound H. The compound H is hydrolyzed under alkaline conditions (for example, in an aqueous solution of lithium hydroxide, sodium hydroxide, or potassium hydroxide, which can be a mixed solution of water, tetrahydrofuran, and alcohol). After acid adjustment (the acid can be an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, formic acid, etc.), compound I with a carboxylic acid structure is obtained. The compound I is then amidated with an amino compound R3H under amide condensation reagent conditions (for example, a combination of EDCI and NHS, EDCI and Hobt, or EDCI and Hoat) to obtain compound J. Finally, potassium tert-butoxide is reacted as a base with a phenylacetylene compound R4CCH in a DMF solution at room temperature for 6 hours to obtain compound K (general formula 2), wherein R3 and R4 are as described in the above claims. DETAILED DESCRIPTION

[0080] The present invention is described in detail below through specific preparation examples and examples, but the use and purpose of these exemplary embodiments are only used to illustrate the present invention and do not constitute any form of limitation on the actual protection scope of the present invention, nor do they limit the protection scope of the present invention to them.

[0081] Example 1: 2-Bromoimidazole[2,1-b][1,3,4]thiadiazole (Compound A)

[0082]

[0083] 5-Bromo-2-amino-1,3,4-thiadiazole was reacted with chloroacetaldehyde in ethanol under reflux to obtain compound A with a yield of 17.6%. 1 H NMR (500MHz, CDCl3) δ7.76(s,1H),7.36(s,1H).

[0084] Example 2: Methyl 4-(imidazole[2,1-b][1,3,4]thiadiazole)benzoate (Compound B)

[0085]

[0086] 300 mg (1.47 mmol) of 2-bromoimidazole[2,1-b][1,3,4]thiadiazole (Compound A) and 317 mg (1.76 mmol) of 4-methylformylphenylboronic acid underwent Suzuki condensation in the presence of a catalyst. The reaction was then purified by silica gel column chromatography (PE:EA=10:1) to obtain 93.2 mg of a white solid (Compound B) in a yield of 24.3%. 1H NMR (500MHz, CDCl3) δ8.19–8.15(m,2H),7.97–7.93(m,2H),7.81(d,J=1.4Hz,1H),7.37(d,J=1.4Hz,1H),3.97(s,3H).

[0087] Example 3: Methyl 4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (Compound C)

[0088]

[0089] 350 mg (1.35 mmol) of methyl 4-(imidazole[2,1-b][1,3,4]thiadiazole)benzoate was reacted with 286 mg (1.62 mmol) of N-bromosuccinimide and purified by silica gel column chromatography to obtain 340 mg of a light green solid (Compound C) in a yield of 74.7%. 1 H NMR (500MHz, CDCl3) δ8.18(d,J=8.4Hz,2H),7.99(d,J=8.4Hz,2H),7.29(s,1H),3.98(s,3H). 13 C NMR (125MHz, CDCl3) δ165.9,161.5,144.2,133.8,133.7,133.1,130.5,126.9,96.3,52.5.

[0090] Example 4: 4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (Compound D)

[0091]

[0092] 340 mg (1 mmol) of methyl 4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzoate and 424 mg (10 mmol) of lithium hydroxide monohydrate were mixed in 30 mL of THF / H2O (V:V = 1:1) solution. After the reaction was completed, 320 mg of a white solid was obtained by purification, namely compound D, with a yield of 98%.

[0093] Example 5: Methyl 4-(2-bromoacetyl)benzoate (Compound G)

[0094]

[0095] 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. The mixture was reacted and purified by column chromatography (PE:EA = 10:1) to obtain 4.6 g of a white solid (Compound G) in a yield of 63.9%. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.1Hz,2H),8.02(d,J=8.1Hz,2H),4.46(s,2H),3.94(s,3H); 13 C NMR (100MHz, CDCl3) δ190.84,165.95,137.16,134.62,130.01,128.87,52.58,30.71.

[0096] Example 6: Methyl 4-(2-(2-amino-1,3,4-thiadiazole)acetyl)benzoate (Compound H)

[0097]

[0098] To a 250 mL eggplant-shaped flask, 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) were added. The mixture was refluxed at 80°C under magnetic stirring for 6 h. TLC confirmed the complete reaction. The reaction flask was cooled to room temperature, filtered, and the filter cake was washed three times with ethanol to obtain 3.2 g of a white solid (Compound H), with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 8.1Hz, 2H), 8.05 (d, J = 8.1Hz, 2H), 7.67 (s, 1H), 5.41 (s, 2H), 3.96 (s, 3H); 13 C NMR (100MHz, CDCl3) δ192.06,166.05,161.55,137.93,134.56,133.53,130.03,128.07,53.71,52.55.

[0099] Example 7: 4-(Imidazole[2,1-b][1,3,4]thiadiazole)benzoic acid (Compound I)

[0100]

[0101] To a 100 mL eggplant-shaped flask, methyl 4-(2-(2-amino-1,3,4-thiadiazole)acetyl)benzoate (3 g, 10.8 mmol) and 2N hydrochloric acid (60 mL) were added and refluxed at 100°C for 6 h. TLC confirmed the complete reaction. The reaction 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 and allowed to stand. The aqueous layer was separated and the pH was adjusted to 2-3 with 1N hydrochloric acid to produce a khaki solid. Filtration yielded 2.2 g of the solid (Compound I), with a yield of 83%. 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.87(s,1H),7.98–7.92(m,4H); 13 C NMR (100MHz, DMSO-d6) δ167.62,151.69,145.50,145.26,138.49,130.38,129.83,125.12,112.39.

[0102] Example 8: Methyl 4-(5-4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoate (Compound L)

[0103] To a 100 mL eggplant-shaped flask, 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) were added. Under nitrogen, the mixture was reacted at 100°C for 6 h. TLC confirmed the reaction was complete. After cooling to room temperature, the mixture was filtered to obtain 16 mg of a yellow solid (Compound L), in a 30% yield. 1 H NMR (400MHz, DMSO-d6) δ8.14 (m, 9H), 3.91 (s, 3H).

[0104] Example 9: 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazole)-2-benzoylmorpholine (Intermediate 1)

[0105]

[0106] 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 reaction was complete as detected by TLC. DMF was removed by rotary evaporation and purified by column chromatography (CH2Cl2:CH3OH=50:1) to obtain 1.8 g of a white solid (i.e., intermediate 1) in a yield of 75%. 1 H NMR (400MHz, CDCl3) δ7.97(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.39(s,1H),3.61(s,4H),3.51(s,2H),3.30(s,2H). 13 C NMR (101MHz, CDCl3) δ168.95,161.56,144.10,138.68,133.74,131.25,128.14,127.24,96.26,66.82,48.17,42.65.

[0107] Example 10: 4-(5-bromoimidazo[2,1-B][1,3,4]thiadiazole)-2-(4-dimethylaminobenzamide piperidine) (Intermediate 2)

[0108]

[0109] 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 reaction was complete as detected by TLC. DMF was removed by rotary evaporation and purified by column chromatography (CH2Cl2:CH3OH=50:1) to obtain 1.6 g of a white solid (i.e., intermediate 2) in a yield of 59.3%. 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=8.4Hz,2H),7.60(d,J=8.0Hz,2H),7.46(s,1H),4.45(d,J=13.1Hz,1H),3.56(d,J=13.6Hz,1H),3.06(t,J= 12.9Hz,1H),2.83(t,J=12.6Hz,1H),2.47–2.37(m,1H),2.21(s,6H),1.86(d,J=12.9Hz,1H),1.70(d,J=12.6Hz,1H),1.39(q,J=13.5Hz,2H); 13C NMR (101MHz, DMSO-d6) δ168.13,162.63,144.34,140.26,133.98,130.48,128.44,127.58,96.51,61.73,46.71,41.78,28.74,28.10.

[0110] Example 11: (N-methylpiperazine)-4-(5-bromoimidazole[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Intermediate 3)

[0111]

[0112] 8 mg (0.18 mmol) of compound D, 69 mg (0.36 mmol) of (1-ethyl-3-(3-dimethylpropylamino)carbodiimide), and 42 mg (0.36 mmol) of N-hydroxysuccinimide were mixed in 10 mL of DMF. The mixture was stirred at room temperature for 10 h, and then 99 μL of N-methylpiperazine was added. Stirring was continued for 1 h, and the mixture was washed with water, extracted with chloroform, and purified by column chromatography to obtain 50 mg of a yellow solid (Intermediate 3) in a yield of 68%. 1 H NMR(400MHz, CDCl3)δ7.97–7.93(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 CNMR (100MHz, CDCl3) δ168.8,161.7,144.1,139.2,133.7,131.0,128.1,127.2,96.2,55.2,54.6,47.6,46.0,42.1.

[0113] Example 12: 6-(4-morpholinylcarbonylphenyl)imidazole[2,1-b][1,3,4]thiadiazole (Intermediate 4)

[0114]

[0115] 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 complete reaction as determined by TLC. DMF was removed by rotary evaporation and the product was purified by column chromatography (CH2Cl2:CH3OH = 50:1) to afford 1.8 g of a white solid (Intermediate 4) in a 69.8% yield. 1H NMR (400MHz, CDCl3) δ8.57(s,1H),8.14(s,1H),7.88(d,J=8.1Hz,2H),7.47(d,J=8.0Hz,2H),3.72(s,6H),3.56(s,2H); 13 C NMR (100MHz, CDCl3) δ170.22,147.03,146.49,144.67,135.43,134.24,127.80,125.18,110.13,66.89,48.27,42.68.

[0116] Example 13: 6-(4-(N-methylpiperazinylcarbonylphenyl)imidazole[2,1-b][1,3,4]thiadiazole (Intermediate 5)

[0117]

[0118] Using compound I (2 g, 8.2 mmol) and N-methylpiperazine (1.6 g, 16.4 mmol) as raw materials, a white solid (1.6 g) was obtained according to the synthesis method of intermediate 4. The yield was 59.6%. 1 H NMR (400MHz, CDCl3) δ8.56 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.3Hz, 2H), 7.47 (d, J=8.3Hz,2H),3.82(s,2H),3.51(s,2H),2.50(s,2H),2.39(s,2H),2.34(s,3H); 13 C NMR (100MHz, CDCl3) δ170.13,146.80,146.70,144.61,135.22,134.82,127.76,125.15,110.08,55.18,47.73,46.04,42.15.

[0119] Example 14: 6-(4-(4-dimethylamino)piperidinylcarbonylphenyl)imidazole[2,1-b][1,3,4]thiadiazole (Intermediate 6)

[0120]

[0121] Using compound I (2 g, 8.2 mmol) and 4-dimethylaminopiperidine (2.1 g, 16.4 mmol) as raw materials, a white solid (1.5 g) was obtained according to the synthesis method of intermediate 4. The yield was 51.5%. 1H NMR (400MHz, CDCl3) δ8.66(s,1H),8.17(s,1H),7.87(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),4.76(s,1H),3.9 2(s,1H),3.06(s,1H),2.82(s,1H),2.53(ddt,J=11.4,7.5,3.6Hz,1H),2.35(s,6H),1.87(s,2H),1.52(s,2H); 13 C NMR (100MHz, CDCl3) δ170.52,147.55,146.49,144.95,135.26,134.73,127.62,125.29,110.34,62.19,47.17,41.66,41.27,28.78,27.63.

[0122] Example 15: 6-(4-morpholinopiperidinylcarbonylphenyl)imidazole[2,1-b][1,3,4]thiadiazole (Intermediate 7)

[0123]

[0124] Using compound I (2 g, 8.2 mmol) and 4-morpholinopiperidine hydrochloride (3.4 g, 16.4 mmol) as raw materials, a white solid (900 mg) was obtained according to the synthesis method of intermediate 4. The yield was 27.6%. 1 H NMR (400MHz, CDCl3-CD3OD) δ8.59(s,1H),8.10(s,1H),7.80(d,J=8.2Hz,2H),7.40(d,J=8.2Hz,2H),4.67(s,1H),3.85(s,1H) ,3.71(t,J=4.7Hz,4H),3.01(s,1H),2.75(s,1H),2.59(t,J=4.8Hz,4H),2.52(s,1H),1.97(s,1H),1.83(s,1H),1.46(s,2H); 13 C NMR (100MHz, CDCl3-CD3OD) δ172.74,170.12,147.22,146.08,144.60,134.86 ,134.34,127.27,124.95,109.98,66.36,61.72,49.24,46.70,41.26,25.06.

[0125] Example 16: 4-(5-4-Cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzoic acid (Intermediate 8)

[0126] Compound L (340 mg, 1.01 mmol) and LiOH·H₂O (420 mg, 10 mmol) were mixed in 30 ml of THF / H₂O (V:V = 1:1) and stirred at room temperature for 12 hours. The pH was adjusted to 2-3 with HCl and filtered to afford compound M (i.e., intermediate 8) as a white solid, which was used in the next step without further purification.

[0127] Example 17: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 1)

[0128] In a 100 mL eggplant-shaped flask, 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazole)-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) were added. Under N2 protection, the reaction was carried out at 100 °C for 6 h. TLC indicated that the reaction of the starting material was complete. The dioxane was removed by distillation under reduced pressure. Dichloromethane and water were added, and the mixture was transferred to a separatory funnel. The mixture was shaken and allowed to stand. The organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined and washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, and the filtrate was evaporated to dryness. The mixture was purified by column chromatography (CH2Cl2:CH3OH=50:1) to give 40 mg of a white solid. The yield was 19.2%. 1 H NMR (500MHz, CDCl3) δ8.14(d,J=6.9Hz,2H),8.02(d,J=7.2Hz,2H),7.77(d,J=7.8Hz,3H),7.62(d,J=7.3Hz,2H),3.82(s,4H),3.68(s,2H),3.48(s,2H); 13 C NMR (125MHz, CDCl3) δ168.85,162.00,146.97,138.84,132.76,132.52,132.06,13 1.13,128.58,128.25,127.21,124.83,118.78,110.66,66.81,48.18,42.62; HRMS calcd for(C 22 H 18 O2N5S+H) + 416.1176, found 416.1168.

[0129] Example 18: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 2)

[0130] In a 100 mL eggplant-shaped flask, 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazole)-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) were added. Under N2 protection, the reaction was carried out at 100 °C for 6 h. TLC detected that the reaction of the raw material was complete, and the dioxane was removed by rotary evaporation. Dichloromethane and water were added, and the mixture was transferred to a separatory funnel. The mixture was shaken and allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, and the filtrate was rotary dried. The mixture was purified by column chromatography (CH2Cl2:CH3OH=50:1) to give 56 mg of a white solid. Yield: 27.5%. 1 HNMR (500MHz, CDCl3) δ8.00(d,J=6.4Hz,2H),7.98–7.94(m,2H),7.59(d,J=6.4Hz,3H),7.20(t,J=7.8Hz,2H),3.82(s,4H),3.68(s,2H),3.48(s,2H); 13 C NMR (125MHz, CDCl3) δ168.92,163.29,161.50,144.92,138.62,135.70,131.33,129.69,128.17,127.16,126.99,124.36,116.08,114.45, 66.82,48.12,42.64; HRMS calcd for(C 21 H 18 O2N4FS+H) + 409.1129, found 409.1119.

[0131] Example 19: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-hydroxyphenyl) (Compound 3)

[0132] In a 100 mL eggplant-shaped flask, 4-(5-bromoimidazo[2,1-b][1,3,4]thiadiazole)-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) were added. Under N2 protection, the reaction was carried out at 100 °C for 6 h. TLC detected that the reaction of the raw material was complete, and the dioxane was removed by rotary evaporation. Dichloromethane and water were added, and the mixture was transferred to a separatory funnel. The mixture was shaken and allowed to stand. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed twice with saturated NaCl solution, dried over anhydrous Mg(SO4)2, filtered, and the filtrate was rotary dried. The mixture was purified by column chromatography (CH2Cl2:CH3OH=50:1) to give 60 mg of a white solid. Yield: 29.5%. 1 HNMR(500MHz,DMSO-d6)δ9.69(s,1H),8.08(d,J=7.9Hz,2H),7.87(d,J=8.2Hz,2H), 7.64(d,J=8.2Hz,3H),6.91(d,J=8.8Hz,2H),3.65(s,4H),3.57(s,2H),3.36(s,2H); 13 C NMR(125MHz,DMSO-d6)δ168.41,161.20,157.55,139.21,131.02,129.93,1 28.65,128.05,127.47,126.71,119.54,116.22,66.48,48.08,42.48; HRMS calcd for(C 21 H 19 O3N4S+H) + 407.1172, found 407.1172.

[0133] Example 20: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methoxycarbonylphenyl) (Compound 4)

[0134] Using intermediate 1 (200 mg, 0.5 mmol) and 4-methoxycarbonylphenylboronic acid (180 mg, 1 mmol) as raw materials, the synthesis method of compound 1 was used to obtain 78 mg of a white solid with a yield of 34.8%. 1H NMR (400MHz, CDCl3) δ8.15(d,J=8.5Hz,3H),8.08(d,J=8.6Hz,3H),8.02(d,J=8.4Hz,2H) ,7.77(s,1H),7.60(d,J=8.4Hz,2H),3.95(s,3H),3.82(s,4H),3.66(s,2H),3.48(s,2H); 13 C NMR (100MHz, CDCl3) δ169.02,166.77,161.97,146.13,138.83,133.72,132.34,131.2 5,130.40,129.11,128.79,128.35,127.36,124.63,66.93,52.37,48.28,42.75; HRMS calcd for(C 23 H 21 O4N4S+H) + 499.1278, found 499.1269.

[0135] Example 21: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 5)

[0136] Intermediate 1 (200 mg, 0.5 mmol) and 4-trifluoromethylphenylboronic acid (190 mg, 1 mmol) were used as raw materials to obtain 80 mg of a white solid according to the synthesis method of compound 1. The yield was 34.9%. 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.1Hz,2H),8.01(d,J=8.1Hz,2H),7.73(d,J=8.1Hz,3H),7.59(d,J=8.2Hz,2H),3.82(s,4H),3.66(s,2H),3.48(s,2H); 13 C NMR (100MHz, CDCl3) δ168.98,161.50,146.46,138.67,132.29,131.80,131.4 1,129.44,128.24,127.20,125.92,124.85,122.76,66.85,48.22,42.77; HRMS calcd for(C 22 H 18 O2N4F3S+H) + 459.1097, found 459.1086.

[0137] Example 22: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-chlorophenyl) (Compound 6)

[0138] Using intermediate 1 (200 mg, 0.5 mmol) and 4-chlorophenylboronic acid (160 mg, 1 mmol) as raw materials, 76 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 35.8%. 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.6Hz,2H),7.93(d,J=8.7Hz,2H),7.61(s,1H),7.58(d, J=8.6Hz,2H),7.45(d,J=8.7Hz,2H),3.80(s,4H),3.67(s,2H),3.51(s,2H),3.47(s,2H); 13 C HRMS calcd for(C 21 H 18 O2N4ClS+H) + 425.0834,found 425.0823.

[0139] Example 23: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-methylphenyl) (Compound 7)

[0140] Using intermediate 1 (200 mg, 0.5 mmol) and 4-methylphenylboronic acid (140 mg, 1 mmol) as raw materials, 64 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 31.7%. 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.6Hz,2H),7.87(d,J=8.2Hz,2H),7.58(m,3H ),7.30(d,J=7.9Hz,3H),3.80(s,4H),3.67(s,2H),3.50(s,2H),2.42(s,3H); 13C NMR (100MHz, CDCl3) δ169.11,160.63,145.06,138.33,137.64,131.79,130.55,1 29.59,128.33,128.13,127.14,125.63,125.09,66.86,48.14,42.67,21.36; HRMS calcd for(C 22 H 21 O2N4S+H) + 405.1380, found 405.1374.

[0141] Example 24: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(4-hydroxymethylphenyl) (Compound 8)

[0142] Intermediate 1 (200 mg, 0.5 mmol) and 4-hydroxymethylphenylboronic acid (152 mg, 1 mmol) were used as raw materials to obtain 54 mg of a white solid according to the synthesis method of compound 1. The yield was 25.7%. 1 H NMR(400MHz, CDCl3)δ7.95(dd,J=8.4,5.1Hz,4H),7.58(s,1H),7.54(d,J=8.4Hz,2H),7 .46(d,J=8.2Hz,2H),4.74(s,2H),3.81(s,4H),3.65(s,2H),3.46(s,2H),2.40(s,1H); 13 C NMR (100MHz, CDCl3) δ169.19,161.00,145.43,140.62,138.36,131.65,130.8 6,128.21,128.01,127.58,127.19,125.19,66.92,65.02,48.31,42.72; HRMS calcd for(C 22 H 21 O3N4S+H) + 421.1329, found 421.1322.

[0143] Example 25: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-trifluoromethylphenyl) (Compound 9)

[0144] Using intermediate 1 (200 mg, 0.5 mmol) and 3-fluoro-4-trifluoromethylphenylboronic acid (208 mg, 1 mmol) as raw materials, 78 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 32.8%.1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.2Hz,2H),7.92(dd,J=11.8,1.6Hz,1H),7.83(d,J=8.3Hz,1H), 7.74(s,1H),7.69(t,J=7.8Hz,1H),7.60(d,J=8.2Hz,2H),3.81(s,4H),3.67(s,2H),3.47(s,2H); 13 C NMR (100MHz, CDCl3) δ168.91,161.95,147.00,138.85,134.21,133.03,131.18, 128.29,127.80,127.24,125.74,119.84,112.71,66.84,48.24,42.67; HRMS calcd for(C 22 H 17 O2N4F4S+H) + 477.1003, found 477.0989.

[0145] Example 26: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-hydroxyphenyl) (Compound 10)

[0146] Intermediate 1 (200 mg, 0.5 mmol) and 3-fluoro-4-hydroxyphenylboronic acid (156 mg, 1 mmol) were used as raw materials to obtain 98 mg of a white solid according to the synthesis method of compound 1. The yield was 46.2%. 1 H NMR (400MHz, CDCl3-CD3OD) δ7.94(d,J=8.3Hz,2H),7.66(dd,J=12.2,2.1Hz,1H),7.51(dd,J =8.6,2.5Hz,3H),7.41(s,1H),6.98(t,J=8.7Hz,1H),3.75(s,4H),3.60(s,2H),3.42(s,2H); 13 C NMR (100MHz, CDCl3-CD3OD) δ169.60,161.23,152.93,150.54,144.95,138.31,131 .76,129.74,128.24,127.41,121.70,120.44,118.34,113.07,66.91,42.84; HRMS calcd for(C 21 H 18 O3N4FS+H) +425.1078, found 425.1066.

[0147] Example 27: 2-(4-(Benzoylmorpholinyl))imidazo[2,1-b][1,3,4]thiadiazole-5-(3,4-difluorophenyl) (Compound 11)

[0148] Intermediate 1 (200 mg, 0.5 mmol) and 3,4-difluorophenylboronic acid (160 mg, 1 mmol) were used as raw materials to obtain 68 mg of a white solid according to the synthesis method of compound 1. The yield was 31.9%. 1 H NMR (400MHz, CDCl3) δ8.00(d,J=8.3Hz,2H),7.87(ddd,J=11.6,7.5,2.2Hz,1H),7.68(dddd,J=8.7,3. 9,2.2,1.4Hz,1H),7.59(m,3H),7.26(dt,J=10.1,8.5Hz,1H),3.80(s,4H),3.67(s,2H),3.48(s,2H); 13 C NMR (100MHz, CDCl3) δ169.00,161.50,151.90,150.99,149.43,148.50,145.76,138.63,13 1.38,128.23,127.20,126.29,125.49,121.11,118.03,114.14,66.84,48.21,42.69; HRMS calcd for(C 21 H 17 O2N4F2S+H) + 427.1035, found 427.1024.

[0149] Example 28: 2-(4-(4-dimethylaminopiperidinyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 12)

[0150] Intermediate 2 (300 mg, 0.7 mmol) and 4-cyanophenylboronic acid (200 mg, 1.4 mmol) were used as raw materials to obtain 50 mg of a white solid according to the synthesis method of compound 1. The yield was 15.6%. 1H NMR (400MHz, CDCl3) δ8.14(d,J=8.1Hz,2H),8.01(d,J=7.9Hz,2H),7.80–7.73(m,3H),7.60(d,J=7.9Hz,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 CNMR (100MHz, CDCl3) δ168.82,161.88,147.05,139.18,133.01,132.78,132.64,131.13,130.45,128 .06,127.20,126.58,126.37,124.79,118.86,110.53,62.29,46.59,41.28,40.89,28.62,26.98; HRMS calcd for(C 25 H 25 ON6S+H) + 457.1805, found 457.1792.

[0151] Example 29: 2-(4-(4-dimethylaminopiperidinyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 13)

[0152] Intermediate 2 (300 mg, 0.7 mmol) and 4-fluorophenylboronic acid (200 mg, 1.4 mmol) were used as raw materials to obtain 40 mg of a white solid according to the synthesis method of compound 1. The yield was 12.7%. 1 H NMR (400MHz, DMSO-d6) δ8.09(m,4H),7.82(s,1H),7.61(d,J=8.0Hz,2H),7.36(d,J=7.9Hz,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 (100MHz, DMSO-d6) δ168.29,161.80,160.64,145.44,139.58,131.69,130.92,128. 45,127.57,127.18,126.78,125.23,116.59,116.37,62.21,55.06,29.51,26.30; HRMS calcd for(C24 H 25 ON5FS+H) + 450.1758,found 450.1750.

[0153] Example 30: 2-(4-(4-dimethylaminopiperidinyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-hydroxyphenyl) (Compound 14)

[0154] Intermediate 2 (300 mg, 0.7 mmol) and 4-hydroxyphenylboronic acid (190 mg, 1.4 mmol) were used as raw materials to obtain 50 mg of a white solid according to the synthesis method of compound 1. The yield was 15.9%. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.04(d,J=8.2Hz,2H),7.84(d,J=8.7Hz,2H),7.63(s,1H),7.59(d,J=8.2Hz,2H),6.88(d,J= 8.7Hz,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(100MHz,DMSO-d6)δ168.17,161.26,157.60,144.25,139.90,130.85,129.92,128.34 ,128.06,127.45,126.71,119.54,116.25,61.73,46.60,41.54,41.05,28.54,27.89; HRMS calcd for(C 24 H 26 O2N5S+H) + 448.1802,found448.1798.

[0155] Example 31: 2-(4-(4-dimethylaminopiperidinyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-methoxyphenyl) (Compound 15)

[0156] Intermediate 2 (300 mg, 0.7 mmol) and 4-methoxyphenylboronic acid (210 mg, 1.4 mmol) were used as raw materials to obtain 40 mg of a light yellow solid according to the synthesis method of compound 1. The yield was 12.4%. 1H NMR (400MHz, CDCl3) δ7.98(d,J=8.4Hz,2H),7.90(d,J=8.9Hz,2H),7.55(d,J=8.5Hz,2H),7.51(s,1H),7.02( d,J=8.9Hz,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 (101MHz, CDCl3) δ169.05,160.73,159.24,144.76,138.81,132.58,131.70,1 29.93,127.98,127.14,126.65,121.23,114.40,62.37,55.47,41.11,29.80; HRMS calcdfor(C 25 H 28 O2N5S+H) + 462.1958, found 462.1947.

[0157] Example 32: 2-(4-(4-dimethylaminopiperidinyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 16)

[0158] Using intermediate 2 (300 mg, 0.7 mmol) and 4-trifluoromethylphenylboronic acid (260 mg, 1.4 mmol) as raw materials, the synthetic method of compound 1 was used to obtain 32 mg of a white solid with a yield of 9.2%. 1 H NMR (400MHz, CDCl3) δ8.11 (d, J = 8.1Hz, 2H), 7.99 (d, J = 8.0Hz, 2H),7.72(d,J=9.7Hz,3H),7.57(d,J=8.6Hz,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); 13 CNMR (100MHz, CDCl3) δ168.87,161.55,146.44,139.10,132.24,131.79,131.28,128 .01,127.15,126.83,125.94,124.84,62.31,46.67,41.04,31.93,29.71,29.37; HRMS calcdfor(C 25 H 25ON5F3S+H) + 500.1726,found 500.1718.

[0159] Example 33: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 17)

[0160] Intermediate 3 (200 mg, 0.5 mmol) and 4-cyanophenylboronic acid (150 mg, 1 mmol) were used as raw materials to obtain 45 mg of a white solid according to the synthesis method of compound 1. The yield was 21%. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.3Hz,2H),7.99(d,J=7.9Hz,2H),7.75(d,J=8.3Hz,3H) ,7.59(d,J=8.0Hz,2H),3.83(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.33(s,3H); 13 C NMR (100MHz, CDCl3) δ168.78,161.94,147.06,139.34,133.01,132.77,132.65,131.01,1 28.20,127.15,126.37,124.79,118.85,110.55,55.23,54.64,47.65,46.02,42.18; HRMS calcd for(C 23 H 21 ON6S+H) + 429.1492, found 429.1485.

[0161] Example 34: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-fluorophenyl) (Compound 18)

[0162] Intermediate 3 (200 mg, 0.5 mmol) and 4-fluorophenylboronic acid (140 mg, 1 mmol) were used as raw materials to obtain 60 mg of a white solid according to the synthesis method of compound 1. The yield was 28.6%. 1 H NMR (400MHz, CDCl3) δ7.97(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); 13C NMR (100MHz, CDCl3) δ168.99,163.51,161.27,161.05,145.36,139.06,131.43,130.65,128. 20,127.42,127.17,126.94,124.77,116.17,115.95,55.32,54.71,47.70,46.12,42.18; HRMS calcd for(C 22 H 21 ON5FS+H) + 422.1445, found 422.1437.

[0163] Example 35: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-methoxycarbonylphenyl) (Compound 19)

[0164] Using intermediate 3 (200 mg, 0.5 mmol) and 4-methoxycarbonylphenylboronic acid (180 mg, 1 mmol) as raw materials, the synthetic method of compound 1 was used to obtain 46 mg of a white solid with a yield of 20%. 1 H NMR (400MHz, CDCl3) δ8.14(d,J=8.6Hz,2H),8.08(d,J=8.7Hz,2H),8.00(d,J=8.3Hz,2H),7.73(s,1H) ,7.58(d,J=8.3Hz,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 (100MHz, CDCl3) δ168.95,166.83,161.54,146.61,139.20,132.73,132.56,131.30,130. 37,128.81,128.24,127.27,127.22,124.42,55.33,52.33,47.73,46.15,42.25,29.80; HRMS calcd for(C 24 H 24 O3N5S+H) + 462.1594, found 462.1582.

[0165] Example 36: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-pyridine) (Compound 20)

[0166] Using intermediate 3 (200 mg, 0.5 mmol) and pyridine-4-boronic acid (120 mg, 1 mmol) as raw materials, 50 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 24.7%. 1 H NMR (400MHz, CDCl3) δ8.67(d,J=6.3Hz,2H),7.99(d,J=8.4Hz,2H),7.89(d,J=6.3Hz,2H),7.81( s,1H),7.57(d,J=8.5Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.32(s,3H); 13 C NMR (100MHz, CDCl3) δ168.86,162.03,150.51,147.41,139.33,135.55,133.49,1 31.07,128.27,127.23,125.53,118.44,55.30,54.68,47.69,46.11,42.20; HRMS calcd for(C 21 H 20 ON6S+H) + 405.1458, found 405.1465.

[0167] Example 37: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethylphenyl) (Compound 21)

[0168] Using intermediate 3 (200 mg, 0.5 mmol) and 4-trifluoromethylphenylboronic acid (190 mg, 1 mmol) as raw materials, 54 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 23%. 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.1Hz,2H),7.98(d,J=8.4Hz,2H),7.71(d,J=8.7Hz,3H) ,7.57(d,J=8.4Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.36(s,2H),2.33(s,3H); 13C NMR (100MHz, CDCl3) δ168.93,161.71,146.51,139.25,132.25,131.83,131.23,1 28.25,127.21,126.88,125.99,124.91,55.34,54.72,47.74,46.15,42.24; HRMS calcd for(C 23 H 21 ON5F3S+H) + 472.1413,found472.1407.

[0169] Example 38: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-chlorophenyl) (Compound 22)

[0170] Using intermediate 3 (200 mg, 0.5 mmol) and 4-chlorophenylboronic acid (160 mg, 1 mmol) as raw materials, 56 mg of a white solid was obtained according to the synthesis method of compound 1. The yield was 25.6%. 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.3Hz,2H),7.93(d,J=8.6Hz,2H),7.61(s,1H),7.57(d,J=8.3H z,2H),7.45(d,J=8.6Hz,2H),3.83(s,2H),3.46(s,2H),2.52(s,2H),2.38(s,2H),2.34(s,3H); 13 C NMR (100MHz, CDCl3) δ168.99,161.37,145.83,139.18,133.42,131.43,131.30,129. 24,128.23,127.26,127.20,127.07,126.28,55.38,54.78,47.78,46.17,42.30; HRMS calcd for(C 22 H 21 ON5ClS+H) + 438.1150, found 438.1145.

[0171] Example 39: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-trifluoromethylphenyl) (Compound 23)

[0172] Using intermediate 3 (200 mg, 0.5 mmol) and 3-fluoro-4-trifluoromethylphenylboronic acid (210 mg, 1 mmol) as raw materials, the synthesis method of compound 1 was used to obtain 78 mg of a white solid with a yield of 31.8%. 1 H NMR (600MHz, CDCl3) δ8.00–7.89(m,3H),7.83(d,J=8.2Hz,1H),7.73(d,J=2.2Hz,1H),7.68(t ,J=7.9Hz,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 (150MHz, CDCl3) δ168.86,162.14,147.09,139.44,134.28,133.77,133.07,131. 06,128.29,128.16,127.25,119.95,112.59,55.31,54.72,47.70,46.09,42.22; HRMS calcd for(C 23 H 20 ON5F4S+H) + 490.1319, found 490.1307.

[0173] Example 40: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(3-fluoro-4-cyanophenyl) (Compound 24)

[0174] Intermediate 3 (200 mg, 0.5 mmol) and 3-fluoro-4-cyanophenylboronic acid (160 mg, 1 mmol) were used as raw materials to obtain 66 mg of a white solid according to the synthesis method of compound 1. The yield was 29.6%. 1 H NMR (600MHz, CDCl3) δ7.99(d,J=8.3Hz,2H),7.96(dd,J=10.4,1.6Hz,1H),7.85(dd,J=8.1,1.6Hz,1H),7.78(s,1H), 7.69(dd,J=8.2,6.7Hz,1H),7.59(d,J=8.3Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.37(s,2H),2.33(s,3H); 13C NMR (150MHz, CDCl3) δ168.79,162.50,147.71,139.60,135.22,134.00,130.87,1 28.34,127.28,120.44,114.11,111.73,55.33,54.71,47.70,46.10,42.22; HRMS calcd for(C 23 H 20 ON6FS+H) + 477.1398, found 477.1400.

[0175] Example 41: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-nitrophenyl) (Compound 25)

[0176] Intermediate 3 (200 mg, 0.5 mmol) and 4-nitrophenylboronic acid (170 mg, 1 mmol) were used as raw materials to obtain 88 mg of a white solid according to the synthesis method of compound 1. The yield was 39.3%. 1 H NMR (400MHz, CDCl3) δ8.35(d,J=8.9Hz,2H),8.20(d,J=8.6Hz,2H),8.02(d,J=8.0Hz,2H),7.83( s,1H),7.61(d,J=8.0Hz,2H),3.84(s,2H),3.48(s,2H),2.53(s,2H),2.39(s,2H),2.35(s,3H); 13 C NMR (100MHz, CDCl3) δ167.43,160.80,146.13,145.11,138.12,133.23,132.28,129. 64,126.91,125.86,124.84,123.44,123.17,53.92,53.37,46.36,44.72,40.83; HRMS calcd for(C 22 H 21 O3N6S+H) + 449.1390, found 449.1386.

[0177] Example 42: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(2,4-difluorophenyl) (Compound 26)

[0178] Using intermediate 3 (200 mg, 0.5 mmol) and 3,4-difluoro-phenylboronic acid (160 mg, 1 mmol) as raw materials, the synthetic method of compound 1 was used to obtain 78 mg of a white solid with a yield of 35.6%. 1 H NMR(400MHz, CDCl3)δ8.39–7.90(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=1.0Hz,5H); 13 C NMR (100MHz, CDCl3) δ168.86,161.68,161.11,144.13,139.23,139.09,134.16,133.71,1 31.31,131.05,128.09,127.17,111.78,104.67,55.23,54.67,47.64,46.03,42.18; HRMS calcd for(C 22 H 20 ON5F2S+H) + 440.1351,found440.1348.

[0179] Example 43: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-cyano-3-pyridine) (Compound 27)

[0180] Using intermediate 3 (200 mg, 0.5 mmol) and 2-cyano-5-pyridineboronic acid (150 mg, 1 mmol) as raw materials, the synthetic method of compound 1 was used to obtain 76 mg of a white solid with a yield of 35%. 1 H NMR (400MHz, CDCl3) δ9.40 (d, J = 2.3Hz, 1H), 8.46 (ddd, J = 8.2, 2.3, 0.8Hz, 1H), 7.99 (d, J = 8.5Hz, 2H), 7. 82–7.76(m,2H),7.59(d,J=8.6Hz,2H),3.83(s,2H),3.46(s,2H),2.52(s,2H),2.38(s,2H),2.34(s,3H); 13CNMR (100MHz, CDCl3) δ168.70,162.68,147.88,146.78,139.59,133.72,131.37,130.72,128 .62,128.27,127.80,127.20,123.53,117.34,55.20,54.60,47.63,46.01,42.15; HRMScalcd for(C 22 H 20 ON7S+H) + 430.1445,found 430.1435.

[0181] Example 44: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-fluoro-3-pyridine) (Compound 28)

[0182] Intermediate 3 (200 mg, 0.5 mmol) and 2-fluoro-5-pyridineboronic acid (140 mg, 1 mmol) were used as raw materials to obtain 65 mg of a white solid according to the synthesis method of compound 1. The yield was 30.8%. 1 H NMR (400MHz, CDCl3) δ8.88(d,J=2.5Hz,1H),8.36(ddd,J=8.6,7.5,2.5Hz,1H),7.98(d,J=8.5Hz,2H),7.65(s,1H),7.58(d, J=8.5Hz,2H),7.07(ddd,J=8.6,3.1,0.7Hz,1H),3.83(s,2H),3.46(s,2H),2.50(d,J=5.9Hz,2H),2.38(s,2H),2.34(s,3H); 13 C NMR (100MHz, CDCl3) δ168.83,163.91,161.87,161.52,146.18,144.13,139.25,137.46,131.39,1 31.09,128.18,127.12,124.19,122.98,110.08,109.71,55.21,54.65,47.60,46.00,42.13; HRMS calcd for(C 21 H 20 ON6FS+H) + 423.1398, found 423.1393.

[0183] Example 45: 2-(4-(N-methylpiperazinecarbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-trifluoromethyl-3-pyridine) (Compound 29)

[0184] Intermediate 3 (200 mg, 0.5 mmol) and 2-(trifluoromethyl)pyridine-5-boronic acid (190 mg, 1 mmol) were used as raw materials to obtain 75 mg of a white solid according to the synthesis method of compound 1. The yield was 31.8%. 1 H NMR (400MHz, CDCl3) δ9.35(dd,J=2.3,0.9Hz,1H),8.45(dd,J=8.2,2.3Hz,1H),7.98(d,J=8.3Hz,2H),7.83(s,1H),7 .78(dd,J=8.2,0.8Hz,1H),7.58(d,J=8.4Hz,2H),3.82(s,2H),3.45(s,2H),2.51(s,2H),2.38(s,2H),2.33(s,3H); 13 C NMR (100MHz, CDCl3) δ168.75,162.34,147.31,145.88,139.48,132.99,132.37,130. 88,128.22,127.46,127.14,123.86,120.66,55.26,54.61,47.64,46.03,42.16; HRMS calcd for(C 22 H 20 ON6F3S+H) + 473.1366, found 473.1355.

[0185] Example 46: 4-(2-(4-pyrrolidinyl-1-carbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(benzocyanate) (Compound 30)

[0186] A mixture of intermediate 8 (65 mg, 0.18 mmol), EDCI (69 mg, 0.36 mmol), and NHS (42 mg, 0.36 mmol) in 10 mL of DMF was stirred at room temperature for 10 h. Pyrrolidinoidine (65 μL, 0.9 mmol) was then added and allowed to react for an additional 1 h. TLC confirmed the reaction was complete, and 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 evaporated to dryness. Purification by column chromatography (DCM:MeOH = 15:1) afforded a white solid (50 mg) in a 68% yield. 1H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.3Hz,2H),8.08–8.02(m,3H),7.91(d,J=8.3Hz,2H) ,7.71(d,J=8.1Hz,2H),3.46(t,J=6.6Hz,2H),3.37(t,J=6.2Hz,2H),1.89-1.76(m,4H). 13 CNMR(100MHz,DMSO-d6)δ167.5,162.5,147.3,141.0,134.3,133.5,132.8 ,130.8,128.7,127.4,126.1,124.9,119.4,109.7,49.3,46.6,26.5,24.5. HRMS calculated for (M+H)+400.1227, found 400.1217.

[0187] Example 47: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(2-(pyrrolidinyl)ethyl)benzoyl ester (Compound 31)

[0188] Using 1-(2-hydroxyethyl)pyrrolidine (104 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as starting materials, a white solid was obtained according to the synthetic method of compound 30 with a yield of 60%. 1 H NMR(400MHz, DMSO-d6)δ,8.29(d,J=8.2Hz,2H),8.16–8.09(m,3H),8.05(d,J=8.2Hz,2H),7.96(d,J=8 .2Hz,2H),4.42(dd,J=12.5,6.3Hz,2H),2.80(t,J=6.8Hz,2H),2.51–2.47(m,4H),1.64–1.74(m,4H). HRMScalculated for(M+H)+443.1449, found 443.1452.

[0189] Example 48: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(n-pentyl)benzoyl ester (Compound 32)

[0190] Using n-pentanethiol (91.8 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 53%. 1H NMR (400MHz, DMSO-d6) δ8.08(d,J=8.4Hz,2H),8.04(d,J=9.7Hz,3H),8.01(d,J=8.4Hz,2H),7.96(d,J=8.4Hz,2H),3 .53(t,J=5.1Hz,1H),1.97(dd,J=11.5,6.1Hz,2H),1.82–1..77(m,4H),1.32(p,J=6.5Hz,2H), 0.8(p,J=6.5Hz,2H). HRMS calculated for (M+H)+432.1176, found 432.1163.

[0191] Example 49: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(3-(morpholinyl)propyl)benzoyl ester (Compound 33)

[0192] Using N-(3-hydroxypropyl)morpholine (131 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.4Hz,2H),8.03–8.09(m,3H),7.82(d,J=8.4Hz,2H),7.71(d, J=8.4Hz,2H),3.50(t,J=4.3Hz,4H),3.35–3.30(m,2H),2.41–2.31(m,2H),1.72(p,J=7.0Hz,2H). HRMS calculatedfor(M+H)+473.1528,found 473.1542

[0193] Example 50: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(5-hydroxypentyl)benzoyl ester (Compound 34)

[0194] Using 1,5-pentanediol (94 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 45%. 1H NMR (400MHz, DMSO-d6) δ8.19(d,J=8.5Hz,2H),8.10(d,J=9.5Hz,3H),7.96(d,J=8.4Hz,2H),7.87(d,J=8.5Hz,2H), 3.21(t,J=5.1Hz,2H), 3.41(dd,J=11.6,6.3Hz,2H), 1.69(dd,J=12.9,6.7Hz,2H), 1.31–1.22(m,2H), 1.06(m,2H). HRMS calculated for (M+H)+432.1347, found 432.1356.

[0195] Example 51: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(2-hydroxyethyl)benzoyl thioester (Compound 35)

[0196] A yellow solid was obtained using 2-mercaptoethanol (70.2 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as starting materials according to the synthetic method of compound 30 in a 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 calculated for (M+H)+ 406.0622, found 406.0635.

[0197] Example 52: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(2-(dimethylamino)ethyl)benzamide (Compound 36)

[0198] Using N,N-dimethyl-1,2-ethylenediamine (80 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 35%. 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.26(d,J=7.8Hz,2H),8.10(d,J=10.0Hz,3H),8.03(d,J =7.5Hz, 2H), 7.94 (d, J = 7.8Hz, 2H), 3.37 (t, J = 4.0Hz, 2H), 2.43 (t, J = 8.0Hz, 2H), 2.20 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ162.5,147.4,138.1,134.4,133.5,132.9,132.1,128.9,127.5,126.1,125.1,119.5,109.8,100.00,58.6,45.8,38.1. HRMS calculated for(M+H)+417.1492,found417.1488.

[0199] Example 53: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(3-(morpholinyl)propyl)benzamide (Compound 37)

[0200] Using N-(3-aminopropyl)morpholine (130 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ8.72(t,J=5.4Hz,1H),8.27(d,J=8.4Hz,2H),8.08–8.14(m,3H),8.04(d,J=8.4Hz,2H ),7.95(d,J=8.4Hz,2H),3.58(t,J=4.3Hz,4H),3.35–3.30(m,2H),2.41–2.31(m,6H),1.72(p,J=7.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ165.5,162.4,147.3,138.1,134.3,133.4,132.8,13 1.9,128.7,127.4,126.0,124.9,119.4,109.7,66.7,56.5,53.8,38.4,26.4. HRMScalculated for(M+H)+473.1730, found 473.1742.

[0201] Example 54: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(2-(pyrrolidinyl)ethyl)benzamide (Compound 38)

[0202] Using 1-(2-aminoethyl)pyrrolidine (102 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a white solid was obtained according to the synthesis method of compound 30 with a yield of 62%. 1 H NMR(400MHz, DMSO-d6)δ8.69(t,J=5.2Hz,1H),8.29(d,J=8.2Hz,2H),8.16–8.09(m,3H),8.05(d,J=8.2Hz,2H),7 .96(d,J=8.2Hz,2H),3.42(dd,J=12.5,6.3Hz,2H),2.60(t,J=6.8Hz,2H),2.51–2.47(m,4H),1.64–1.74(m,4H). 13 C NMR (100MHz, DMSO-d6) δ165.5,162.4,147.2,138.0,134.4,133.5,132.9,132.0,128.8,127.4,126.1,125.0,119.4,109.7,55.3,54.2,23.6. HRMS calculated for (M+H)+443.1649, found 473.1642.

[0203] Example 55: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(3-hydroxypropyl)benzamide (Compound 39)

[0204] Using 3-aminopropanol (68 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 28%. 1 H NMR (400MHz, DMSO-d6) δ8.70(t,J=5.4Hz,1H),8.28(d,J=8.4Hz,2H),8.12(d,J=9.7Hz,3H),8.05(d,J=8.4Hz,2H),7 .96(d,J=8.4Hz,2H),4.53(t,J=5.1Hz,1H),3.50(dd,J=11.5,6.1Hz,2H),3.40–3.35(m,2H),1.72(p,J=6.5Hz,2H). 13C NMR (100MHz, DMSO-d6) δ165.5,162.3,147.2,138.1,134.3,133.4,132.8,131.9,128.7,127.3,126.0,124.9,119.4,109.7,59.1,37.3,32.8. HRMS calculated for (M+H)+404.1176, found 404.1173.

[0205] Example 56: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(2-hydroxyethyl)benzamide (Compound 40)

[0206] Using ethanolamine (55 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ8.71(t,J=5.5Hz,1H),8.28(d,J=8.4Hz,2H),8.15–8.10(m,3H),8.07(d,J=8.5H z, 2H), 7.96 (d, J = 8.4Hz, 2H), 4.80 (t, J = 5.6Hz, 1H), 3.56 (q, J = 6.0Hz, 2H), 3.38 (dd, J = 11.7, 5.8Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ165.7,162.4,147.3,138.0,134.3,133.5,132.9,131.9,128.8,127.3,126.0,124.9,119.4,109.7,60.1,42.8. HRMS calculated for (M+H)+390.1019, found 390.1018.

[0207] Example 57: 4-(2-(4-methylpiperidinyl-1-carbonyl)phenyl)imidazole[2,1-b][1,3,4]thiadiazole-5-(4-cyanophenyl) (Compound 41)

[0208] Using 2-methylpiperidine (89 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 46%. 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=8.5Hz,2H),8.09(d,J=8.6Hz,3H),7.96(d,J=8.5Hz,2H),7.60(d ,J=8.1Hz,2H),5.03–3.59(m,2H),2.99(d,J=37.9Hz,1H),1.75–1.33(m,6H),1.22(d,J=6.8Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ168.4,162.5,147.2,140.9,134.3,133.4,132.9,130.3,127.8,127.7,126.0,124.9,119.4,109.7,30.2,25.9,18.9.HRMS calculated for (M+H)+428.1540, found 428.1533.

[0209] Example 58: 4-(5-(4-cyanophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)N-(5-hydroxypentyl)benzamide (Compound 42)

[0210] Using 5-amino-1-pentanol (93 mg, 0.9 mmol) and intermediate 8 (65 mg, 0.18 mmol) as raw materials, a yellow solid was obtained according to the synthesis method of compound 30 with a yield of 48%. 1 H NMR (400MHz, DMSO-d6) δ8.70(t,J=5.4Hz,1H),8.29(d,J=8.5Hz,2H),8.13(d,J=9.5Hz,3H),8.06(d,J=8.4Hz,2H),7.97(d,J=8.5Hz,2H),4.39( t,J=5.1Hz,1H),3.41(dd,J=11.6,6.3Hz,2H),3.29(dd,J=12.9,6.7Hz,2H),1.61–1.52(m,2H),1.46(dd,J=13.9,6.8Hz,2H),1.40–1.31(m,2H). 13 C NMR(100MHz,DMSO-d6)δ165.4,162.4,147.3,138.2,134.3,133.5,132.8,13 1.9,128.8,127.4,126.0,125.0,119.4,109.7,61.1,32.7,29.5,23.6.HRMS calculated for (M+H)+432.1489, found 432.1479.

[0211] Example 59: 6-(4-morpholinylcarbonylphenyl)-3-(4-cyanophenyl)imidazo[2,1-b]thiazole (Compound 43)

[0212] To a 50 mL eggplant-shaped flask, intermediate 4 (500 mg, 1.6 mmol), 4-cyanophenylacetylene (240 mg, 1.9 mmol), potassium tert-butoxide (540 mg, 4.8 mmol), and DMF (40 mL) were added. The reaction was allowed to react at room temperature for 6 h under magnetic stirring. TLC confirmed the complete reaction. Dichloromethane and water were added to the reaction flask, which was then transferred to a separatory funnel. The mixture was shaken and allowed to stand. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed twice with saturated NaCl solution, dried over anhydrous Mg(SO₄)₂, filtered, and the filtrate was evaporated to dryness. The product was purified by column chromatography (CH₂Cl₂:CH₃OH = 50:1) to afford a white solid (200 mg) in a yield of 30.2%. 1 H NMR (400MHz, CDCl3) δ7.94 (s, 1H), 7.89 (m, 1H), 7.87 (m, 3H), 7.81 (m, 2H), 7.46 (d, J = 8.3Hz, 2H), 6.98 (s, 1H), 3.76 (s, 6H), 3.52 (s, 2H); 13 C NMR (100MHz, CDCl3) δ170.29,150.45,147.16,135.21,134.26,133.86,133.28,130.7 8,127.84,127.29,125.39,117.98,113.43,111.64,107.75,66.91,48.08,42.57; HRMS calcd for(C 23 H 19 O2N6S+H) + 415.1223, found 415.1226.

[0213] Example 60: 6-(4-morpholinylcarbonylphenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 44)

[0214] Using intermediate 4 (500 mg, 1.6 mmol) and 4-fluorophenylacetylene (230 mg, 1.9 mmol) as raw materials, a white solid (170 mg) was obtained according to the synthesis method of compound 30. The yield was 26%. 1H NMR (400MHz, CDCl3) δ7.88(m,3H),7.65(dd,J=8.8,5.1Hz,2H),7.45(d,J=8.3Hz,2H),7.24(m,2H),6.77(s,1H),3.75(s,6H),3.51(s,2H); 13 C NMR (100MHz, CDCl3) δ170.36,164.64,162.14,150.41,146.96,135.73,133.99,131.57,129.04,12 8.96,127.78,126.03,126.00,125.25,116.76,116.54,108.72,107.71,66.93,48.10,42.46; HRMS calcd for(C 22 H 19 O2N3FS+H) + 408.1177,found408.1178.

[0215] Example 61: 6-(4-morpholinylcarbonylphenyl)-3-(4-methoxyphenyl)imidazo[2,1-b]thiazole (Compound 45)

[0216] Using intermediate 4 (500 mg, 1.6 mmol) and 4-methoxyphenylacetylene (250 mg, 1.9 mmol) as raw materials, a white solid (280 mg) was obtained according to the synthesis method of compound 30. The yield was 41.7%. 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.00(d,J=8.2Hz,2H),7.77(d,J=8.4Hz,2H),7.44(d, J=8.2Hz,2H),7.35(d,J=1.2Hz,1H),7.13(d,J=8.5Hz,2H),3.85(s,3H),3.73–3.47(m,8H); 13 C NMR (100MHz, DMSO-d6) δ169.53,162.85,161.52,160.58,149.93,146.21,135.86,134.35,132. 17,128.84,128.07,125.20,122.03,115.17,110.04,108.62,67.19,66.21,55.87,45.58; HRMS calcdfor(C 23 H 22 O3N3S+H) + 420.1376, found 420.1370.

[0217] Example 62: 6-(4-morpholinylcarbonylphenyl)-3-(4-trifluoromethylphenyl)imidazo[2,1-b]thiazole (Compound 46)

[0218] Using intermediate 4 (500 mg, 1.6 mmol) and 4-trifluoromethylphenylacetylene (320 mg, 1.9 mmol) as raw materials, a white solid (220 mg) was obtained according to the synthesis method of compound 30. The yield was 30.1%. 1 H NMR (400MHz, CDCl3) δ7.93(s,1H),7.89(d,J=8.3Hz,2H),7.82(m,4H),7.46(d,J=8.3Hz,2H),6.93(s,1H),3.76(s,6H),3.52(s,2H); 13 C NMR (100MHz, CDCl3) δ170.31,150.45,147.19,135.53,134.15,133.22,131.1 9,127.81,127.22,126.53,125.30,110.52,107.73,66.93,48.32,42.60; HRMS calcdfor(C 23 H 19 O2N3S+H) + 458.1145, found 458.1144.

[0219] Example 63: 6-(4-morpholinylcarbonylphenyl)-3-(4-chlorophenyl)imidazo[2,1-b]thiazole (Compound 47)

[0220] Using intermediate 4 (500 mg, 1.6 mmol) and 4-chlorophenylacetylene (260 mg, 1.9 mmol) as raw materials, a white solid (265 mg) was obtained according to the synthesis method of compound 30. The yield was 39.1%. 1 H NMR (400MHz, CDCl3) δ7.88(d,J=4.4Hz,2H),7.85(s,1H),7.59(d,J=8.6Hz,2H),7. 51(d,J=8.6Hz,2H),7.44(d,J=8.4Hz,2H),6.80(s,1H),3.73(s,6H),3.51(s,2H); 13C NMR (100MHz, CDCl3) δ170.32,150.40,146.95,135.77,135.66,134.01,131.4 4,129.71,128.17,127.78,125.24,109.22,107.80,66.92,48.30,42.71; HRMS calcd for(C 22 H 19 O2N3ClS+H) + 424.0881, found 424.0870.

[0221] Example 64: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-cyanophenyl)imidazo[2,1-b]thiazole (Compound 48)

[0222] Intermediate 5 (500 mg, 1.5 mmol) and 4-cyanophenylacetylene (230 mg, 1.8 mmol) were used as raw materials to obtain a white solid (280 mg) according to the synthesis method of compound 30. The yield was 43.7%. 1 H NMR (400MHz, CDCl3) δ7.92 (s, 1H), 7.88-7.84 (m, 4H), 7.80 (d, J = 8.7Hz, 2H), 7.45 (d, J = 8 .6Hz,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 (100MHz, CDCl3) δ170.15,150.41,147.48,135.24,134.71,133.99,133.26,130.77,1 27.77,127.26,125.26,118.00,113.37,111.39,107.63,55.05,47.56,45.96,41.99; HRMS calcd for(C 24 H 22 ON5S+H) + 428.1540, found 428.1535.

[0223] Example 65: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 49)

[0224] Using intermediate 5 (500 mg, 1.5 mmol) and 4-fluorophenylacetylene (220 mg, 1.8 mmol) as raw materials, a white solid (220 mg) was obtained according to the synthesis method of compound 30. The yield was 34.9%. 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.0Hz,3H),7.64(dd,J=8.8,5.1Hz,2H),7.43(d,J=8.5Hz,2H),7. 22(d,J=8.8Hz,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 (100MHz, CDCl3) δ170.24,164.61,162.11,150.35,147.03,135.51,134.48,131.55,129. 02,127.71,126.04,125.17,116.51,108.65,107.65,55.21,54.82,47.70,46.02,42.15; HRMS calcd for(C 23 H 22 ON4FS+H) + 421.1493, found 421.1490.

[0225] Example 66: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-trifluoromethylphenyl)imidazo[2,1-b]thiazole (Compound 50)

[0226] Using intermediate 5 (500 mg, 1.5 mmol) and 4-trifluoromethylphenylacetylene (310 mg, 1.8 mmol) as raw materials, a white solid (300 mg) was obtained according to the synthesis method of compound 30. The yield was 42.5%. 1 H NMR (400MHz, CDCl3) δ7.92(s,1H),7.86(d,J=8.6Hz,2H),7.80(m,4H),7.44(d,J=8.6H z,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 (100MHz, CDCl3) δ168.66,148.87,145.72,133.82,133.04,131.68,129.63,1 26.19,125.66,124.97,123.68,108.92,106.15,53.55,46.07,44.43,40.52; HRMS calcd for(C 24 H 22 ON4F3S+H) + 471.1461,found471.1452.

[0227] Example 67: 6-(4-(N-methylpiperazinylcarbonyl)phenyl)-3-(4-chlorophenyl)imidazo[2,1-b]thiazole (Compound 51)

[0228] Using intermediate 5 (500 mg, 1.5 mmol) and 4-chlorophenylacetylene (245 mg, 1.8 mmol) as raw materials, a white solid (264 mg) was obtained according to the synthesis method of compound 30. The yield was 40.3%. 1 H NMR (400MHz, CDCl3) δ7.87(s,1H),7.84(d,J=8.5Hz,2H),7.58(d,J=8.7Hz,2H),7.50(d,J=8.7Hz,2H) ,7.42(d,J=8.5Hz,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 (101MHz, CDCl3) δ170.22,150.37,147.04,135.77,135.45,134.47,131.44,129.70,128 .23,128.17,127.70,125.17,109.15,107.72,55.18,54.86,47.68,46.00,42.09; HRMScalcd for(C 23 H 22 ON4ClS+H) + 437.1197, found 437.1197.

[0229] Example 68: 6-(4-(4-morpholinopiperidinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 52)

[0230] Intermediate 6 (500 mg, 1.3 mmol) and 4-fluorophenylacetylene (190 mg, 1.6 mmol) were used as raw materials to obtain a white solid (280 mg) according to the synthesis method of compound 30. The yield was 43.9%. 1 H NMR (400MHz, CDCl3) δ7.85(m,3H),7.64(dd,J=8.8,5.1Hz,2H),7.42(d,J=8.6Hz,2H),7.23(d,J=8.7Hz,2H),6.75(s,1H),4.71(s,1H),3 .88(s,1H),3.71(t,J=4.6Hz,4H),3.02(s,1H),2.81(s,1H),2.55(t,J=4.6Hz,4H),2.43(m,1H),1.96(s,1H),1.82(s,1H),1.58(s,2H); 13 C NMR (100MHz, CDCl3) δ170.19,164.62,162.13,150.36,147.07,135.44,134.75,131.56,129.03,128.95,127 .53,126.02,125.18,116.75,116.52,108.64,107.62,67.14,61.98,49.81,46.93,41.55,28.96,28.15; HRMS calcd for(C 27 H 28 O2N4FS+H) + 491.1912, found 491.1908.

[0231] Example 69: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-fluorophenyl)imidazo[2,1-b]thiazole (Compound 53)

[0232] Using intermediate 7 (500 mg, 1.4 mmol) and 4-fluorophenylacetylene (200 mg, 1.7 mmol) as raw materials, a white solid (215 mg) was obtained according to the synthesis method of compound 30. The yield was 34.2%. 1H NMR (400MHz, CDCl3) δ7.85(d,J=9.1Hz,3H),7.64(dd,J=8.8,5.1Hz,2H),7.42(d,J=8.4Hz,2H),7.22(d,J=8.6Hz,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 (100MHz, CDCl3) δ170.22,164.61,162.12,150.35,147.05,135.47,134.69,131.56,129.02,128.94,1 27.54,126.04,126.01,125.18,116.73,116.52,108.64,107.65,62.26,46.93,41.38,28.88,27.86; HRMS calcd for(C 25 H 26 ON4FS+H) + 499.1806, found 499.1795.

[0233] Example 70: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-trifluoromethylphenyl)imidazole[2,1-b]thiazole (Compound 54)

[0234] Using intermediate 7 (500 mg, 1.4 mmol) and 4-trifluoromethylphenylacetylene (290 mg, 1.7 mmol) as raw materials, a white solid (284 mg) was obtained according to the synthesis method of compound 30. The yield was 40.7%. 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.85(d,J=8.3Hz,2H),7.79(m,4H),7.42(d,J=8.3Hz,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); 13C NMR (100MHz, CDCl3) δ170.17,150.40,147.25,135.31,134.81,133.22,131.17,127.56,1 27.20,126.50,125.22,122.33,110.49,107.72,62.26,46.96,41.36,28.88,27.77; HRMS calcd for(C 26 H 26 ON4F3S+H) + 499.1774, found 499.1783.

[0235] Example 71: 6-(4-(4-dimethylamino)piperidinylcarbonyl)phenyl)-3-(4-chlorophenyl)imidazole[2,1-b]thiazole (Compound 55)

[0236] Using intermediate 7 (500 mg, 1.4 mmol) and 4-chlorophenylacetylene (230 mg, 1.7 mmol) as raw materials, a white solid (254 mg) was obtained according to the synthesis method of compound 30. The yield was 39%. 1 H NMR (400MHz, CDCl3) δ7.87(s,1H),7.84(d,J=8.3Hz,2H),7.59(d,J=8.6Hz,2H),7.50(d,J=8.6Hz,2H),7.41(d,J=8.3Hz,2 H),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 (100MHz, CDCl3) δ170.21,150.38,147.08,135.79,135.44,134.66,131.46,129.72,1 28.25,128.18,127.55,125.19,109.13,107.71,62.29,46.89,41.27,28.70,27.68; HRMS calcd for(C 25 H 26 ON4ClS+H) + 465.1510,found 465.1501.

[0237] Example 72: Preparation of Compounds 56-61

[0238]

[0239] Thiosemicarbazide and methyl paraformylbenzoate were stirred in methanol at room temperature for 2 hours. FeCl₃·6H₂O dissolved in methanol was then added, heated and stirred at 75°C for 30 minutes, cooled to room temperature, and the solid was filtered and rinsed with methanol until the filtrate was colorless to yield compound O. Compound O was then mixed with 2-bromo-1-phenylketone, 2-bromo-1-(4-fluorophenyl)ketone, or 2-bromo-1-(4-cyanophenyl)ketone and refluxed in acetonitrile for 12 hours. Column chromatography afforded a yellow intermediate, which was then refluxed in acetic acid for 5 hours. The mixture was then poured into ice water and filtered to yield the corresponding compound P1, P2, or P3. A mixture of P1, P2, or P3 with LiOH·H₂O in THF / H₂O (1:1) was stirred at room temperature for 12 hours. The pH was adjusted to 2-3 with HCl, and the mixture was filtered to yield a yellow solid, Q1, Q2, or Q3, which was used in the next step without further purification. Q1, Q2 or Q3, EDCI, NHS and corresponding amine were added to DMF solvent, mixed and stirred, and stirred at room temperature for 12 h to obtain compounds 51-56.

[0240] N-(3-(Dimethylamino)-2,2-dimethylpropyl)-4-(6-phenylimidazolyl[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Compound 56)

[0241] 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). DMF was then added and stirred at room temperature for 12 h. After completion of the reaction as determined by thin-layer chromatography (TLC), the reaction mixture was diluted with water and extracted three times with ethyl acetate (20 mL). The combined organic layers 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 afford Compound 51 as a white solid in a 45% yield. 1 H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.08(s,4H),7.90(d,J=7.2Hz,2H),7.43(t,J=7 .7Hz,2H),7.30(t,J=7.4Hz,1H),3.30(s,2H),3.01(s,2H),2.88(s,6H),1.07(s,6H). 13C NMR (125MHz, DMSO-d6) δ166.9,161.1,159.1,158.8,158.5,158.1,145.9,145.0,137.3,133.7,132.4,12 9.1(d,J=3.4Hz),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 calculated for(M+H) + 434.2009,found 434.2010.

[0242] 4-(6-phenylimidazole[2,1-b][1,3,4]thiadiazol-2-yl)-N-(3-(tetrahydropyrrolyl)propyl)benzamide (Compound 57)

[0243] Using Q2 and 1-(3-aminopropyl)tetrahydropyrrole as raw materials, according to the synthesis method of compound 51, white solid compound 52 was obtained with a yield of 49%. 1 H NMR (500MHz, DMSO-d6) δ8.82–8.77(m,2H),8.05(q,J=8.4Hz,4H),7.91(d,J=7.6Hz,2H),7.43( t,J=7.7Hz,2H),7.30(t,J=7.3Hz,1H),3.37–3.34(m,2H),2.81(d,J=86.5Hz,6H),1.83(s,6H). 13 C NMR(125MHz,DMSO-d6)δ165.8,160.9,146.3,145.02,137.5,134.1,132.3 ,129.2,128.8,127.9,127.1,125.2,111.1,53.9,52.9,37.4,26.9,23.2. HRMS calculated for(M+H) + 432.1853, found 432.1855.

[0244] 4-(6-(4-Fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (Compound 58)

[0245] Using Q1 and 4-(2-aminoethyl)pyridine as raw materials, according to the synthesis method of compound 51, white solid compound 53 was obtained with a yield of 31%. 1H NMR (500MHz, DMSO-d6) δ8.79(t,J=5.6Hz,1H),8.77(s,1H),8.47(d,J=5.9Hz,2H),8.05(d,J=8.4Hz,2H),7.99(d,J=8. 4Hz,2H),7.96–7.91(m,2H),7.27(dd,J=15.5,6.7Hz,4H),3.57(dd,J=12.9,6.9Hz,2H),2.90(dd,J=11.9,4.7Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ165.6,162.1(d,J=244.2Hz),160.9,149.8,148.9,145.2(d,J=29.8Hz),137.6,132 .2,130.7(d,J=2.8Hz),128.7,127.2(d,J=6.9Hz),124.7,116.1(d,J=21.6Hz),111.0,109.9,40.56,34.57. HRMS calculated for(M+H) + 444.1289,found444.1291.

[0246] N-(2-Hydroxyethyl)-4-(6-phenylimidazolyl[2,1-b][1,3,4]thiadiazol-2-yl)benzamide (Compound 59)

[0247] Using Q2 and ethanolamine as raw materials, the white solid compound 54 was obtained according to the synthetic method of compound 51 with a yield of 51%. 1 H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.66(t,J=5.5Hz,1H),8.05(s,4H),7.91(d,J=7.3Hz,2H),7.4 3(t,J=7.7Hz,2H),7.30(t,J=7.3Hz,1H),4.76(s,1H),3.53(t,J=6.2Hz,2H),3.36(d,J=5.0Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ165.7,160.9,146.2,145.0,137.7,134.1,132.2,129.2,128.8,127.9,127.0,125.2,111.2,60.1,42.8. HRMScalculated for(M+H) + 365.1067,found 365.1065.

[0248] 4-(2-(4-(tetrahydropyrrolyl-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)cyanobenzene (Compound 60)

[0249] Using Q3 and tetrahydropyrrole as raw materials, the white solid compound 55 was obtained according to the synthesis method of compound 51 with a yield of 51%. 1 H NMR(400MHz,TFA-d1)δ8.47(s,1H),8.19(d,J=7.9Hz,2H),7.92(d,J=8.8Hz,4H),7.86( d,J=7.9Hz,2H),3.93(s,2H),3.70(s,2H),2.18(d,J=6.3Hz,2H),2.10(d,J=5.9Hz,2H). 13 C NMR (400MHz, 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.

[0250] 4-(2-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)cyanobenzene (Compound 61)

[0251] Using Q3 and N-methylpiperazine as raw materials, the green solid compound 56 was obtained according to the synthesis method of compound 51 with a yield of 63%. 1 H NMR(400MHz,TFA-d1)δ8.47(s,1H),8.15(d,J=8.1Hz,2H),7.96–7.89(m,4H),7.73(d,J=8.1Hz,2H),5.04(d,J=14.5Hz,1H),4.08(d ,J=14.0Hz,1H),3.85(d,J=6.8Hz,2H),3.73(d,J=12.0Hz,1H),3.57(t,J=13.0Hz,1H),3.32(dt,J=37.8,11.3Hz,2H),3.11(s,3H). 13 C NMR (100MHz, DMSO-d6) δ168.2,161.9,145.8,144.3,139.7,138.7,133.3,130.7,128.6,127.5,125.7,119.5,113.4,109.9,55.0,46.0.

[0252] Example 73: Test of the inhibitory activity of the compounds of the present invention on MNKs protease

[0253] MNK1 and MNK2 kinase inhibition assays were performed using the PerkinElmer LANCE Ultra kinase assay. Staurosporine (STSP) served as a positive control. The assay steps were as follows: 1.00 ng of MNK1 or 0.05 ng of MNK2 was mixed with various concentrations of the test compound (10,000, 1,000, 100, 10, and 1 nM) in a 10 μL reaction mixture (MNK1: 12.5 nM CREB, 450 μM ATP, 2 mM DTT, 1× buffer; MNK2: 12.5 nM CREB, 100 μM ATP, 2 mM DTT, 1× buffer) at 25°C for 60 min. The reaction was then terminated by the addition of 5 μL of EDTA / detection buffer and 5 μL of Eu-CREB / detection buffer. After 60 min of incubation, the ratio of the HTRF signals at 615 nm and 665 nm was measured. First, test the compound at 1000 nM and calculate the inhibition rate. When the inhibition rate is >75%, 50%, and 25%, it is recorded as +++, ++, and +, respectively. See Table 1.

[0254] Then, five different concentrations (10000, 1000, 100, 10, 1 nM) of the test compound were measured, and the IC was calculated based on the inhibition rate fitting curve. 50 IC values of test compounds against MNK1 / 2 in vitro 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(*).

[0255] Table 1. Inhibitory activity of 1 μM compounds on MNKs protease

[0256]

[0257] Table 2. IC values of compounds against MNKs proteases 50 value

[0258]

[0259] We tested the effects of the above compounds on different mouse disease models, and compound 12 is used as a specific example below.

[0260] Example 74: High-fat diet obesity model weight loss test

[0261] C57BL / 6J male mice were fed a high-fat diet (60 kcal%) or a low-fat diet (10 kcal%). After 16 weeks, an obesity model was successfully established (weight of the high-fat-fed mice was 20% greater than that of the low-fat-fed mice). The mice were then divided into three groups: a blank group, 12 high-dose groups (100 mg / kg), 12 low-dose groups (50 mg / kg), and an orlistat group (50 mg / kg). Orlistat was administered daily by gavage in the afternoon, with the blank group receiving saline as a control. The mice were administered with the drug for four consecutive weeks. During this period, the mice's food intake and weight changes were regularly measured. Results showed that after one month, the treated group experienced a significant decrease in weight, while food intake remained unchanged.

[0262] Example 75: STZ+high-fat diet diabetic mouse model hypoglycemic test

[0263] Fifty male Kunming mice were housed at 25°C with free access to food and water. After five days of acclimatization, they were divided into two groups. Group 1 (10 mice) served as a blank control (C) group fed a standard diet, while Group 2 (40 mice) were fed a 60% high-fat diet for four weeks to induce a high-fat diet model. At week five, mice in Group 2 were injected with streptozotocin (STZ) to induce type 2 diabetes. These injections were divided into three doses, one day apart, for a total of 150 mg / kg. Housed under the same conditions, fasting blood glucose levels were measured one week later using a glucometer and disposable test strips. Mice with blood glucose levels above 11 mmol / L were considered type 2 diabetic mice. These mice were then divided into two groups, each containing 10 mice: a model group (M, distilled water), a metformin group (Meft, 225 mg / kg / d), a low-dose compound 12 group (2A-L, 50 mg / kg / d), and a high-dose compound 12 group (2A-H, 100 mg / kg / d). Mice were gavaged daily in the mornings. Group M received distilled water, with the doses of Meft (225 mg / kg), 2A-L (50 mg / kg), and 2A-H (100 mg / kg) administered at a dose of 0.2 mL / g. The mice were gavaged for 8 weeks, during which body weight and fasting blood glucose were measured regularly.

[0264] The results show that ( Figure 1 ), compound 12 significantly lowered blood sugar in mice in both the low-dose group (50 mg / kg) and the high-dose group (100 mg / kg). The low-dose group had a comparable blood sugar-lowering effect to the positive control group (metformin, 225 mg / kg), while the high-dose group showed a better blood sugar-lowering effect than the positive control.

[0265] Compound 12 has the effect of improving glucose tolerance ( Figure 2The results of the insulin tolerance test showed that after intraperitoneal injection of insulin, blood glucose gradually decreased and reached its lowest value after 55 minutes. Compared with the model group, both the low-dose and high-dose groups of compound 12 had lower insulin sensitivity, indicating that compound 12 can restore insulin sensitivity in mice. This shows that compound 12 has the effect of lowering blood glucose and restoring insulin sensitivity.

[0266] Compound 12 can significantly reduce the serum AST level ( Figure 3 Compared with the model group, the Compound 12-treated group showed significant decreases in serum TG and TC, indicating that Compound 12 has a certain lipid-lowering effect. Compound 12 has a similar TG-lowering effect as metformin, and even has a better TC-lowering effect than metformin. A serum creatinine value higher than normal generally indicates kidney damage. Compared with the control group, CREA in the model group was significantly increased, indicating that the model causes kidney damage. After administration, CREA decreased significantly, indicating that Compound 12 can repair diabetic kidney damage.

[0267] Example 76: Insulin tolerance and liver function improvement test in male db / db mouse model

[0268] Six-week-old male db / db mice were randomly divided into six groups, with 12 mice in each group: model group (M, distilled water), metformin group (Meft, 200 mg / kg / d), lovastatin group (6 mg / kg), low-dose compound 12 group (20 mg / kg / d), medium-dose compound 12 group (40 mg / kg / d), and high-dose compound 12 group (80 mg / kg / d). The mice were housed at a constant temperature of 25°C with free access to food and water. The drug was administered orally at a dose of 0.2 mL / g for 6 weeks, during which time body weight and fasting blood glucose levels were measured regularly.

[0269] Insulin tolerance test (ITT) was conducted with normal saline solution at a concentration of 1.0 U / ml and a dosage of 1.0 U / kg. The animals were fasted for 4 hours in the morning and allowed to drink water normally. In the afternoon, the animals were weighed and their blood sugar was measured before insulin injection. The injection dosage of insulin was calculated based on body weight. Blood sugar was measured at 15 minutes, 30 minutes, 45 minutes, and 60 minutes. After the experiment, each cage was supplemented with feed. The insulin tolerance test showed that ( Figure 4 ), each drug treatment group could significantly improve the insulin sensitivity of db / db mice, especially the 12 high-dose group was the most significant.

[0270] Liver function serum biochemical indicators ( Figure 5 ), compared with the model group, the ALT, AST and total bile acid contents in the high-dose administration group were significantly decreased, indicating that the drug can attenuate liver damage and alleviate liver inflammatory response in db / db mice.

[0271] Serum active protein index ( Figure 6 ) After high-dose administration, the insulin INS content can be significantly increased, indicating that the compound promotes the secretion of insulin by pancreatic islet cells; the level of GLP-1, a brain gut peptide, in the blood is increased, which indicates the beneficial therapeutic effect of the drug; at the same time, the BNP, an indicator of heart failure, and the inflammatory factors TNF and IL-6 in the plasma are significantly decreased when administered at low doses, further confirming that the drug is very effective in eliminating inflammation in mice.

[0272] These test results demonstrate that the compounds of the present invention exhibit potent inhibitory activity against MNK1 / 2 protein kinases and exhibit good safety in cells. Compound 12, as a representative example, demonstrates significant blood sugar control, weight reduction, improvement in various blood biochemical parameters, and protection of vital organs such as the liver in diabetic and obese mouse models, demonstrating promising drug development and application prospects.

[0273] The present invention has been introduced in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The above examples are only used to help understand the methods of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements that are not different from the literal wording of the claims, or if they include equivalent structural elements that are not substantially different from the literal wording of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. An imidazothiazole derivative or a pharmaceutically acceptable salt thereof, characterized in that The imidazothiazole derivative has a structure shown in formula (I): Formula (I) includes general formula 1 and general formula 2, R1 and R3 are each independently selected from a 5-membered to 6-membered heterocyclic group containing 1-2 nitrogen atoms, which is optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, a 5-membered to 6-membered heterocyclic ring, halogen, hydroxyl, cyano, nitro, amino, or carbonyl, or R1 is selected from a C1-C6 alkoxy group optionally substituted by one or more hydroxyl, halogen, amino, dimethylamino, or a 5-membered to 6-membered heterocyclic ring, R2 is selected from a C1-C6 alkoxy group optionally substituted by one or more hydroxyl, halogen, amino, dimethylamino, or a 5-membered to 6-membered heterocyclic ring. C1-C6 alkylthio, R1 is selected from C1-C6 alkylamino optionally substituted with one or more hydroxyl, halogen, amino, dimethylamino, or a 5- to 6-membered heterocycle, R2 and R4 are each independently selected from aryl or heteroaryl substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, or a hydroxyl group; the aryl is selected from phenyl and naphthyl, and the heteroaryl is selected from furyl, thienyl, pyridyl, thiazolyl, or imidazolyl.

2. The imidazothiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that The 5-membered to 6-membered heterocyclic group is selected from 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 pyrrol group, and a tetrahydropyrrol group.

3. The imidazothiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that The C1-C6 alkylamino group refers to an amino group (-NH2) in which one or two hydrogen atoms are replaced by the same or different "C1-C6 alkyl" groups; it can be represented as -NR 1 R 2 , R 1 、R 2 are each independently selected from H, C1-C6 alkyl, and R 1 、R 2 Cannot be H at the same time.

4. The imidazothiazole derivative of formula (I) according to any one of claims 1 to 2 is selected from compound 1-55 or a pharmaceutically acceptable salt thereof, wherein the structure of compound 1-55 is as follows:

5. A method for preparing an imidazothiazole derivative of formula (I) according to any one of claims 1 to 4, characterized in that The steps include: Synthesis method of general formula 1: The compound of formula (II) undergoes a Suzuki condensation reaction with the corresponding boronic acid derivative B(OH)2R2 to obtain a compound of formula 1, wherein R1 and R2 are as defined in any one of claims 1 to 4, and X is a halogen; Synthesis method of general formula 2: The compound of formula (III) and the corresponding acetylene derivative The reaction is carried out under alkaline conditions to obtain a compound of the general formula 2, wherein the definitions of R3 and R4 are the same as those in any one of claims 1-4.

6. The preparation method according to claim 5, characterized in that The steps include: The synthesis method of general formula 1 comprises the steps of preparing a compound of formula (II) from a compound of formula (IV): The synthesis method of general formula 2 comprises the steps of preparing a compound of formula (III) from a compound of formula (V):

7. A method for preparing an imidazothiazole derivative of formula (I) according to any one of claims 1 to 4, characterized in that The imidazothiazole derivative of formula (I) is selected from the general formula 1 in which R2 is 4-cyanophenyl, represented by compound N, comprising the following steps: Compound M undergoes a condensation reaction with R1H to obtain compound N, where R1 has the same definition as in any one of claims 1-4.

8. An intermediate for preparing an imidazothiazole derivative of formula (I) according to any one of claims 1 to 4, characterized in that The intermediate has the structure shown in formula (II), formula (III), formula (IV), and formula (V): R1 and R3 are defined as in any one of claims 1 to 4, and X is a halogen.

9. An intermediate for preparing an imidazothiazole derivative of formula (I) according to any one of claims 1 to 4, characterized in that The intermediate has the following structure:

10. Use of the compound of formula (II), formula (III), formula (IV), or formula (V) according to claim 8 or the intermediate according to claim 9 in the preparation of the imidazothiazole derivative of formula (I) according to any one of claims 1 to 4.

11. Use of an imidazothiazole derivative of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for inhibiting the kinase activity of MNK1 or MNK2 or variants thereof.

12. Use of an imidazothiazole derivative of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for preventing and / or treating metabolic diseases associated with MNK activity.

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

14. Use of an imidazothiazole derivative of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for preventing and / or treating cancer caused by abnormal MNK1 and / or MNK2 levels.

15. Use of an imidazothiazole derivative of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of an MNK1 and / or MNK2 inhibitor.

16. A pharmaceutical composition, characterized in that The pharmaceutical composition uses the imidazothiazole derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

17. The pharmaceutical composition according to claim 16, characterized in that The pharmaceutical composition may further include pharmaceutically acceptable excipients.

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

19. The pharmaceutical composition according to any one of claims 16 to 17, characterized in that The dosage form of the pharmaceutical composition is a solid preparation, a liquid preparation or a semisolid preparation.

20. The pharmaceutical composition according to claim 19, characterized in that The dosage form of the pharmaceutical composition is selected from tablets, capsules and injections.

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