4-(1-(Azoacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonist

Abstract

The present invention relates to the field of medicinal chemistry, and in particular to a class of 4-(1-(azaacyl-3-butyl)-1H-imidazole-2-yl)aniline PKM2 agonists. The present invention provides a class of novel PKM2 agonists for treating aortic dissection. Compared with the original drug, the agonist activity of the compound at each concentration is significantly better than that of the original drug. AC 50 It is comparable to positive drugs and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonists. Background Art

[0002] Aortic aneurysm and dissection are cardiovascular diseases that seriously threaten human life worldwide. Aortic dissection is mainly caused by the tearing of the aortic intima and the degeneration of the smooth muscle layer of the media, which further causes the blood in the vascular cavity to enter the middle layer of the aortic wall through the intimal damage, forming a hematoma and causing a critical vascular disease. When aortic dissection ruptures, it will lead to insufficient perfusion of various organs and endanger the patient's life.

[0003] Smoking, Marfan syndrome, and elevated blood pressure are risk factors for aortic dissection / anesm. At present, aortic dissection / anesm is mainly treated with surgical or interventional methods, which has certain limitations. The postoperative mortality rate is as high as 10%-30%, and the recurrence rate of patients is high; medical treatment mainly intervenes in aortic dissection / anesm by using drugs such as beta-blockers and calcium channel antagonists. The therapeutic effects of these drugs on aortic dissection / anesm are relatively limited and there are certain controversies. Therefore, finding important targets for occurrence and developing corresponding treatment methods are of great social and economic significance to reduce the mortality rate of aortic dissection and aortic aneurysm. One of the most important pathological characteristics of aortic aneurysm / dissection is the enhancement of local inflammatory response, including inflammatory cell infiltration, smooth muscle cell phenotype conversion caused by the release of inflammatory factors, endothelial dysfunction, and degradation of extracellular matrix. Among them, macrophages play an extremely critical role in the progression of aortic inflammation and tissue remodeling.

[0004] Pyruvate kinase (PK) is a metabolic enzyme that converts phosphoenolpyruvate to pyruvate during glycolysis. There are four PK isoforms in mammals: L and R isoforms are expressed in the liver and erythrocytes, M1 isoform (PKM1) is expressed in most terminally differentiated tissues, such as cardiomyocytes, and cells with proliferative activity, such as fibroblasts or endothelial cells, express both M1 and M2 pyruvate kinases (PKM2). In addition, tumor cells and immune cells highly express PKM2. M1 and M2 pyruvate kinases depend on alternative splicing of the PK gene. In addition, there are functional differences between the two: M2 is a low-activity enzyme that is allosterically activated by the upstream glycolytic intermediate fructose-1,6-bisphosphate (FBP). In addition, it has been found to have transcriptional cofactor and kinase activity; PKM1 is a constitutively activated enzyme, and its activity is not regulated by cellular FBP.

[0005] Studies have shown that during the process of smooth muscle phenotypic transformation, PK alternative splicing changes, generating more PKM2, while the expression of PKM1 decreases. PKM2 can specifically enhance the phenotypic transformation of smooth muscle cells and participate in intimal hyperplasia. In addition, during the process of inflammatory activation, PKM2 monomers or dimers use the PKM2 agonist TEPP-46 to reduce the activation of inflammasomes and the release of IL-1β during aortic dissection, thereby improving aortic dissection. The above studies show that PKM2 agonists may improve aortic dissection through multiple pathways, so the development of new PKM2 agonists is of great significance for the prevention and treatment of aortic dissection. Summary of the invention

[0006] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a class of 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonists.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides a class of 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonists or pharmaceutically acceptable salts thereof:

[0009]

[0010] in:

[0011] W, X, Y and Z are each independently selected from CH or N;

[0012] L is selected from a bond, -C(O)-, or -(CR a R a ) m -;

[0013] Q is selected from -C(O)- or ;

[0014] Each R 1 is selected from aryl, heteroaryl or heterocyclic; each of which is replaced by R b Replace 0-5 times;

[0015] Each R 2 is selected from alkyl, carbocyclic, aryl, heteroaryl or heterocyclic; each of which is replaced by R b Replace 0-5 times;

[0016] Each R 3 are independently selected from halogen, haloalkyl, alkyl or -OR c ;

[0017] Each R aare independently selected from hydrogen, halogen, alkyl, alkoxy or haloalkoxy, or two R a together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl group;

[0018] Each R b independently selected from halogen, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, carboxyl, -C(O)R c 、-OC(O)R c 、-C(O)OR c 、-SR c 、-NR c R d OR b or two R b together with the carbon atom to which they are attached, form an optionally substituted heterocyclyl;

[0019] Each R c independently selected from hydrogen, alkyl, acyl, hydroxyalkyl or haloalkyl;

[0020] Each R d Independently selected from hydrogen or alkyl;

[0021] m is selected from 1, 2 or 3;

[0022] n is selected from 1 or 2.

[0023] In a specific embodiment,

[0024] W, X, Y and Z are each independently selected from CH or N;

[0025] L is selected from a bond, -C(O)-, or -(CR a R a ) m -;

[0026] Q is selected from -C(O)- or ;

[0027] Each R 1 Selected from C6-C 10 Aryl or N-containing 8-10 membered heteroaryl; each of which is R b Replaced 0-3 times;

[0028] Each R 2 Selected from C1-C6 alkyl, C6-C 10 aryl or 5-9 membered heteroaryl containing N, O or S; each of which is replaced by R b Replaced 0-3 times;

[0029] Each R 3are independently selected from hydrogen or halogen;

[0030] Each R a are independently selected from hydrogen, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy or two R a together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl group;

[0031] Each R b independently selected from halogen, C1-C6 alkyl, cyano, -C(O)R c 、-NR c R d OR b or two R b together with the carbon atom to which they are attached, form an optionally substituted heterocyclyl;

[0032] Each R c Independently selected from hydrogen or C1-C6 alkyl;

[0033] Each R d Independently selected from hydrogen or C1-C6 alkyl;

[0034] m is selected from 1, 2 or 3;

[0035] n is selected from 1 or 2.

[0036] In a specific embodiment,

[0037] W, X, Y and Z are each independently selected from CH;

[0038] L is selected from a bond, -C(O)-, or -(CR a R a ) m -;

[0039] Q is selected from -C(O)- or ;

[0040] Each R 1 Selected from C6-C 10 Aryl or N-containing 8-10 membered heteroaryl; each of which is R b Replaced 0-2 times;

[0041] Each R 2 is selected from C1-C6 alkyl, C6-C8 aryl or 5-7 membered heteroaryl containing N, O or S; each of which is replaced by R b Replaced 0-2 times;

[0042] Each R 3 are independently selected from hydrogen or halogen;

[0043] Each Ra are independently selected from hydrogen, halogen, C1-C3 alkoxy or C1-C3 haloalkoxy or two R a together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl group;

[0044] Each R b independently selected from halogen, C1-C6 alkyl, cyano, -C(O)R c or C1-C3 alkoxy or two R b together with the carbon atom to which they are attached, form an optionally substituted heterocyclyl;

[0045] Each R c Independently selected from hydrogen or C1-C3 alkyl;

[0046] m is selected from 1 or 2;

[0047] n is 1.

[0048] In a specific embodiment,

[0049] L is selected from a bond, -C(O)-, or -(CR a R a ) m -;

[0050] Q is selected from -C(O)- or ;

[0051] Each R 1 Selected from 8-10 membered heteroaryl containing 1 N or C6-C 10 Aryl; each of which is R b Replaced 0-2 times;

[0052] Each R 2 is selected from C1-C6 alkyl, C6-C7 aryl or 5-6 membered heteroaryl containing N, O or S, each of which is replaced by R b Replaced 0-2 times;

[0053] Each R a are independently selected from hydrogen;

[0054] Each R b Independently selected from halogen, C1-C3 alkyl, cyano or -OR b or two R b Together with the carbon atom to which they are attached, form an optionally substituted heterocyclic group;

[0055] m is 1;

[0056] n is 1.

[0057] In a specific embodiment,

[0058] R 1 is selected from quinoline, isoquinoline, naphthalene or benzene; each of which is R b Replaced 0-2 times;

[0059] R 2 is selected from C1-C6 alkyl, benzene, benzyl, pyrimidine, pyrazine, thiophene, oxazole or isoxazole, each of which is replaced by R b Replaced 0-2 times;

[0060] Each R b are independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, cyano or -OR b or two R b Together with the carbon atom to which they are attached they form an optionally substituted heterocyclyl.

[0061] In a more specific embodiment, R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, benzyl, pyrimidine, pyrazine, thiophene, oxazole or isoxazole, each of which is replaced by R b Replaced 0-2 times;

[0062] Each R b independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, cyano, methoxy or two R b Together with the carbon atom to which they are attached they form an optionally substituted heterocyclyl.

[0063] The present invention also provides any of the following 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonists or pharmaceutically acceptable salts thereof:

[0064] .

[0065] The pharmaceutically acceptable salts described in the present invention are acid addition salts of the compounds of the general formula (I), wherein the acids used for salt formation include inorganic acids and organic acids, wherein the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include acetic acid, trifluoroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid, etc.

[0066] In a second aspect, the present invention protects a pharmaceutical composition, which contains the 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonist described above or a pharmaceutically acceptable salt thereof.

[0067] In a specific embodiment, the pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0068] Pharmaceutically acceptable carriers refer to excipients or diluents that do not cause significant irritation to organisms and do not interfere with the biological activity and properties of the administered compound. The excipients include adhesives, fillers, disintegrants, lubricants, preservatives, antioxidants, flavoring agents, aromatics, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc., and the diluents include physiological saline, starch, dextrin, sucrose, lactose, etc.

[0069] In a third aspect, the present invention also protects the use of the 4-(1-(azaacyl-3-butyl)-1H-imidazol-2-yl)aniline PKM2 agonist or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the preparation of a drug for treating aortic dissection.

[0070] In a fourth aspect, the present invention also protects a method for treating aortic dissection, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0071] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0072] The present invention further modifies and transforms N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (NZT) to provide a new type of PKM2 agonist for the treatment of aortic dissection. Compared with the original drug, the agonist activity of the compound at each concentration is better than that of the original drug. AC 50 It is comparable to positive drugs and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 The activity concentration curves of compound 11, compound 30 and NZT.

[0074] Figure 2 Compound 11 and compound 30 inhibited the expression of interleukin-6 and interleukin-1β in bone marrow-derived macrophages induced by tumor inducing factor-α. N=3, ***P<0.0001, **P<0.01.

[0075] Figure 3 Compound 11 improves aortic dissection induced by β-aminopropionitrile. Figure 3 Figure A in the figure is a gross picture of blood vessels in different treatment groups, the scale is 5 mm, N=6; Figure 3 Figure B shows the inner diameter of the aorta at the ascending aorta, aortic arch, and thoracic aorta, N=6, *P<0.05; Figure 3Figure C shows the survival rate of mice in the β-aminopropionitrile-fed group and the β-aminopropionitrile-fed group + intragastric administration of compound 11, N=6-8, **P<0.01; Figure 3 Figure D shows the infiltration of macrophages detected by immunofluorescence staining, where red is CD68 and blue is the cell nucleus. The scale of the enlarged icon is 100 μm, and the scale of the full icon in the lower left corner is 200 μm, N=6. DETAILED DESCRIPTION

[0076] The present invention is further described in detail below with reference to the examples. The reagents or instruments used without indicating the manufacturer are all regarded as conventional products that can be purchased on the market.

[0077] Example 1 Synthesis of Compound 1

[0078]

[0079]

[0080] Dissolve p-nitrobenzonitrile (4.44 g, 29.98 mmol) in methanol (30 mL), and add 1.14 mL of 5 mol / L sodium methoxide solution to the solution. Stir the mixture at room temperature for 4 hours. Add aminoacetaldehyde diethyl acetal (4 g, 30.03 mmol) and 3.6 mL of glacial acetic acid to the solution, and stir the mixture at 50 ° C for 1 hour. Add 15 mL of 6 mol / L HCl aqueous solution and 60 mL of methanol to the solution, and reflux overnight. Then pour the solution into water, the product precipitates, and is filtered and dried under an infrared lamp to obtain pure intermediate 1 (5 g, 88%).

[0081] Intermediate 1 (3 g, 15.86 mmol) was dissolved in N, N-dimethylformamide, cesium carbonate (15.50 g, 47.58 mmol) and 1-Boc-3-iodoazetidine (13.47 g, 47.58 mmol) were added to the solution, and then the reaction temperature was raised to 120 ° C. The reaction was terminated after 18 hours of reaction and then cooled to room temperature. The mixture was quenched with aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by column chromatography (EA / PE 1:1, v / v) to obtain pure intermediate 2 (2 g, 37%) as a yellow oily liquid.

[0082] Intermediate 2 (2 g, 5.81 mmol) was dissolved in 50 mL NH4Cl / EtOH (1:1). Reduced iron powder (1.3 g, 23.23 mmol) was added to the solution. The mixture was stirred at 65 °C for 4 hours and then cooled to room temperature. The mixture was added with water, filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to obtain pure intermediate 3 (1.6 g, 87 %).

[0083] Intermediate 3 (1 g, 3.18 mmol) was dissolved in 40 mL DCM. Triethylamine (884.26 μL, 6.36 mmol) and quinoline-8-sulfonyl chloride (1.09 g, 4.77 mmol) were added to the solution. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified by column chromatography (MeOH / CH2Cl2 1:120, v / v) to give intermediate 4 (1.5 g, 93 %) as a white solid.

[0084] Intermediate 4 (1 g, 1.98 mmol) was dissolved in 30 ml DCM, 15 ml trifluoroacetic acid was added to the solution, and then stirred at room temperature for 2 hours. The mixture was evaporated to obtain a crude product, which was directly put into the next step without treatment. The crude product was dissolved in DCM, and Et3N (1.37 ml, 9.89 mmol), benzaldehyde (314.86 mg, 2.97 mmol), sodium triacetoxyborohydride (838.40 mg, 3.96 mmol) were added. Then the reaction was carried out at room temperature for 2 hours, the mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by column chromatography (MeOH / CH2Cl2 1:20, v / v) to obtain compound 1 (500 mg, 51 %) as a white solid. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4,1.6 Hz, 1H), 8.37 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.4, 1.6 Hz, 1H), 8.01(dt, J = 7.7, 1.7 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56(t, J= 7.5 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.32 – 7.22 (m, 7H), 4.78 (dq, J = 7.3,6.7 Hz, 1H), 3.59 (s, 2H), 3.29 (dd, J = 12.3, 7.0 Hz, 2H), 3.11 (dd, J = 12.4,7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.69, 144.16, 142.09,137.84, 137.36, 135.13, 134.91, 131.06, 129.81, 128.74, 128.49, 128.29,128.06, 127.95, 127.76, 127.16, 125.37, 122.42, 120.69, 118.61, 60.25, 52.57,49.78.HR-MS(ESI) m / z: calcd for C 28 H 25 N5O2S [M+H] + 495.1729, found 495.1735.

[0085] Example 2 Synthesis of Compound 2

[0086]

[0087]

[0088] 2-Iodoanisole (6 g, 29.4 mmol) was dissolved in DMSO, 3-hydroxyazetidine hydrochloride (9.67 g, 88.2 mmol), L-proline (677.2 mg, 5.88 mmol), potassium carbonate (20.3 g, 147.6 mmol), cuprous iodide (560.1 mg, 2.94 mmol) were added, and then argon was replaced three times, reacted at 90 ° C overnight, and then cooled to room temperature. The mixture was quenched with aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by column chromatography (EA / PE 1:4, v / v) to obtain pure intermediate 6 (2.3 g, 50%) as a colorless oily liquid.

[0089] Intermediate 6 (2 g, 11.16 mmol) was dissolved in DCM, and the solution was then cooled to 0 °C, Et3N (3.1 ml, 22.32 mmol) and methanesulfonyl chloride (1.92 g, 16.74 mmol) were added, and the reaction was then warmed to room temperature for 4 h. The mixture was quenched with aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified by column chromatography (EA / PE 1:6, v / v) to give pure intermediate 7 (2.8 g, 97.5%).

[0090] Intermediate 1 (500 mg, 2.64 mmol) was dissolved in DMF, and intermediate 7 (2.04 g, 7.93 mmol) and cesium carbonate (2.58 g, 7.93 mmol) were added, and the mixture was then heated to 120 ° C. The reaction was terminated after 18 h of reaction and then cooled to room temperature. The mixture was quenched with aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by column chromatography (EA / PE 1:1, v / v) to obtain pure intermediate 8 (350 mg, 38%) as a yellow oily liquid.

[0091] Intermediate 8 (350 mg, 998 μmol) was dissolved in 50 mL NH4Cl / EtOH (1:1). Reduced iron powder (223.14 g, 4 mmol) was added to the solution. The mixture was stirred at 65 °C for 4 hours and then cooled to room temperature. The mixture was added with water, filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to give pure intermediate 9 (258 mg, 81%).

[0092] Intermediate 9 (258 mg, 805 μmol) was dissolved in 20 ml DCM, Et3N (335.79 μl, 2.42 mmol) and quinoline-8-sulfonyl chloride (274.99 g, 1.21 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified by column chromatography (MeOH / CH2Cl2 1:100, v / v) to give compound 2 (300 mg, 73%) as a white solid. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.6,1.7 Hz, 1H), 8.01 (dt, J= 7.6, 1.6 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.66 (t, J =7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.30 (d, J = 7.5 Hz,1H), 7.26 (d, J = 7.5 Hz, 1H), 6.96 – 6.82 (m, 4H), 4.92 – 4.82 (m, 1H), 4.09(dd, J = 12.4, 7.0 Hz, 2H), 4.01 (dd, J = 12.4, 7.0 Hz, 2H), 3.83 (s, 3H). 13 C NMR (125 MHz, Common NMR Solvents) d 149.46, 146.72, 144.16, 142.09, 138.57,137.32, 135.17, 134.90, 131.15, 129.81, 128.28, 128.05 (d, J = 4.1 Hz), 127.51,125.25, 122.56, 122.40 (d, J = 5.2 Hz), 120.69, 118.50, 114.36, 111.44, 55.62,50.91, 50.31.HR-MS(ESI) m / z: calcd for C 28 H 25 N5O3S [M+H] + 511.1678, found511.1670.

[0093] Example 3 Synthesis of Compound 10

[0094]

[0095]

[0096] Dissolve p-nitrobenzonitrile (4.44 g, 29.98 mmol) in methanol (30 mL), and add 1.14 mL of 5 mol / L sodium methoxide solution to the solution. Stir the mixture at room temperature for 4 hours. Add aminoacetaldehyde diethyl acetal (4 g, 30.03 mmol) and 3.6 mL of glacial acetic acid to the solution, and stir the mixture at 50 ° C for 1 hour. Add 15 mL of 6 mol / L HCl aqueous solution and 60 mL of methanol to the solution, and reflux overnight. Then pour the solution into water, the product precipitates, and is filtered and dried under an infrared lamp to obtain pure intermediate 1 (5 g, 88%).

[0097] Intermediate 1 (3 g, 15.86 mmol) was dissolved in N, N-dimethylformamide, cesium carbonate (15.50 g, 47.58 mmol) and 1-Boc-3-iodoazetidine (13.47 g, 47.58 mmol) were added to the solution, and then the reaction temperature was raised to 120 ° C. The reaction was terminated after 18 hours of reaction and then cooled to room temperature. The mixture was quenched with aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product, which was purified by column chromatography (EA / PE 1:1, v / v) to obtain pure intermediate 2 (2 g, 37%) as a yellow oily liquid.

[0098] Intermediate 2 (2 g, 5.81 mmol) was dissolved in 50 mL NH4Cl / EtOH (1:1). Reduced iron powder (1.3 g, 23.23 mmol) was added to the solution. The mixture was stirred at 65 °C for 4 hours and then cooled to room temperature. The mixture was added with water, filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to obtain pure intermediate 3 (1.6 g, 87 %).

[0099] Intermediate 3 (1 g, 3.18 mmol) was dissolved in 40 mL DCM. Triethylamine (884.26 μL, 6.36 mmol) and quinoline-8-sulfonyl chloride (1.09 g, 4.77 mmol) were added to the solution. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified by column chromatography (MeOH / CH2Cl2 1:120, v / v) to give intermediate 4 (1.5 g, 93 %) as a white solid.

[0100] Intermediate 4 (1 g, 1.98 mmol) was dissolved in 30 ml DCM, 15 ml trifluoroacetic acid was added to the solution, and then stirred at room temperature for 2 hours. The mixture was evaporated to give a crude intermediate 5, which was directly put into the next step without treatment. The crude intermediate 5 was dissolved in DCM, Et3N (1.37 ml, 9.89 mmol) and cyclopropanesulfonyl chloride (417.08 mg, 2.97 mmol) were added, and then reacted at room temperature for 2 hours. The mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified by column chromatography (MeOH / CH2Cl2 1:20, v / v) to give compound 10 (900 mg, 89%) as a white solid. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J =7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H),7.92 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.86 –4.76 (m, 1H), 3.76 (qd, J = 12.4, 7.1 Hz, 4H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) δ 146.69, 144.16, 142.09,137.32, 135.14, 134.91, 131.02, 129.81, 129.03, 128.28, 128.05 (d, J= 3.6 Hz),125.37, 122.42, 120.82, 118.50, 48.02, 45.78, 38.22, 14.04.HR-MS(ESI) m / z:calcd for C 24 H 23 N5O4S [M+H] + 509.1191, found 509.1185.

[0101] Example 4 Synthesis of Compound 3

[0102]

[0103] Refer to the synthesis method of compound 1 in Example 1, except that benzaldehyde is replaced by cyclopropanaldehyde. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.5, 1.5 Hz, 1H), 8.37 (dd, J = 7.5, 1.5Hz, 1H), 8.25 (dt, J = 7.9, 1.7 Hz, 1H), 8.00 (dt, J = 7.8, 1.7 Hz, 1H), 7.91 –7.85 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.33 (m,2H), 7.31 – 7.22 (m, 2H), 4.81 – 4.72 (m, 1H), 3.41 (dd, J = 12.5, 7.0 Hz, 2H),3.33 (dd, J = 12.4, 7.0 Hz, 2H), 2.61 (d, J = 6.7 Hz, 2H), 1.44 – 1.26 (m, 3H), 0.94 – 0.81 (m, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d146.60, 144.16,142.26, 137.49, 135.08, 134.89, 131.23, 129.81, 129.03, 128.29, 128.07,127.30, 125.37, 122.43, 120.85, 118.59, 58.63, 53.29, 49.73, 9.14, 6.45.HR-MS(ESI) m / z: calcd for C 25 H 25 N5O2S [M+H] + 459.1729, found 459.1735.

[0104] Example 5 Synthesis of Compound 4

[0105]

[0106] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 3-iodoanisole. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.6, 1.6 Hz, 1H), 8.01 (dt, J = 7.6, 1.6 Hz, 1H), 7.91– 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.29(m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.57 (dt, J = 7.5, 1.6Hz, 1H), 6.45 – 6.38 (m, 2H), 4.94 – 4.84 (m, 1H), 4.08 (dd, J = 12.4, 7.0 Hz,2H), 4.00 (dd, J = 12.4, 7.0 Hz, 2H), 3.81 (s, 3H). 13C NMR (125 MHz, Common NMR Solvents) d 159.00, 147.67, 146.72, 144.16, 142.09, 137.32, 135.17, 134.90,131.15, 129.81, 129.04, 128.28, 128.05 (d, J = 4.1 Hz), 127.51, 125.25, 122.42,120.69, 118.50, 109.87, 109.25, 99.06, 54.98, 50.42, 50.08.HR-MS(ESI) m / z:calcd for C 28 H 25 N5O3S [M+H] + 511.1678, found 511.1674.

[0107] Example 6 Synthesis of Compound 5

[0108]

[0109] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by p-fluoroiodobenzene. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.34 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.6, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.7 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.29 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.04 – 6.95 (m, 4H), 4.93 – 4.83 (m,1H), 4.06 (dd, J = 12.5, 7.0 Hz, 2H), 3.98 (dd, J = 12.4, 7.0 Hz, 2H).13 C NMR (125 MHz, Common NMR Solvents) d 146.69, 144.16, 142.09, 137.32, 135.17,134.91, 131.06, 129.81, 128.29, 128.05 (d, J = 4.1 Hz), 127.64, 125.37, 122.42,120.69, 118.50, 117.88, 117.81, 116.32, 116.16, 50.28, 49.85.HR-MS(ESI) m / z:calcd for C 27 H 22 FN5O2S [M+H] + 499.1478, found 499.1485.

[0110] Example 7 Synthesis of Compound 6

[0111]

[0112] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by m-fluoroiodobenzene. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.6, 1.7 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H), 7.91– 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.29(m, 3H), 7.28 – 7.21 (m, 2H), 6.76 (dt, J = 7.6, 1.5 Hz, 1H), 6.63 (tt, J = 7.7,1.5 Hz, 1H), 6.34 (dt, J = 7.9, 1.5 Hz, 1H), 4.93 – 4.83 (m, 1H), 4.08 (dd,J =12.3, 7.0 Hz, 2H), 3.99 (dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.69, 144.16, 142.09, 137.32, 135.17, 134.91, 131.06, 130.13,130.06, 129.81, 128.29, 128.05 (d, J = 4.1 Hz), 127.64, 125.37, 122.42, 120.69,118.50, 110.58, 110.42, 109.12 (d, J = 3.1 Hz), 100.27, 100.11, 50.28,49.93.HR-MS(ESI) m / z: calcd for C 27 H 22 FN5O2S [M+H] + 499.1478, found 499.1483.

[0113] Example 8 Synthesis of Compound 7

[0114]

[0115] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 2-fluoroiodobenzene. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.6, 1.7 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H), 7.91– 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.33(m, 2H), 7.30 (d, J = 7.5 Hz, 1H), 7.26 (d,J = 7.5 Hz, 1H), 7.10 (td, J = 7.5,1.5 Hz, 1H), 7.02 – 6.94 (m, 2H), 6.85 (tdd, J = 7.5, 5.1, 1.6 Hz, 1H), 4.92 –4.82 (m, 1H), 4.11 (dd, J = 12.5, 7.0 Hz, 2H), 4.02 (dd, J = 12.4, 7.0 Hz, 2H). 13 CNMR (125 MHz, Common NMR Solvents) d 146.69, 144.16, 142.09, 137.32, 135.17,134.91, 131.06, 129.81, 128.29, 128.05 (d, J = 4.1 Hz), 127.64, 126.49, 126.43,125.91 (d, J = 2.9 Hz), 125.37, 122.42, 120.69, 118.50, 117.31, 117.25, 116.65,116.48, 50.46 (d, J = 4.1 Hz), 50.31.HR-MS(ESI) m / z: calcd for C 27 H 22 FN5O2S [M+H] + 499.1478, found 499.1477.

[0116] Example 9 Synthesis of Compound 8

[0117]

[0118] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 2-iodobenzonitrile. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt,J = 7.7, 1.6 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.61 – 7.53 (m, 2H), 7.39 – 7.30(m, 3H), 7.27 (q, J = 7.5 Hz, 2H), 7.19 (td, J = 7.5, 1.6 Hz, 1H), 7.00 (dd, J =7.5, 1.5 Hz, 1H), 4.93 – 4.84 (m, 1H), 4.11 (dd, J = 12.5, 7.0 Hz, 2H), 4.02(dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 147.92,146.72, 144.16, 142.09, 137.32, 135.17, 134.90, 134.23, 131.15, 129.81,129.66, 128.28, 128.05 (d, J = 5.2 Hz), 127.51, 125.37, 122.42, 121.99, 120.69,118.50, 117.97, 115.45, 103.91, 51.02, 50.45.HR-MS(ESI) m / z: calcd forC 28 H 22 N6O2S [M+H] + 506.1525, found 506.1521.

[0119] Example 10 Synthesis of Compound 9

[0120]

[0121] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 4-iodobenzonitrile. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J=7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.7, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.6 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.39 – 7.29(m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.01 – 6.96 (m, 2H), 4.93 – 4.83 (m, 1H), 4.06 (dd, J = 12.4, 7.0 Hz, 2H), 3.98 (dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 149.17, 146.72, 144.16, 142.09, 137.32, 135.17, 134.90,133.37, 131.15, 129.81, 128.28, 128.05 (d, J = 5.2 Hz), 127.51, 125.37, 122.42,120.69, 118.50, 118.37, 112.37, 102.80, 50.42, 50.05.HR-MS(ESI) m / z: calcdfor C 28 H 22 N6O2S [M+H] + 506.1525, found 506.1527.

[0122] Example 11 Synthesis of Compound 11

[0123]

[0124] The synthesis method of compound 1 in Example 1 is referred to, except that benzaldehyde is replaced by p-valeraldehyde. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.37 (dd, J= 7.5, 1.5Hz, 1H), 8.24 (dt, J = 7.6, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.6 Hz, 1H), 7.90 –7.84 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.37 – 7.32(m, 2H), 7.31 – 7.22 (m, 2H), 4.82 – 4.73 (m, 1H), 3.49 (dd, J = 12.4, 7.0 Hz,2H), 3.41 (dd, J = 12.3, 7.0 Hz, 2H), 2.51 (s, 2H), 1.05 (s, 9H). 13 C NMR (125MHz, Common NMR Solvents) d 146.59, 144.16, 142.23, 137.40, 135.08, 134.93,131.27, 129.81, 129.03, 128.29, 128.06, 127.30, 125.37, 122.43, 120.81,118.59, 68.56, 52.95, 49.69, 32.64, 27.94.HR-MS(ESI) m / z: calcd for C 26 H 29 N5O2S[M+H] + 475.2042, found 475.2048.

[0125] Example 12 Synthesis of Compound 12

[0126]

[0127] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 3-iodobenzonitrile. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J =7.5, 1.5 Hz, 1H), 8.25 (dt, J= 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.6, 1.6 Hz,1H), 7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),7.48 (dt, J = 7.5, 1.6 Hz, 1H), 7.42 – 7.29 (m, 4H), 7.26 (d, J = 7.5 Hz, 1H),7.21 (t, J = 1.5 Hz, 1H), 7.02 (dt, J = 7.5, 1.6 Hz, 1H), 4.93 – 4.83 (m, 1H), 4.08 (dd, J = 12.4, 7.0 Hz, 2H), 3.99 (dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125MHz, Common NMR Solvents) d 147.21, 146.72, 144.16, 142.09, 137.32, 135.17,134.90, 131.15, 129.81, 129.75, 128.28, 128.05 (d, J = 5.2 Hz), 127.51,125.37, 125.14, 122.42, 120.69, 118.50, 117.95, 116.01 (d, J = 1.4 Hz), 113.20,50.42, 50.03.HR-MS(ESI) m / z: calcd for C 28 H 22 N6O2S [M+H] + 506.1525, found506.1530.

[0128] Example 13 Synthesis of Compound 13

[0129]

[0130] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by cyclopropaneyl chloride. 1H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.37 (dd, J =7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.5, 1.6 Hz,1H), 7.90 – 7.84 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),7.37 – 7.29 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 4.91 – 4.81 (m, 1H), 4.16 (dd, J =12.4, 7.0 Hz, 2H), 4.04 (dd, J = 12.4, 7.0 Hz, 2H), 2.53 (p, J = 7.0 Hz, 1H),0.98 – 0.85 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 171.44, 146.60,144.16, 142.23, 137.40, 135.08, 134.92, 131.27, 129.81, 129.17, 128.29,128.06, 127.47, 125.37, 122.43, 120.81, 118.58, 50.06, 45.98, 15.83, 9.14.HR-MS(ESI) m / z: calcd for C 25 H 23 N5O3S [M+H] + 473.1522, found 473.1530.

[0131] Example 14 Synthesis of Compound 14

[0132]

[0133] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 3-iodotoluene. 1HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.37 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.29 (m, 3H), 7.28 – 7.18 (m, 2H), 7.03 (dt, J = 7.5, 1.5 Hz, 1H), 6.82 (ddq, J = 7.2, 1.5, 0.8 Hz, 1H), 6.69 – 6.65 (m, 1H), 4.93 – 4.83 (m, 1H), 4.08 (dd, J = 12.3, 7.0 Hz, 2H), 4.03 – 3.96 (m, 2H), 2.34 – 2.31 (m, 3H). 13 C NMR (125MHz, Common NMR Solvents) d 147.02, 146.69, 144.16, 142.09, 139.01, 137.36,135.13, 134.91, 131.06, 129.81, 128.94, 128.29, 128.06, 127.95, 127.64,125.37, 123.28, 122.42, 120.69, 118.50, 115.24, 111.37, 50.28, 49.83,21.47.HR-MS(ESI) m / z: calcd for C 28 H 25 N5O2S [M+H] + 495.1729, found 495.1740.

[0134] Example 15 Synthesis of Compound 15

[0135]

[0136] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 2-iodotoluene. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.37 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.5, 1.7 Hz, 1H), 7.91– 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.29(m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.17 (ddq, J = 7.5, 1.6, 0.8 Hz, 1H), 7.11(td, J = 7.5, 1.6 Hz, 1H), 7.02 (td, J = 7.5, 1.5 Hz, 1H), 6.66 (dd, J = 7.4, 1.5Hz, 1H), 4.93 – 4.84 (m, 1H), 4.07 (dd, J = 12.5, 7.0 Hz, 2H), 4.02 – 3.95 (m,2H), 2.33 (s, 3H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.66 (d, J = 6.7Hz), 144.16, 142.09, 137.36, 135.13, 134.91, 131.98, 131.06, 129.81, 129.39,128.29, 128.06, 127.95, 127.74, 127.64, 125.37, 123.22, 122.42, 120.69,118.50, 117.04, 50.74, 50.31, 17.70.HR-MS(ESI) m / z: calcd for C28 H 25 N5O2S [M+H] + 495.1729, found 495.1723.

[0137] Example 16 Synthesis of Compound 16

[0138]

[0139] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 4-iodotoluene. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.37 (dd, J = 7.5,1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.29 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.17 (dq, J = 7.2, 0.8 Hz, 2H), 6.88 –6.82 (m, 2H), 4.93 – 4.83 (m, 1H), 4.07 (dd, J = 12.4, 7.0 Hz, 2H), 3.99 (dd, J =12.4, 7.0 Hz, 2H), 2.32 (d, J = 1.0 Hz, 3H). 13 C NMR (125 MHz, Common NMR Solvents) d148.00, 146.69, 144.16, 142.09, 137.36, 135.13, 134.91, 131.06,129.81, 129.43, 128.29, 128.06, 127.95, 127.64, 127.30, 125.37, 122.42,120.69, 118.50, 113.97, 50.28, 49.85, 20.67.HR-MS(ESI) m / z: calcd forC 28 H 25 N5O2S [M+H] + 495.1729, found 495.1718.

[0140] Example 17 Synthesis of Compound 17

[0141]

[0142] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 2-chloropyrimidine. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.37 (dd, J = 7.5,1.5 Hz, 1H), 8.31 (d, J = 7.5 Hz, 2H), 8.25 (dt, J = 7.5, 1.7 Hz, 1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J =7.5 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 6.50 (t, J = 7.5 Hz,1H), 5.02 – 4.93 (m, 1H), 4.16 (dd, J = 12.4, 6.9 Hz, 2H), 4.10 (dd, J = 12.4,7.1 Hz, 2H). 13C NMR (125 MHz, Common NMR Solvents) d 159.08, 158.04, 146.69,144.16, 142.35, 137.40, 135.08, 134.92, 131.00, 129.81, 129.17, 128.29,128.06, 127.75, 125.37, 122.42, 120.81, 118.50, 110.25, 50.00, 46.65.HR-MS(ESI) m / z: calcd for C 25 H 21 N7O2S [M+H] + 483.1477, found 483.1485.

[0143] Example 18 Synthesis of Compound 18

[0144]

[0145] Refer to the synthesis method of compound 2 in Example 2, except that 2-iodoanisole is replaced by 2-chloropyrazine. 1 HNMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.37 (dd, J = 7.5,1.5 Hz, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.28 – 8.22 (m, 2H), 8.01 (dt, J = 7.7,1.7 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.83 (s, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.56(t, J = 7.5 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 4.96 – 4.87(m, 1H), 4.18 (dd, J = 12.4, 7.0 Hz, 2H), 4.10 (dd, J = 12.4, 7.0 Hz, 2H). 13C NMR (125 MHz, Common NMR Solvents) d 151.02, 146.69, 145.54, 144.16, 142.35,137.40, 135.08, 134.92, 134.84, 131.00, 130.71, 129.81, 129.17, 128.29,128.06, 127.75, 125.37, 122.42, 120.81, 118.50, 50.09, 48.27.HR-MS(ESI) m / z:calcd for C 25 H 21 N7O2S [M+H] + 483.1477, found 483.1459.

[0146] Example 19 Synthesis of Compound 19

[0147]

[0148] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by 2-thiophenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J =7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.6 Hz, 1H),7.92 – 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.60 – 7.50 (m, 3H), 7.39 – 7.28(m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 4.88 – 4.79 (m, 1H), 3.86 (dd, J = 12.5, 7.0 Hz, 2H), 3.78 (dd, J = 12.4, 7.0 Hz, 2H). 13C NMR (125 MHz, Common NMR Solvents) d 146.72, 144.16, 142.09, 138.42, 137.39, 135.13, 134.90,131.00 (d, J = 5.0 Hz), 130.58, 129.80, 128.87, 128.17, 128.07, 127.92, 127.51,125.23, 122.42, 120.69, 118.55, 48.03, 45.94.HR-MS(ESI) m / z: calcd forC 25 H 21 N5O4S3[M+H] + 551.0756, found 551.0770.

[0149] Example 20 Synthesis of Compound 20

[0150]

[0151] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by benzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.04 (dd, J = 7.5, 1.5 Hz, 1H), 8.34 (dd, J =7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.6, 1.6 Hz, 1H), 8.01 (dt, J = 7.9, 1.6 Hz, 1H),7.92 – 7.86 (m, 2H), 7.76 (ddq, J = 5.1, 2.5, 1.3, 0.8 Hz, 2H), 7.69 – 7.60 (m,4H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.30 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 4.88 – 4.79 (m, 1H), 3.91 – 3.83 (m, 2H), 3.79 (dd, J = 12.4, 7.0 Hz, 2H). 13CNMR (125 MHz, Common NMR Solvents) d 146.82, 144.16, 142.09, 137.32, 136.89,135.13, 134.90, 132.91, 131.02, 129.80, 129.21, 128.17, 128.05 (d, J = 5.2 Hz),127.65, 127.51, 125.23, 122.42, 120.69, 118.55, 48.03, 46.08.HR-MS(ESI) m / z:calcd for C 27 H 23 N5O4S2[M+H] + 545.1191, found 545.1195.

[0152] Example 21 Synthesis of Compound 21

[0153]

[0154] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by 3-thiophenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.7 Hz,1H), 7.95 (dd, J = 2.9, 1.5 Hz, 1H), 7.92 – 7.86 (m, 2H), 7.78 (dd, J = 7.5, 2.9Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (dd, J = 7.5, 1.5Hz, 1H), 7.39 – 7.30 (m, 3H), 7.26 (d, J= 7.5 Hz, 1H), 4.88 – 4.79 (m, 1H), 3.87 (dd, J = 12.4, 7.0 Hz, 2H), 3.79 (dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.72, 144.16, 142.09, 137.39, 135.13, 134.90, 134.33,131.02, 130.86, 129.80, 128.17, 128.07, 127.99, 127.92, 127.51, 125.76,125.23, 122.42, 120.69, 118.55, 48.03, 45.96.HR-MS(ESI) m / z: calcd forC 25 H 21 N5O4S3[M+H] + 551.0756, found 551.0751.

[0155] Example 22 Synthesis of Compound 22

[0156]

[0157] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by 2-thiazolesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.7 Hz, 1H), 8.04 – 7.97 (m, 2H), 7.92 –7.86 (m, 3H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.33 (m,2H), 7.30 (d, J = 7.5 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 4.88 – 4.79 (m, 1H), 3.91 (dd, J = 12.5, 7.0 Hz, 2H), 3.84 (dd, J = 12.4, 7.0 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 159.68, 146.72, 144.16, 142.09, 140.35, 137.39, 135.13,134.90, 131.02, 129.80, 128.17, 128.07, 127.92, 127.51, 125.23, 122.42,120.69, 119.36, 118.55, 48.03, 45.87.HR-MS(ESI) m / z: calcd for C 24 H 20 N6O4S3[M+H] + 552.0708, found 552.0723.

[0158] Example 23 Synthesis of Compound 23

[0159]

[0160] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by 3,5-dimethylisoxazole-4-sulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.04 (dd, J = 7.5, 1.5 Hz, 1H),8.34 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.7, 1.7 Hz, 1H), 8.01 (dt, J = 7.6,1.6 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz,1H), 7.38 – 7.28 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 4.90 – 4.81 (m, 1H), 3.91(dd,J = 12.4, 7.0 Hz, 2H), 3.82 (dd, J = 12.4, 7.0 Hz, 2H), 2.60 (s, 3H), 2.31(s, 3H). 13 C NMR (125 MHz, Common NMR Solvents) d 165.65, 164.96, 146.82,144.16, 142.09, 137.39, 135.13, 134.88, 131.02, 129.80, 128.17, 128.06 (d, J =6.7 Hz), 127.75, 125.28, 122.42, 120.69, 118.55, 112.27, 48.03, 45.93, 12.95,11.21.HR-MS(ESI) m / z: calcd for C 26 H 24 N6O5S2[M+H] + 564.1250, found 564.1255.

[0161] Example 24 Synthesis of Compound 24

[0162]

[0163] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by methanesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.34 (dd, J =7.5, 1.6 Hz, 1H), 8.25 (dt, J = 7.5, 1.7 Hz, 1H), 8.01 (dt, J = 7.5, 1.6 Hz, 1H),7.91 – 7.86 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.33 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 4.84 – 4.75 (m,1H), 3.83 (dd, J = 12.4, 7.0 Hz, 2H), 3.75 (dd, J = 12.5, 7.0 Hz, 2H), 2.82 (s,3H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.60, 144.16, 141.60, 137.40,135.08, 134.91, 131.26, 129.81, 129.17, 128.29, 128.07, 127.51, 125.37,122.42, 120.85, 118.50, 47.93, 45.42, 37.99.HR-MS(ESI) m / z: calcd forC 22 H 21 N5O4S2[M+H] + 483.1035, found 483.1044.

[0164] Example 25 Synthesis of Compound 25

[0165]

[0166] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by ethylsulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.5 Hz, 1H), 8.32 (dd, J =7.5, 1.6 Hz, 1H), 8.24 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.5, 1.6 Hz, 1H),7.91 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 –7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 4.85 –4.76 (m, 1H), 3.85 (dd, J = 12.4, 7.0 Hz, 2H), 3.77 (dd, J = 12.4, 7.0 Hz, 2H),3.33 (q, J = 8.0 Hz, 2H), 1.35 – 1.28 (m, 3H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.60, 144.16, 142.09, 137.39, 135.14, 134.90, 131.27, 129.81,129.03, 128.29, 128.06, 127.72, 125.37, 122.42, 120.95, 118.50, 47.98, 46.70,45.55, 6.84.HR-MS(ESI) m / z: calcd for C 23 H 23 N5O4S2[M+H] + 497.1191, found497.1198.

[0167] Example 26 Synthesis of Compound 26

[0168]

[0169] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by trifluoromethylsulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.34(dd, J = 7.5, 1.5 Hz, 1H), 8.25 (dt, J = 7.5, 1.6 Hz, 1H), 8.01 (dt, J = 7.5, 1.6Hz, 1H), 7.92 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),7.39 – 7.33 (m, 2H), 7.26 (d, J= 1.2 Hz, 2H), 4.81 (p, J = 7.0 Hz, 1H), 3.91(dd, J = 12.4, 7.0 Hz, 2H), 3.80 (dd, J = 12.4, 7.1 Hz, 2H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.60, 144.16, 142.09, 137.32, 135.13, 134.91, 131.02,129.80, 129.03, 128.17, 128.06, 127.92, 125.23, 122.42, 120.69, 118.58,47.99, 45.83 (q, J = 3.9 Hz).HR-MS(ESI) m / z: calcd for C 22 H 18 F3N5O4S2[M+H] + 537.0752, found 537.0758.

[0170] Example 27 Synthesis of Compound 27

[0171]

[0172] The synthesis method of compound 10 in Example 3 was referred to, except that cyclopropanesulfonyl chloride was replaced by isopropylsulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.03 (dd, J = 7.4, 1.6 Hz, 1H), 8.33 (dd, J = 7.5, 1.5 Hz, 1H), 8.24 (dt, J = 7.5, 1.7 Hz, 1H), 8.01 (dt, J = 7.6, 1.7 Hz,1H), 7.92 – 7.86 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d,J = 7.5 Hz, 1H),4.86 – 4.76 (m, 1H), 3.76 (qd, J = 12.4, 7.1 Hz, 4H), 2.96 (hept, J = 6.8 Hz,1H), 1.27 (d, J = 6.8 Hz, 6H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.69,144.16, 142.09, 137.32, 135.14, 134.91, 131.02, 129.81, 129.03, 128.28,128.06, 127.76, 125.26, 122.42, 120.82, 118.50, 51.38, 48.02, 45.81,16.51.HR-MS(ESI) m / z: calcd for C 24 H 25 N5O4S2[M+H] + 511.1348, found 511.1360.

[0173] Example 28 Synthesis of Compound 28

[0174]

[0175] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 1-naphthalenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.94 (s, 1H), 8.50 – 8.45 (m, 1H), 8.05(ddq, J = 6.6, 5.1, 1.6 Hz, 2H), 7.94 – 7.86 (m, 3H), 7.79 (t, J = 7.7 Hz, 1H),7.57 (td, J = 7.7, 1.5 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.38 – 7.29 (m,3H), 7.26 (d, J = 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.76 (qd, J= 12.4, 7.1 Hz,4H), 2.02 (p, J = 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) δ 144.16, 137.26, 135.84, 133.15, 131.31, 129.81, 129.03, 128.28,128.11, 127.85 (d, J = 6.9 Hz), 127.03, 126.07, 123.73 (d, J = 3.1 Hz), 120.88,118.50, 48.02, 45.78, 38.22, 14.04.HR-MS(ESI) m / z: calcd for C 25 H 24 N4O4S2[M+H] + 508.1239, found 508.1250.

[0176] Example 29 Synthesis of Compound 29

[0177]

[0178] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 2-naphthalenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 8.51 (t, J = 1.6 Hz, 1H), 8.17 – 8.12 (m,1H), 8.04 (dt, J = 7.4, 1.5 Hz, 1H), 7.95 – 7.85 (m, 4H), 7.57 (dtd, J = 23.8,7.4, 1.6 Hz, 2H), 7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.76 (qd, J = 12.5, 7.1 Hz, 4H), 2.02 (p, J= 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 144.16, 137.94, 136.75, 134.45, 132.60, 129.81, 129.03, 128.58, 128.27 (d, J =2.4 Hz), 127.59, 127.47, 127.41, 127.11, 126.68, 120.88, 118.50, 48.02,45.78, 38.22, 14.04.HR-MS(ESI) m / z: calcd for C 25 H 24 N4O4S2[M+H] + 508.1239, found508.1221.

[0179] Example 30 Synthesis of Compound 30

[0180]

[0181] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 5-chloro-2-methoxybenzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 7.94 – 7.86 (m, 3H), 7.39 –7.29 (m, 4H), 7.26 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 4.86 – 4.76 (m,1H), 3.89 (s, 3H), 3.80 (dd, J = 12.5, 7.0 Hz, 2H), 3.74 (dd, J = 12.4, 7.0 Hz,2H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13C NMR (125 MHz, Common NMR Solvents) δ 154.78, 144.16, 137.39, 134.99, 129.81, 129.03, 128.56, 128.34,128.15, 127.65, 120.95, 118.50, 113.73, 55.90, 48.02, 45.78, 38.22, 13.36.HR-MS(ESI) m / z: calcd for C 22 H 23 ClN4O5S2[M+H] + 522.0798, found 522.0790.

[0182] Example 31 Synthesis of Compound 31

[0183]

[0184] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 5-bromo-2-methoxybenzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 8.02 (d, J = 1.6 Hz, 1H), 7.90 –7.84 (m, 2H), 7.55 (dd, J = 7.4, 1.6 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.30 (d, J =7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 4.87 – 4.78 (m,1H), 3.89 (s, 3H), 3.80 (dd, J = 12.5, 7.0 Hz, 2H), 3.74 (dd, J = 12.4, 7.0 Hz,2H), 2.02 (p, J = 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d155.57, 144.16, 137.39, 136.60, 131.45, 129.80, 129.08, 128.67,128.15, 120.93, 118.58, 114.69 (d, J = 3.8 Hz), 55.90, 48.02, 45.66, 38.22,13.36.HR-MS(ESI) m / z: calcd for C 22 H 23 BrN4O5S2[M+H] + 566.0293, found 566.0296.

[0185] Example 32 Synthesis of Compound 32

[0186]

[0187] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by benzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.92 (s, 1H), 7.89 – 7.84 (m, 2H), 7.78 –7.72 (m, 2H), 7.62 – 7.55 (m, 1H), 7.46 – 7.30 (m, 5H), 7.26 (d, J = 7.5 Hz,1H), 4.87 – 4.78 (m, 1H), 3.80 (dd, J = 12.3, 7.0 Hz, 2H), 3.74 (dd, J = 12.4,7.1 Hz, 2H), 2.02 (p, J = 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 144.16, 138.23 (d, J = 3.3 Hz), 133.10, 129.82, 129.15 (d, J = 5.2 Hz), 128.27, 127.76, 120.89, 118.55, 48.02, 45.62, 38.22, 15.56.HR-MS(ESI) m / z: calcd for C21 H 22 N4O4S2[M+H] + 458.1082, found 458.1099.

[0188] Example 33 Synthesis of Compound 33

[0189]

[0190] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 2,3-dihydro-1,4-benzodioxy-6-sulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 7.91 – 7.86 (m, 2H),7.43 (dd, J = 7.5, 1.5 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz,1H), 7.26 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 4.34 – 4.23 (m, 4H), 3.76 (qd, J = 12.4, 7.1 Hz, 4H), 2.07– 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 148.37, 145.52, 144.16, 137.94, 133.98, 129.81, 129.03, 128.28, 122.96,120.88, 118.50, 115.13, 114.24, 64.19 (d, J = 3.1 Hz), 48.02, 45.78, 38.22,14.96.HR-MS(ESI) m / z: calcd for C 23 H 24 N4O6S2[M+H] + 516.1137, found 516.1145.

[0191] Example 34 Synthesis of Compound 34

[0192]

[0193] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 1,3-benzodioxy-5-sulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 7.90 – 7.84 (m, 2H), 7.47 (dd, J =7.5, 1.5 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.05 (s, 2H), 4.86 – 4.76 (m, 1H), 3.80 (dd, J = 12.4, 7.0 Hz, 2H), 3.74 (dd, J = 12.4, 7.0 Hz,2H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 150.41, 147.62, 144.16, 137.94, 134.42, 129.81, 129.03, 128.28,122.15, 121.02, 118.50, 109.93, 109.46, 101.54, 48.02, 45.78, 38.22,14.23.HR-MS(ESI) m / z: calcd for C 22 H 22 N4O6S2[M+H] + 502.0981, found 502.0989.

[0194] Example 35 Synthesis of Compound 35

[0195]

[0196] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 3-methoxybenzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.81 (s, 1H), 7.90 – 7.84 (m, 2H), 7.73 (dt, J = 7.3, 1.5 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 1.5 Hz, 1H),7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H),7.02 (dt, J = 7.5, 1.6 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.84 – 3.77 (m, 5H), 3.74(dd, J = 12.4, 7.0 Hz, 2H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 157.74, 144.16, 138.24, 138.13, 129.81,129.55, 128.74, 128.29, 123.21, 120.89, 118.64, 118.50, 112.74, 55.65, 48.02,45.78, 38.22, 13.89.HR-MS(ESI) m / z: calcd for C 22 H 24 N4O5S2[M+H] + 488.1188, found488.1195.

[0197] Example 36 Synthesis of Compound 36

[0198]

[0199] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 4-methylbenzenesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 7.89 – 7.84 (m, 2H), 7.74 – 7.68 (m,2H), 7.40 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.29 – 7.20 (m, 3H), 4.86 – 4.76 (m, 1H), 3.80 (dd, J = 12.3, 7.0 Hz, 2H), 3.74 (dd, J = 12.4, 7.0 Hz,2H), 2.38 (d, J = 0.9 Hz, 3H), 2.02 (p, J = 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 CNMR (125 MHz, Common NMR Solvents) d 144.16, 142.82, 138.13, 137.27, 129.82,129.15 (d, J = 4.1 Hz), 128.29, 127.26, 120.76, 118.55, 48.02, 45.78, 38.22,21.52, 15.56.HR-MS(ESI) m / z: calcd for C 22 H 24 N4O4S2[M+H] + 472.1239, found472.1250.

[0200] Example 37 Synthesis of Compound 37

[0201]

[0202] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 5-quinolinesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.72 (s, 1H), 9.10 (dd, J = 7.5, 1.7 Hz,1H), 8.94 (dd, J = 7.5, 1.5 Hz, 1H), 8.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.96 (dd, J=7.6, 1.4 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5Hz, 1H), 7.39 – 7.29 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.76 (qd, J = 12.4, 7.1 Hz, 4H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 CNMR (125 MHz, Common NMR Solvents) d 150.30, 147.78, 144.16, 137.40, 134.73,129.96 – 129.75 (m), 129.03, 128.28, 127.39, 126.24, 125.93, 122.30, 120.88,118.50, 48.02, 45.78, 38.22, 14.04.HR-MS(ESI) m / z: calcd for C 24 H 23 N5O4S2[M+H] + 509.1191, found 509.1181.

[0203] Example 38 Synthesis of Compound 38

[0204]

[0205] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 6-quinolinesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.94 (s, 1H), 9.26 (d, J = 1.4 Hz, 1H),8.69 (d, J = 7.3 Hz, 1H), 8.20 (dt, J = 7.5, 1.6 Hz, 1H), 7.88 (dd, J = 7.7, 1.6Hz, 3H), 7.68 (t, J = 7.5 Hz, 1H), 7.43 (d,J = 7.6 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.76 (qd, J = 12.5, 7.1 Hz, 4H), 2.02 (p, J = 6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 CNMR (125 MHz, Common NMR Solvents) d 150.38, 146.95, 144.16, 137.26, 134.80,130.63, 130.04, 129.81, 129.03, 128.93, 128.28, 126.99, 124.98, 120.88,118.50, 117.08, 48.02, 45.78, 38.22, 14.04.HR-MS(ESI) m / z: calcd forC 24 H 23 N5O4S2[M+H] + 509.1191, found 509.1205.

[0206] Example 39 Synthesis of Compound 39

[0207]

[0208] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 3-methyl-8-quinolinesulfonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 8.62 (dd, J = 1.5, 0.8 Hz, 1H),8.29 (dd, J = 7.6, 1.4 Hz, 1H), 7.95 – 7.86 (m, 4H), 7.62 (t, J = 7.7 Hz, 1H),7.39 – 7.34 (m, 2H), 7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H),4.86 – 4.76 (m, 1H), 3.76 (qd, J = 12.5, 7.1 Hz, 4H), 2.39 (s, 3H), 2.02 (p, J =6.9 Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 146.22, 144.16, 141.31, 137.32, 134.21, 133.13, 130.70, 130.17, 129.81,128.17, 128.01, 127.75, 127.64, 126.31, 120.69, 118.50, 48.04, 45.78, 38.22,18.50, 14.84.HR-MS(ESI) m / z: calcd for C 25 H 25 N5O4S2[M+H] + 523.1348, found523.1360.

[0209] Example 40 Synthesis of Compound 40

[0210]

[0211] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by quinoline-8-carbonyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 8.90 (dd, J = 7.5, 1.5 Hz, 1H), 8.34 (dt, J = 7.5, 1.7 Hz, 1H), 8.07 – 8.02 (m, 2H), 7.99 (dt, J = 7.5, 1.7 Hz, 1H), 7.88(dd, J = 7.5, 1.5 Hz, 1H), 7.76 – 7.71 (m, 2H), 7.58 (dt, J = 7.7, 7.1 Hz, 2H),7.32 (dd, J = 7.5, 0.7 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 4.86 – 4.76 (m, 1H), 3.80 (dd, J = 12.5, 7.0 Hz, 2H), 3.74 (dd, J = 12.4, 7.0 Hz, 2H), 2.02 (p, J = 6.9Hz, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d 165.61,148.81, 144.16, 143.61, 138.38, 136.06, 130.84, 130.45, 129.81, 129.51,129.00, 128.55, 127.66, 127.48, 121.88, 121.31, 118.55, 48.02, 45.78, 38.22,14.23.HR-MS(ESI) m / z: calcd for C 25 H 23 N5O3S [M+H] + 473.1522, found 473.1531.

[0212] Example 41 Synthesis of Compound 41

[0213]

[0214] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by benzoyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 9.11 (s, 1H), 8.06 – 8.01 (m, 2H), 7.99 –7.93 (m, 2H), 7.76 – 7.70 (m, 2H), 7.57 – 7.46 (m, 3H), 7.33 – 7.24 (m, 2H),4.90 – 4.80 (m, 1H), 3.82 (dd, J = 12.3, 7.0 Hz, 2H), 3.74 (dd, J = 12.3, 7.0 Hz,2H), 2.07 – 1.98 (m, 1H), 1.84 (d, J = 6.9 Hz, 4H). 13C NMR (125 MHz, Common NMR Solvents) d 167.59, 144.14, 138.36, 134.48, 131.74, 129.81, 128.55, 128.32,128.20, 127.75, 121.31, 118.58, 48.02, 45.52, 38.22, 15.96.HR-MS(ESI) m / z:calcd for C 22 H 22 N4O3S [M+H] + 422.1413, found 422.1426.

[0215] Example 42 Synthesis of Compound 42

[0216]

[0217] The synthesis method of compound 10 in Example 3 was referred to, except that quinoline-8-sulfonyl chloride was replaced by 3-methoxybenzoyl chloride. 1 H NMR (500 MHz, Chloroform-d) d 8.85 (s, 1H), 8.06 – 8.01 (m, 2H), 7.76 – 7.70 (m, 2H), 7.59 (dt, J = 7.5, 1.5 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.32(d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.07 (dt, J = 7.5, 1.5 Hz, 1H), 4.87– 4.78 (m, 1H), 3.86 – 3.70 (m, 7H), 2.07 – 1.98 (m, 1H), 1.89 – 1.75 (m, 4H). 13 C NMR (125 MHz, Common NMR Solvents) d165.27, 158.54, 144.16, 138.56,133.12, 129.82, 129.51, 128.99, 128.53, 121.80, 121.31, 118.55, 117.10,111.84, 55.43, 48.02, 45.62, 38.22, 15.56.HR-MS(ESI) m / z: calcd for C 23 H 24 N4O4S[M+H] + 452.1518, found 452.1525.

[0218] Embodiment 43

[0219] The compound dissolved in DMSO was diluted in buffer (1 mL HEPES buffer, 74.55 mg KCl, 13.33 mg MgCl2, 2 μl Tween20, 10 mg BSA) in a gradient manner. 3 μl compound solution and 3 μl PKM2 kinase (1 mg / mL) were added to each well and incubated at 25 °C for 5 min. 3 μl ADP (200 μM / mL) and 3 μl PEP (1 mM / mL) were added to each well and incubated at 25 °C for 90 min. After the reaction, 12 μl luminescent solution was added to terminate the reaction and the absorbance was detected. A blank group and a basic stimulation group were set up. The blank group used an equal volume of buffer solution to replace the compound and enzyme solution, and the basic stimulation group used an equal volume of buffer solution to replace the compound solution.

[0220]

[0221] As shown in Table 1, by comparing the maximum excitation rates at three different concentrations, it was found that the maximum excitation rates of compound 11 and compound 30 were better than the existing positive drug NZT, among which compound 11 was better.

[0222]

[0223] As shown in Table 2, AC of compound 11 50 It is obviously better than the positive drug NZT, and the maximum agonist efficiency level is 46% higher than that of the positive drug NZT. Therefore, at the enzyme activity level, the present invention has discovered a PKM2 agonist with a new structure and better activity. Other compounds of the present invention also show similar agonist activity on PKM2.

[0224] Embodiment 44

[0225] Mouse bone marrow-derived macrophages were isolated and stimulated with macrophage colony-stimulating factor for 7 days and then with tumor necrosis factor-α for 24 hours to induce bone marrow-derived macrophages to differentiate into inflammatory macrophages. After treatment with compound 30 and compound 11 (10 μM), the levels of interleukin-6 and interleukin-1β were detected by Q-PCR.

[0226] The results are as follows Figure 2 As shown, after bone marrow-derived macrophages were stimulated with tumor necrosis factor-α for 24 hours, the levels of interleukin-6 and interleukin-1β mRNA increased significantly. Compound 30 and compound 11 (10 μM) could inhibit the increase of interleukin-6 and interleukin-1β mRNA after treatment, and compound 11 had a better inhibitory effect ( Figure 2 ). Other compounds of the present invention exhibit similar activities and can inhibit the increase of interleukin-6 and interleukin-1β mRNA.

[0227] Embodiment 45

[0228] In order to explore the effect of compound 11 on aortic dissection at the animal level, we selected SPF-grade 3-week-old male C57BL / 6 mice (purchased from the Medical Experimental Animal Center of Nanjing Medical University) and randomly divided them into the following 4 groups: ① control group (fed with normal saline), ② aortic dissection model group (fed with β-aminopropionitrile, w / v=0.25%, 28 days), ③ control mice gavaged with compound 11 (50 mg / kg / day, 28 days) group. ④ aortic dissection mice gavaged with compound 11 (50 mg / kg / day, 28 days) group. The aorta was isolated and the mortality rate and modeling rate of the mice were calculated. The diameters of different parts of the aorta were measured; the vascular tissue was embedded in OCT, and the CD68 infiltration was detected by frozen section.

[0229] The results are as follows Figure 3 As shown, the aorta of mice fed with β-aminopropionitrile alone showed obvious pathological dilatation, while the pathological dilatation of the aorta of mice with aortic dissection was significantly inhibited after oral administration of compound 11 (50 mg / kg / day, 28 days) ( Figure 3 The expansion of the ascending aorta, aortic arch, and thoracic aorta was significantly inhibited (Figure A). Figure 3 The survival rate of mice was significantly improved ( Figure 3 In addition, immunofluorescence staining of frozen sections of vascular tissue showed that administration of compound 11 (50 mg / kg / day) could significantly improve the CD68 infiltration induced by β-aminopropionitrile ( Figure 3 Other compounds of the present invention also show similar therapeutic effects on aortic dissection.

[0230] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in: W, X, Y and Z are each independently selected from CH; L is selected from a bond, -C(O)-, or -(CR a R a ) m -; Q is selected from -C(O)- or Each R 1 Selected from C6-C 10 Aryl or N-containing 8-10 membered heteroaryl; each of which is R b Replaced 0-3 times; Each R 2 Selected from C1-C6 alkyl, C6-C 10 aryl or 5-9 membered heteroaryl containing N, O or S; each of which is replaced by R b Replaced 0-3 times; Each R 3 are independently selected from hydrogen; Each R a are independently selected from hydrogen; Each R b Independently selected from halogen, C1-C6 alkyl, cyano or -OR b’ or two R b Together with the carbon atom to which they are attached, they form a heterocyclic group; R b’ Independently selected from C1-C6 alkyl; m is selected from 1; n is selected from 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: W, X, Y and Z are each independently selected from CH; L is selected from a bond, -C(O)-, or -(CR a R a ) m -; Q is selected from -C(O)- or Each R 1 Selected from C6-C 10 Aryl or N-containing 8-10 membered heteroaryl; each of which is R b Replaced 0-2 times; Each R 2 is selected from C1-C6 alkyl, C6-C8 aryl or 5-7 membered heteroaryl containing N, O or S; each of which is replaced by R b Replaced 0-2 times; Each R 3 are independently selected from hydrogen; Each R a are independently selected from hydrogen; Each R b Independently selected from halogen, C1-C6 alkyl, cyano or -OR b’ or two R b Together with the carbon atom to which they are attached, they form a heterocyclic group; R b’ Independently selected from C1-C6 alkyl; m is selected from 1; n is 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from a bond, -C(O)-, or -(CR a R a ) m -; Q is selected from -C(O)- or Each R 1 Selected from 8-10 membered heteroaryl containing 1 N or C6-C 10 Aryl; each of which is R b Replaced 0-2 times; Each R 2 is selected from C1-C6 alkyl, C6-C7 aryl or 5-6 membered heteroaryl containing N, O or S, each of which is replaced by R b Replaced 0-2 times; Each R a are independently selected from hydrogen; Each R b Independently selected from halogen, C1-C3 alkyl, cyano or -OR b’ or two R b Together with the carbon atom to which they are attached, they form a heterocyclic group; R b’ Independently selected from C1-C3 alkyl; m is 1; n is 1.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 is selected from quinoline, isoquinoline, naphthalene or benzene; each of which is R b Replaced 0-2 times; R 2 is selected from C1-C6 alkyl, benzene, benzyl, pyrimidine, pyrazine, thiophene, oxazole or isoxazole, each of which is replaced by R b Replaced 0-2 times; Each R b are independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, cyano or -OR b’ or two R b Together with the carbon atom to which they are attached, they form a heterocyclic group; R b’ Independently selected from C1-C3 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that: R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene, benzyl, pyrimidine, pyrazine, thiophene, oxazole or isoxazole, each of which is replaced by R b Replaced 0-2 times; Each R b independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, cyano, methoxy or two R b Together with the carbon atom to which they are attached they form a heterocyclic group.

6. A compound as described in any one of the following or a pharmaceutically acceptable salt thereof:

7. A pharmaceutical composition, characterized in that The composition contains the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further contains a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 7 or 8 in the preparation of a medicament for treating aortic dissection.

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