Cyanoethenylsulfonanilide compounds, preparation methods thereof and pharmaceutical applications

Abstract

The present invention relates to cyanoethenylsulfonanilide compounds, their preparation methods and pharmaceutical applications, belonging to the technical field of chemical synthesis. The cyanoethenylsulfonanilide compounds are shown in general formula I. Such compounds have certain inhibitory activities against Gram-positive bacteria and Gram-negative bacteria, can be used to prepare antibacterial drugs, and have no obvious drug resistance, thus providing more efficient and safe candidate drugs for clinical anti-microbial treatment and helping to solve clinical treatment problems such as increasingly serious drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to cyano vinyl sulfonanilide compounds, a preparation method thereof, and a pharmaceutical application thereof. Background Art

[0002] Sulfonamides are one of the earliest classes of chemically synthesized antibacterial drugs and have been widely used as prophylactic and chemotherapeutic agents for various diseases for more than 80 years. Sulfonamide drugs competitively bind to the enzyme with p-aminobenzoic acid in the biosynthesis of bacterial dihydrofolic acid, effectively preventing the synthesis of nucleic acids and proteins, and thereby inhibiting the growth of various microorganisms. The p-aminobenzenesulfonamide skeleton hybridized with aromatic heterocycles has produced a large number of first-line sulfonamide drugs, including sulfathiazole, sulfamethoxazole, sulfapyridine, sulfadiazine, sulfapyridine and other drugs, which play an indispensable role in the treatment of clinical infections. However, drug resistance caused by the abuse of antibacterial drugs and the side effects of drugs are still the main factors limiting their clinical application. Therefore, the structural modification of the p-aminobenzenesulfonamide core skeleton has received particular attention in the development of new sulfonamide drugs. Therefore, the research on new sulfonamide compounds with low toxicity and high activity has become a research hotspot.

[0003] Nitrogen-containing heterocyclic compounds are a class of heterocyclic compounds with a wide range of biological activities. Due to their unique biological activities, low toxicity and high absorbability, they are often used in the fields of medicine and pesticides and have always been highly regarded by medicinal chemists. They have amphoteric, highly polar, proton-accepting and donating properties and stand out among many clinical antimicrobial drugs. Electron-rich nitrogen-containing heterocyclic compounds are prone to form various weak interactions with a variety of enzymes and receptors in organisms, such as hydrogen bonds, coordination interactions, ion-dipole, cation-π, π-π stacking, hydrophobic interactions, van der Waals forces, etc., thereby improving their physicochemical properties and enhancing their bioavailability, and thus showing a wide range of biological activities. Common nitrogen-containing heterocycles, such as imidazole, thiazole, indole, benzimidazole, benzothiazole and benzopyrazole, etc., have played an important role in the medical field. In recent years, it has been found that the organic combination of different nitrogen heterocyclic fragments with different functional fragments in the antimicrobial field is beneficial to the improvement of biological activities and can also overcome the increasingly serious drug resistance. Therefore, new nitrogen-containing heterocyclic compounds still have great potential and application prospects in the antimicrobial field. Summary of the Invention

[0004] In view of this, one of the objectives of the present invention is to provide cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts; the second objective is to provide a preparation method of cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts; the third objective is to provide the application of cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts in the preparation of antibacterial agents, so as to provide more efficient and safe candidate drugs for clinical anti-microbial treatment, and help to solve clinical treatment problems such as increasingly serious drug resistance, stubborn pathogenic microorganisms, and newly emerging harmful microorganisms.

[0005] To achieve the above objectives, the present invention provides the following technical solutions:

[0006] 1. Cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts, characterized in that the structure is shown in general formula I:

[0007]

[0008] is a thiophene ring and its substituted thiophene ring, furan ring and its substituted furan ring, pyrrole ring and its substituted pyrrole ring, imidazole ring and its substituted imidazole ring, thiazole ring and its substituted thiazole ring, indole ring and its substituted indole ring, benzimidazole ring and its substituted benzimidazole ring, benzofuran ring and its substituted benzofuran ring, benzothiophene ring and its substituted benzothiophene ring or benzothiazole ring and its substituted benzothiazole ring;

[0009] R 1 、R 2 is hydrogen or acyl;

[0010] X, Y, Z, W are CH, NH, C, N, O or S atoms;

[0011] Preferably, it is any one of the following compounds:

[0012]

[0013]

[0014] When R 5 =H:

[0015] I-5-1, I-6-1: R 6 =H, R 7 =H, R 8 =H, R 9 =H; I-5-2, I-6-2: R 6 =Cl, R 7 =H, R 8 =H, R 9 =H

[0016] I-5-3, I-6-3: R 6 =H, R7 = NO 2 ,R 8 = H,R 9 = H;I-5-4,I-6-4:R 6 = H,R 7 = H,R 8 = F,R 9 = H

[0017] I-5-5,I-6-5:R 6 = H,R 7 = H,R 8 = Br,R 9 = H;I-5-6,I-6-6:R 6 = H,R 7 = H,R 8 = H,R 9 = CH 3

[0018]

[0019] Preferably, the pharmaceutically acceptable salt is hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate or acetate.

[0020] 2. The preparation method of the cyanoethenylsulfonanilide compound and its pharmaceutically acceptable salt according to any one of claims 1 to 4, the method is as follows:

[0021] a. Preparation of intermediate II: Using acetanilide as the starting material, sulfonation reaction with chlorosulfonic acid to obtain p-acetamidobenzenesulfonyl chloride, then through salt formation reaction to obtain sodium p-acetamidobenzenesulfonate, and finally reacting with chloroacetonitrile in water as the solvent at 80-100 °C to obtain the sulfonylacetonitrile compound shown in structural formula II;

[0022]

[0023] b. Preparation of intermediate III: Dissolve indole-3-carbaldehyde in acetonitrile, and react with a halogenated compound under the action of cesium carbonate to obtain intermediate III;

[0024]

[0025] Wherein:

[0026] R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, hydroxyalkyl, ester group, acyl group or heterocyclic group;

[0027] R 10 is hydrogen, alkyl, halogen or nitro;

[0028] c. Preparation of the cyanoethenylsulfonanilide compound shown in general formula I:

[0029] 1) The cyanoethenylsulfonanilide compounds shown in Structural Formulas I-1, I-3, I-5 and I-7 are prepared by reacting Intermediate II with differently substituted heterocyclic aldehydes using piperidine as a catalyst and ethanol as a solvent;

[0030] 2) The cyanoethenylsulfonanilide compounds shown in Structural Formulas I-2, I-4, I-6 and I-8 are obtained by respectively carrying out hydrolysis reactions on the cyanoethenylsulfonanilide compounds shown in Structural Formulas I-1, I-3, I-5 and I-7 under the catalysis of hydrochloric acid and with ethanol refluxing;

[0031] d. Preparation of the pharmaceutically acceptable salts of the cyanoethenylsulfonanilide compounds shown in General Formula I: The cyanoethenylsulfonanilide compounds shown in General Formula I are dissolved in an organic solvent, and a pharmaceutically acceptable acid is added and reacted until no precipitate is formed, thus obtaining the pharmaceutically acceptable salts of the cyanoethenylsulfonanilide compounds shown in I.

[0032] Preferably,

[0033] In step a, the temperature of the sulfonation reaction is 0 - 60°C; in the salt formation reaction, the salt-forming reagent is sodium sulfite or sodium bicarbonate, and the solvent is water;

[0034] In step b, the molar ratio of indole-3-carbaldehyde, the halogenated compound and cesium carbonate is 1:1.0 - 1.2:1.2 - 1.6; specifically, the reaction is carried out in acetonitrile as a solvent at 60 - 80°C for 5 - 8 h;

[0035] In step c, in step 1), the molar ratio of Intermediate II, the aldehyde and piperidine is 1:1.0 - 1.5:0.1 - 0.5; specifically, the condensation reaction is carried out in ethanol as a solvent at 70 - 85°C for 3 - 8 h; in step 2), the temperature of the hydrolysis reaction is 85 - 100°C and the time is 8 - 10 hours;

[0036] In step d, the organic solvent is at least one of chloroform, acetone, acetonitrile, ether or tetrahydrofuran; the pharmaceutically acceptable acid is hydrochloric acid or sulfuric acid.

[0037] 3. Application of the cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts in the preparation of antibacterial drugs.

[0038] Preferably, the bacteria are one or more of methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 or Acinetobacter baumannii.

[0039] 4. Preparations containing the cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts.

[0040] Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.

[0041] The beneficial effects of the present invention are as follows: The present invention provides cyanoethenylsulfonanilide compounds, their preparation methods and applications. By using the principle of drug design and combination, indole and benzene compounds are introduced into the sulfonylacetonitrile structure, and a series of cyanoethenylsulfonanilide compounds are designed and synthesized. These compounds are found to have certain inhibitory activities against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC 29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) through in vitro antimicrobial activity tests, and can be used to prepare antibacterial drugs without obvious drug resistance, providing more efficient and safe candidate drugs for clinical antibacterial treatment, and helping to solve clinical treatment problems such as increasingly serious drug resistance, stubborn pathogenic microorganisms and newly emerging harmful microorganisms.

[0042] Other advantages, objectives and features of the present invention will be described to some extent in the subsequent specification, and to some extent, will be obvious to those skilled in the art based on the study of the following text, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be achieved and obtained through the following specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] To make the objectives, technical solutions and beneficial effects of the present invention clearer, the present invention provides the following drawings for illustration:

[0044] Figure 1 It is a reference for the drug resistance of compound I-6-19 and the reference drug norfloxacin against Escherichia coli ATCC 25922 and Acinetobacter baumannii. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] The following specific examples illustrate the embodiments of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0046] Example 1. Preparation of Intermediate II

[0047]

[0048] Prepared by the method disclosed in the reference "Kim, J.; Kwon, J.; Lee, D.; Jo, S.; Park, D. S.; Choi, J.; Park, E.; Hwang, J. Y.; Ko, Y.; Choi, I.; Ju, M. K.; Ahn, J. Y.; Kim, J.; Han, S. J.; Kim, T. H.; Cechetto, J.; Nam, J.; Ahn, S.; Sommer, P.; Liuzzi, M.; No, Z.; Lee, J. Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 153–157." Intermediate II was obtained.

[0049] Example 2, Preparation of Intermediate III

[0050]

[0051] Prepared by the method disclosed in the reference "Santosh, C.; Nagaiyan, S.; Indole-based nlophoric donor-p-Acceptor styryl dyes: synthesis, spectral properties and computational studies, J. Fluoresc. 2016, 26, 2063-2077." Intermediate VII was obtained.

[0052] Example 13, Preparation of Intermediate I-1-1

[0053]

[0054] Intermediate II (0.300 g, 1.26 mmol), thiophene-2-carboxaldehyde (0.145 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-1-1 (0.312 g, 0.986 mmol), yield: 78.33%, melting point: 252.1–253.3 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.51 (s, 1H, NHCOCH 3 ), 8.72 (s, 1H, CH=C), 8.25 (d, J = 4.9 Hz, 1H, thiophene-5-H), 8.12 (d, J = 3.0 Hz, 1H, thiophene-3-H), 7.92 (d, J = 9.0 Hz, 2H, SO 2 -Ph-2,6-H), 7.89 (d, J = 9.1 Hz, 2H, SO 2 -Ph-3,5-H), 7.38 (t, J = 4.4 Hz, 1H, thiophene-4-H), 2.12 (s, 3H, NHCOCH 3 ).

[0055] Example 14. Preparation of Compound I-2-1

[0056]

[0057] Compound I-1-1 (0.150 g, 0.45 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-2-1 (0.128 g, 0.441 mmol), yield: 97.7%; red solid; melting point: 152.3–153.8 °C; 1 HNMR (600 MHz, DMSO-d 6 ) δ 8.57 (s, 1H, CH=C), 8.19 (d, J = 5.0 Hz, 1H, thiophene-5-H), 8.05 (d, J = 3.9 Hz, 1H, thiophene-3-H), 7.56 (d, J = 8.4 Hz, 2H, SO 2-Ph-2,6-H), 7.35 (t, J = 4.4 Hz, 1H, thiophene-4-H), 6.71 (d, J = 8.4 Hz, 2H, SO 2 -Ph-3,5-H), 6.46 (s, 2H, NH 2 ).

[0058] Example 15, Preparation of Intermediate I-1-2

[0059]

[0060] Intermediate II (0.300 g, 1.26 mmol), 5-methylthiophene-2-carbaldehyde (0.191 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-1-2 (0.375 g, 1.08 mmol), yield: 84.2%, melting point: 277.0–278.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.50 (s, 1H, NHCOCH 3 ), 8.39 (s, 1H, CH=C), 8.16 (d, J = 5.0 Hz, 1H, thiophene-3-H), 7.95 (d, J = 8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.89 (d, J = 8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.25 (d, J = 5.0 Hz, 1H, thiophene-4-H), 2.51 (d, J = 1.8 Hz, 3H, CH 3 ), 2.11 (s, 3H, NHCOCH 3 ).

[0061] Example 16, Preparation of Compound I-2-2

[0062]

[0063] Compound I-1-2 (0.150 g, 0.43 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, and then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain compound I-2-2 (0.111 g, 0.364 mmol) with a yield of 80.1%; yellow solid; melting point: 190.8–192.2 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.28 (s, 1H, CH=C), 8.09 (s, 1H, thiophene-3-H), 7.58 (d, J = 8.4 Hz, 2H, SO 2 -Ph-2,6-H), 7.21 (s, 1H, thiophene-4-H), 6.70 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.43 (s, 2H, NH 2 ), 2.47 (s, 3H, CH 3 ).

[0064] Example 9. Preparation of Intermediate I-1-4

[0065]

[0066] Intermediate II (0.300 g, 1.26 mmol), furan-2-carbaldehyde (0.145 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to dryness to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-1-3 (0.324 g, 1.02 mmol) with a yield of 81.4% and a melting point of 216.8–217.4 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.51 (s, 1H, NHCOCH 3 ), 8.27 (s, 1H, CH=C), 8.24 (s, 1H, furan-5-H), 7.90 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H)), 7.89 (d, J = 8.8 Hz, 2H, SO 2-Ph-3,5-H), 7.59 (d, J=3.7 Hz, 1H, furan-3-H), 6.89 (dd, J=3.7, 1.8 Hz, 1H, furan-4-H), 2.11 (s, 3H, NHCOCH 3 ).

[0067] Example 10. Preparation of Compound I-2-3

[0068]

[0069] Compound I-1-3 (0.150 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-2-3 (0.114 g, 0.326 mmol) with a yield of 80.1%; yellow solid; melting point: 152.2–153.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.19 (s, 1H, CH=C), 8.12 (s, 1H, furan-5-H), 7.54 (d, J=8.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.50 (s, 1H, furan-3-H), 6.86 (s, 1H, furan-4-H), 6.70 (d, J=8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.45 (s, 2H, NH 2 ).

[0070] Example 11. Preparation of Intermediate I-1-4

[0071]

[0072] Intermediate II (0.300 g, 1.26 mmol), 5-methylfuran-2-carbaldehyde (0.166 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to dryness to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-1-4 (0.332 g, 1.00 mmol) with a yield of 79.82% and a melting point of 279.3–280.6 °C; 1 H NMR (600 MHz, DMSO-d6 ) δ 10.49 (s, 1H, NHCOCH 3 ), 8.13 (s, 1H, CH=C), 7.88 (s, 4H, SO 2 -Ph-2,3,5,6-H), 7.52 (d, J=3.6 Hz, 1H, furan-3-H), 6.58 (d, J=3.7 Hz, 1H, furan-4-H), 2.42 (s, 3H, CH 3 ), 2.11 (s, 3H, NHCOCH 3 ).

[0073] Example 12, Preparation of Compound I-2-4

[0074]

[0075] Compound I-1-4 (0.160 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-2-4 (0.114 g, 0.326 mmol) with a yield of 80.1%; yellow solid; melting point: 194.6–196.5 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.99 (s, 1H, CH=C), 7.53 (d, J=8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.43 (d, J=3.5 Hz, 1H, furan-3-H), 6.70 (d, J=8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.53 (d, J=3.6 Hz, 1H, furan-4-H), 6.41 (s, 2H, NH 2 ), 2.40 (s, 3H, CH 3 ).

[0076] Example 3, Preparation of Intermediate I-1-5

[0077]

[0078] Intermediate II (0.300 g, 1.26 mmol), 1H-pyrrole-2-carbaldehyde (0.219 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-1-5 (0.376 g, 1.03 mmol), yield: 81.8%, melting point: 245.3–246.8 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.17 (s, 1H, pyrrole-NH), 10.47 (s, 1H, NHCOCH 3 ), 8.17 (s, 1H, C=CH), 7.88 (d, J = 9.1 Hz, 2H, SO 2 -Ph-2,6-H)), 7.86 (d, J = 9.1 Hz, 2H, SO 2 -Ph-3,5-H), 7.50 (s, 1H, pyrrole-5-H), 7.31 (d, J = 3.4 Hz, 1H, pyrrole-3-H), 6.52–6.48 (m, 1H, pyrrole-4-H), 2.11 (s, 3H, NHCOCH 3 ).

[0079] Example 4. Preparation of Compound I-2-5

[0080]

[0081] Compound I-1-5 (0.160 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain Compound I-2-5 (0.114 g, 0.326 mmol), yield: 80.1%; yellow solid; melting point: 160.6–162.4 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.05 (s, 1H, pyrrole-NH), 8.06 (s, 1H, CH=C), 7.51 (d, J = 8.4 Hz, 2H, SO 2-Ph-2,6-H), 7.43 (s, 1H, pyrrole-5-H), 7.25 (s, 1H, pyrrole-3-H), 6.69 (d, J=8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.46 (s, 1H, pyrrole-4-H), 6.34 (s, 2H, NH 2 ).

[0082] Example 17. Preparation of Intermediate I-1-6

[0083]

[0084] Intermediate II (0.300 g, 1.26 mmol), thiazole-2-carbaldehyde (0.199 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-1-6 (0.356 g, 1.07 mmol), yield: 72.8%, melting point: 247.3–249.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.54 (s, 1H, NHCOCH 3 ), 8.68 (s, 1H, CH=C), 8.37 (d, J=3.0 Hz, 1H, thiazole-5-H), 8.31 (d, J=3.0 Hz, 1H, thiazole-4-H), 7.97 (d, J=8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.91 (d, J=8.9 Hz, 2H, SO 2 -Ph-3,5-H), 2.12 (s, 3H, NHCOCH 3 ).

[0085] Example 18. Preparation of Compound I-2-6

[0086]

[0087] Compound I-1-6 (0.150 g, 0.45 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, after which heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was collected by filtration and dried under vacuum to obtain compound I-2-6 (0.098 g, 0.336 mmol) with a yield of 74.8%; yellow solid; melting point: 174.3–174.2 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.51 (s, 1H, CH=C), 8.28 (d, J=21.7 Hz, 2H, thiazole-4,5-H), 7.59 (s, 2H, SO 2 -Ph-2,6-H), 6.72 (s, 2H, SO 2 -Ph-3,5-H), 6.52 (s, 2H, NH 2 ).

[0088] Example 5. Preparation of Intermediate I-1-7

[0089]

[0090] Intermediate II (0.300 g, 1.26 mmol), 1H-imidazole-2-carbaldehyde (0.145 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain a yellow solid compound I-1-7 (0.243 g, 0.77 mmol) with a yield of 61.01% and a melting point of 252.1–253.4 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.28 (s, 1H, imidazole-1-H), 10.51 (s, 1H, NHCOCH 3 ), 8.10 (s, 1H, CH=C), 7.90 (s, 4H, SO 2 -Ph-2,3,5,6-H), 7.68 (s, 1H, imidazole-4-H), 7.45 (s, 1H, imidazole-5-H), 2.11 (s, 3H, NHCOCH 3 ).

[0091] Example 6. Preparation of Compound I-2-7

[0092]

[0093] Compound I-1-7 (0.150 g, 0.47 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain compound I-2-7 (0.120 g, 0.44 mmol) with a yield of 92.2%; yellow solid; melting point: 183.2–184.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.17 (s, 1H, imidazole-1-H), 7.99 (s, 1H, CH=C), 7.48 (d, J = 78.6 Hz, 4H, SO 2 -Ph-2,3,5,6-H), 6.71 (s, 2H, imidazole-4,5-H), 6.44 (s, 2H, NH 2 ).

[0094] Example 7. Preparation of Intermediate I-1-8

[0095]

[0096] Intermediate II (0.300 g, 1.26 mmol), 1-ethyl-1H-imidazole-2-carbaldehyde (0.219 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-1-8 (0.376 g, 1.03 mmol) with a yield of 81.8% and a melting point of 287.3–289.1 °C; 1 HNMR (600 MHz, DMSO-d 6 ) δ 10.49 (s, 1H, NHCOCH 3 ), 8.07 (s, 1H, CH=C), 7.95 (d, J = 8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.88 (d, J = 8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.66 (s, 1H, imidazole-4-H), 7.38 (s, 1H, imidazole-5-H), 3.93 (s, 3H, CH3 ), 2.11 (s, 3H, NHCOCH 3 ).

[0097] Example 8, Preparation of Compound I-2-8

[0098]

[0099] Compound I-1-8 (0.160 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-2-8 (0.114 g, 0.326 mmol) with a yield of 80.1%; yellow solid; melting point: 240.6 - 242.4 °C; 1 HNMR (600 MHz, DMSO-d 6 ) δ 7.95 (s, 1H, CH=C), 7.60 (d, J = 5.1 Hz, 2H, SO 2 -Ph-2,6-H), 7.58 (s, 1H, imidazole-4-H), 7.34 (s, 1H, imidazole-5-H), 6.70 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.42 (s, 2H, NH 2 ), 3.89 (s, 3H, CH 3 ).

[0100] Example 19, Preparation of Intermediate I-3-1

[0101]

[0102] Intermediate II (0.300 g, 1.26 mmol), 1H-imidazole-5-carbaldehyde (0.145 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1 - 10 / 1, V / V) to obtain a yellow solid compound I-3-1 (0.254 g, 0.802 mmol) with a yield of 63.77% and a melting point of 261.2 - 262.4 °C; 1 H NMR (600 MHz, DMSO-d 6)δ 12.97 (s, 1H, imidazole-1-H), 10.46 (s, 1H, NHCOCH 3 ), 8.25 (s, 1H, CH=C), 8.13 (s, 1H, imidazole-2-H), 8.00 (s, 1H, imidazole-4-H), 7.87 (s, 4H, SO 2 -Ph-2,3,5,6-H), 2.11 (s, 3H, NHCOCH 3 ).

[0103] Example 20: Preparation of Compound I-4-1

[0104]

[0105] Compound I-3-1 (0.150 g, 0.47 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-4-1 (0.105 g, 0.329 mmol) with a yield of 80.7%; yellow solid; melting point: 183.4–184.9 °C; 1 1H NMR (600 MHz, DMSO-d 6 )δ 12.91 (s, 1H, imidazole-1-H), 8.11 (s, 1H, CH=C), 8.05 (s, 1H, imidazole-2-H), 7.97 (s, 1H, imidazole-4-H), 7.52 (d, J = 8.4 Hz, 2H, SO 2 -Ph-2,6-H), 6.69 (d, J = 8.1 Hz, 2H, SO 2 -Ph-3,5-H), 6.34 (s, 2H, NH 2 ).

[0106] Example 21: Preparation of Intermediate I-3-2

[0107]

[0108] Intermediate II (0.300 g, 1.26 mmol), thiazole-5-carbaldehyde (0.170 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-3-2 (0.365 g, 1.09 mmol), yield: 86.9%, melting point: 249.2–251.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, NHCOCH 3 ), 9.55 (s, 1H, thiazole-2-H), 8.88 (s, 1H, thiazole-4-H), 8.82 (s, 1H, CH=C), 7.93 (d, J = 9.1 Hz, 2H, SO 2 -Ph-2,6-H), 7.90 (d, J = 9.1 Hz, 2H, SO 2 -Ph-3,5-H), 2.12 (s, 3H, NHCOCH 3 ).

[0109] Example 22. Preparation of Compound I-4-2

[0110]

[0111] Compound I-3-2 (0.150 g, 0.45 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain Compound I-4-2 (0.094 g, 0.321 mmol), yield: 71.4%; yellow solid; melting point: 176.5–177.2 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.50 (s, 1H, thiazole-2-H), 8.75 (s, 1H, thiazole-4-H), 8.72 (s, 1H, CH=C), 7.57 (d, J = 8.4 Hz, 2H, SO 2 -Ph-2,6-H), 6.72 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H).

[0112] Example 23, Preparation of Intermediate I-3-3

[0113]

[0114] Intermediate II (0.300 g, 1.26 mmol), 2-aminothiazole-5-carbaldehyde (0.193 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-3-3 (0.394 g, 1.03 mmol), yield: 81.7%, melting point: 246.3–247.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.45 (s, 1H, NHCOCH 3 ), 8.85 (s, 2H, thiazole-NH 2 ), 8.38 (s, 1H, CH=C), 8.20 (s, 1H, thiazole-4-H), 7.85 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.83 (d, J = 8.9 Hz, 2H, SO 2 -Ph-3,5-H), 2.11 (s, 3H, NHCOCH 3 ).

[0115] Example 24, Preparation of Compound I-4-3

[0116]

[0117] Compound I-3-3 (0.150 g, 0.43 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-4-3 (0.102 g, 0.333 mmol), with a yield of 77.3%; yellow solid; melting point: 264.3–265.2 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.68 (s, 2H, thiazole-NH 2 ), 8.19 (d, J = 91.4 Hz, 2H, CH=C, thiazole-4-H), 7.49 (s, 2H, SO2 -Ph-2,6-H), 6.68 (s, 2H, SO 2 -Ph-3,5-H), 6.31 (s, 2H, NH 2 ).

[0118] Example 25, Preparation of Intermediate I-3-4

[0119]

[0120] Intermediate II (0.300 g, 1.26 mmol), 2-morpholinothiazole-5-carbaldehyde (0.299 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-3-4 (0.483 g, 1.15 mmol), yield: 91.6%, melting point: 261.2–262.5 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.46 (s, 1H, NHCOCH 3 ), 8.44 (s, 1H, CH=C), 8.34 (s, 1H, thiazole-4-H), 7.86 (d, J = 9.2 Hz, 2H, SO 2 -Ph-2,6-H), 7.83 (d, J = 9.3 Hz, 2H, SO 2 -Ph-3,5-H), 3.71 (d, J = 4.4 Hz, 4H, morpholine-H), 3.67 (d, J = 4.8 Hz, 4H, morpholine-H), 2.10 (s, 3H, NHCOCH 3 ).

[0121] Example 26, Preparation of Compound I-4-4

[0122]

[0123] Compound I-3-5 (0.150 g, 0.36 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, and then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-4-4 (0.119 g, 0.316 mmol), with a yield of 88.2%; yellow solid; melting point: 182.8–183.6 °C;1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.32 (s, 1H, CH=C), 8.25 (s, 1H, thiazole-4-H), 7.50 (d, J=8.4 Hz, 2H, SO 2 -Ph-2,6-H), 6.68 (d, J=8.4 Hz, 2H, SO 2 -Ph-3,5-H), 6.33 (s, 2H, NH 2 ), 3.71 (s, 4H, morpholine-H), 3.64 (s, 4H, morpholine-H).

[0124] Example 27, Preparation of Intermediate I-3-5

[0125]

[0126] Intermediate II (0.300 g, 1.26 mmol), 2-phenylthiazole-5-carbaldehyde (0.285 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-3-5 (0.434 g, 1.06 mmol), yield: 84.2%, melting point: 287.1–288.8 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, NHCOCH 3 ), 8.84 (s, 1H, CH=C), 8.82 (s, 1H, thiazole-4-H), 8.09–8.04 (m, 2H, thiazole-Ph-2,6-H), 7.97–7.93 (m, 2H, SO 2 -Ph-2,6-H), 7.91 (d, J=9.0 Hz, 2H, SO 2 -Ph-3,5-H), 7.61 (t, J=7.3 Hz, 1H, thiazole-Ph-4-H), 7.56 (t, J=7.3 Hz, 2H, thiazole-Ph-3,5-H), 2.12 (s, 3H, NHCOCH 3 ).

[0127] Example 28, Preparation of Compound I-4-5

[0128]

[0129] Compound I-3-5 (0.150 g, 0.37 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain compound I-4-5 (0.121 g, 0.33 mmol) with a yield of 89.9%; yellow solid; melting point: 264.6–265.4 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.75 (s, 1H, CH=C), 8.69 (s, 1H, thiazole-4-H), 8.05 (s, 2H, thiazole-Ph-2,6-H), 7.58 (s, 5H, thiazole-Ph-3,5-H, SO 2 -Ph-2,6-H), 6.73 (s, 2H, SO 2 -Ph-3,5-H), 6.49 (s, 2H, NH 2 ).

[0130] Example 29. Preparation of Intermediate I-5-1:

[0131]

[0132] Intermediate II (0.300 g, 1.26 mmol), 1H-indole-3-carbaldehyde (0.219 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to dryness to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-5-1 (0.376 g, 1.03 mmol) with a yield of 81.8% and a melting point of 287.3–289.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.68 (s, 1H, indole-1-H), 10.45 (s, 1H, NHCOCH 3 ), 8.53 (s, 1H, indole-2-H), 8.51 (s, 1H, CH=C), 8.04 (d, J = 7.1 Hz, 1H, indole-4-H), 7.94 (dd, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (dd, J = 8.8 Hz, 2H, SO 2-Ph-3,5-H), 7.58 (d, J = 7.2 Hz, 1H, indole-7-H), 7.34–7.26 (m, 2H, indole-5,6-H), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0133] Example 30, Preparation of Compound I-6-1:

[0134]

[0135] Compound I-5-1 (0.150 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution. A solid was precipitated, filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-1 (0.116 g, 0.359 mmol) with a yield of 87.4%; yellow solid; melting point 278.2–279.8 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 12.55 (s, 1H, indole-1-H), 8.44 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 7.99 (d, J = 7.7 Hz, 1H, indole-4-H), 7.59 (d, J = 8.2 Hz, 2H, SO 2 -Ph-2,6-H), 7.57 (d, J = 7.7 Hz, 1H, indole-7-H), 7.31 (t, J = 7.4 Hz, 1H, indole-6-H), 7.28 (t, J = 7.4 Hz, 1H, indole-5-H), 6.70 (d, J = 7.8 Hz, 2H, SO 2 -Ph-3,5-H), 6.29 (s, 2H, NH 2 ) ppm.

[0136] Example 31, Preparation of Intermediate I-5-2:

[0137]

[0138] Intermediate II (0.300 g, 1.26 mmol), 4-chloro-1H-indole-3-carbaldehyde (0.271 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-2 (0.375 g, 0.983 mmol), yield: 74.5%, melting point: >300 °C; 1 H NMR (600 MHz, DMSO) δ 12.94 (s, 1H, indole-1-H), 10.46 (s, 1H, NHCOCH 3 ), 9.23 (s, 1H, indole-2-H), 8.63 (s, 1H, CH=C), 7.90 (d, J = 9.1 Hz, 2H, SO 2 -Ph-2,6-H), 7.88 (d, J = 9.2 Hz, 2H, SO 2 -Ph-3,5-H), 7.60 (d, J = 8.0 Hz, 1H, indole-5-H), 7.36 (d, J = 7.6 Hz, 1H, indole-7-H), 7.31 (t, J = 7.9 Hz, 1H, indole-6-H), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0139] Example 32, Preparation of Compound I-6-2:

[0140]

[0141] Compound I-5-2 (0.165 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried in vacuo to obtain Compound I-6-2 (0.122 g, 0.340 mmol), with a yield of 82.5%; yellow solid; melting point: 271.2–272.6 °C; 1 H NMR (600 MHz, DMSO) δ 12.83 (s, 1H, indole-1-H), 9.13 (s, 1H, CH=C), 8.57 (d, J = 2.7 Hz, 1H, indole-2-H), 7.59 (d, J = 8.0 Hz, 1H, indole-7-H), 7.55 (d, J = 8.7 Hz, 2H, SO 2-Ph-2,6-H), 7.34 (d, J = 7.7 Hz, 1H, indole-5-H), 7.29 (t, J = 7.7 Hz, 1H, indole-6-H), 6.71 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.35 (s, 2H, NH 2 ) ppm.

[0142] Example 33. Preparation of Intermediate I-5-3:

[0143]

[0144] Intermediate II (0.300 g, 1.26 mmol), 5-nitro-1H-indole-3-carbaldehyde (0.287 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-3 (0.397 g, 0.967 mmol), yield: 76.8%, melting point: >300 °C; 1 H NMR (600 MHz, DMSO) δ 13.05 (s, 1H, indole-1-H), 10.46 (s, 1H, NHCOCH 3 ), 9.14 (s, 1H, indole-4-H), 8.78 (s, 1H, indole-2-H), 8.70 (s, 1H, CH=C), 8.17 (d, J = 7.9 Hz, 1H, indole-6-H), 8.00 (d, J = 7.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.88 (d, J = 7.6 Hz, 2H, SO 2 -Ph-3,5-H), 7.75 (d, J = 8.4 Hz, 1H, indole-7-H), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0145] Example 34. Preparation of Compound I-6-3:

[0146]

[0147] Compound I-5-3 (0.170 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-3 (0.126 g, 0.343 mmol), with a yield of 82.7%; yellow solid; melting point: 267.2–269.0 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.96 (s, 1H, indole-1-H), 9.09 (s, 1H, indole-4-H), 8.65 (s, 1H, indole-2-H), 8.63 (s, 1H, CH=C), 8.15 (d, J = 8.4 Hz, 1H, indole-6-H), 7.74 (d, J = 8.8 Hz, 1H, indole-7-H), 7.65 (d, J = 8.5 Hz, 2H, SO 2 -Ph-2,6-H), 6.71 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.34 (s, 2H, NH 2 ) ppm.

[0148] Example 35: Preparation of Intermediate I-5-4:

[0149]

[0150] Intermediate II (0.300 g, 1.26 mmol), 6-fluoro-1H-indole-3-carbaldehyde (0.246 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to dryness to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain a yellow solid compound I-5-4 (0.400 g, 1.04 mmol), yield: 82.7%, melting point: >300 °C; 1 H NMR (600 MHz, DMSO) δ 12.53 (s, 1H, indole-1-H), 8.45 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 8.03 (dd, J = 8.6, 5.1 Hz, 1H, indole-4-H), 7.59 (d, J = 8.7 Hz, 2H, SO 2-Ph-2,6-H), 7.37 (dd, J = 9.4, 2.0 Hz, 1H, indole-7-H), 7.17–7.11 (m, 1H, indole-5-H), 6.70 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.33 (s, 2H, NH 2 ) ppm.

[0151] Example 36. Preparation of Compound I-6-4:

[0152]

[0153] Compound I-5-4 (0.170 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, and then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-4 (0.125 g, 0.367 mmol) with a yield of 82.7%; yellow solid; melting point > 300 °C; 1 1H NMR (600 MHz, DMSO) δ 12.53 (s, 1H, indole-1-H), 8.45 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 8.03 (dd, J = 8.6, 5.1 Hz, 1H, indole-4-H), 7.59 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.37 (dd, J = 9.4, 2.0 Hz, 1H, indole-7-H), 7.17–7.11 (m, 1H, indole-5-H), 6.70 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.33 (s, 2H, NH 2 ) ppm.

[0154] Example 37. Preparation of Intermediate I-5-5:

[0155]

[0156] Intermediate II (0.300 g, 1.26 mmol), 6-bromo-1H-indole-3-carbaldehyde (0.338 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-5 (0.409 g, 0.922 mmol), yield: 73.2%, melting point: >300 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.67 (s, 1H, indole-NH), 10.45 (s, 1H, NHCOCH 3 ), 8.54 (s, 1H, indole-2-H), 8.51 (s, 1H, CH=C), 8.02 (d, J = 8.5 Hz, 1H, indole-4-H), 7.94 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.77 (s, 1H, indole-7-H), 7.43 (d, J = 8.5 Hz, 1H, indole-5-H), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0157] Example 38, Preparation of Compound I-6-5:

[0158]

[0159] Compound I-5-5 (0.180 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise, followed by refluxing at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-6-5 (0.138 g, 0.342 mmol), yield 84.4%; yellow solid; melting point 269.6–271.2 °C; 1 H NMR (600 MHz, DMSO-d 6)δ 12.55 (s, 1H, NH), 8.44 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 7.97 (d, J = 8.5 Hz, 1H, indole-4-H), 7.76 (s, 1H, indole-7-H), 7.59 (d, J = 8.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.40 (d, J = 8.5 Hz, 1H, indole-5-H), 6.69 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.31 (s, 2H, NH 2 ) ppm.

[0160] Example 39, Preparation of Intermediate I-5-6:

[0161]

[0162] Intermediate II (0.300 g, 1.26 mmol), 7-methyl-1H-indole-3-carbaldehyde (0.240 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-6 (0.345 g, 0.910 mmol), yield: 72.3%, melting point: >300 °C; 1 H NMR (600 MHz, DMSO) δ 12.74 (s, 1H, indole-1-H), 10.45 (s, 1H, NHCOCH 3 ), 8.51 (s, 1H, indole-2-H), 8.44 (s, 1H CH=C), 7.94 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.6 Hz, 2H, SO 2 -Ph-35-H), 7.86 (d, J = 4.1 Hz, 1H, indole-4-H), 7.20 (t, J = 7.5 Hz, 1H, indole-5-H), 7.12 (d, J = 6.9 Hz, 1H, indole-6-H), 2.51 (s, 3H, indole-7-CH 3 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0163] Example 40, Preparation of Compound I-6-6:

[0164]

[0165] Compound I-5-6 (0.180 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation. The system was dropped into saturated sodium bicarbonate solution, and a solid was precipitated. The solid was filtered by suction, and the collected product was dried under vacuum to obtain compound I-6-6 (0.132 g, 0.392 mmol) with a yield of 82.6%; yellow solid; melting point: 285.3–286.2 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 12.60 (s, 1H, indole-1-H), 8.40 (s, 1H, indole-2-H), 8.38 (d, J = 3.4 Hz, 1H, CH═C), 7.80 (d, J = 8.0 Hz, 1H, indole-4-H), 7.59 (d, J = 8.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.18 (t, J = 7.6 Hz, 1H, indole-5-H), 7.11 (d, J = 7.2 Hz, 1H, indole-6-H), 6.69 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.30 (s, 2H, NH 2 ), 2.51 (s, 3H, NCH 3 ) ppm.

[0166] Example 41: Preparation of Intermediate I-5-7:

[0167]

[0168] Intermediate II (0.300 g, 1.26 mmol), 1-methyl-1H-indole-3-carbaldehyde (0.240 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain a yellow solid compound I-5-7 (0.337 g, 0.889 mmol) with a yield of 70.6% and a melting point of 284.0–286.0 °C; 1 1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, NHCOCH 3), 8.49 (s, 2H, indole-2-H, CH=C), 8.04 (d, J=6.8 Hz, 1H, indole-4-H), 7.94 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J=8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.64 (d, J=3.8 Hz, 1H, indole-7-H), 7.37 (dt, J=14.2, 6.8 Hz, 2H, indole-5,6-H), 3.96 (s, 3H, NCH 3 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0169] Example 42. Preparation of Compound I-6-7:

[0170]

[0171] Compound I-5-7 (0.180 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, and then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-7 (0.139 g, 0.411 mmol) with a yield of 84.4%; yellow solid; melting point: 229.4–231.2 °C; 1 1H NMR (600 MHz, DMSO) δ 8.42 (s, 1H, indole-2-H), 8.38 (s, 1H, CH=C), 7.99 (d, J=7.8 Hz, 1H, indole-4-H), 7.62 (d, J=8.1 Hz, 1H, indole-7-H), 7.59 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.37 (t, J=7.6 Hz, 1H, indole-6-H), 7.32 (t, J=7.5 Hz, 1H, indole-5-H), 6.69 (d, J=8.8 Hz, 2H, SO 2 -Ph-3,5-H), 6.31 (s, 2H, NH 2 ), 3.95 (s, 3H, NCH 3 ) ppm.

[0172] Example 43. Preparation of Intermediate I-5-8:

[0173]

[0174] Intermediate II (0.300 g, 1.26 mmol), 1-ethyl-1H-indole-3-carbaldehyde (0.261 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-8 (0.351 g, 0.891 mmol), yield: 70.8%, melting point: 227.6–228.9 °C; 1 HNMR (600 MHz, DMSO-d 6 δ 10.44 (s, 1H, NHCOCH 3 ), 8.54 (s, 1H, indole-2-H), 8.49 (s, 1H, CH=C), 8.06 (d, J = 7.6 Hz, 1H, indole-4-H), 7.94 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 7.70 (d, J = 7.8 Hz, 1H, indole-7-H), 7.36 (dt, J = 14.5, 7.0 Hz, 2H, indole-5,6-H), 4.39 (q, J = 6.8 Hz, 2H, CH 2 CH 3 ), 2.10 (s, 3H, NHCOCH 3 ), 1.41 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ) ppm.

[0175] Example 44. Preparation of compound I-6-8:

[0176]

[0177] Compound I-5-8 (0.160 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-6-8 (0.114 g, 0.326 mmol), yield: 80.1%; yellow solid; melting point: 240.6–242.4 °C; 1HNMR (600 MHz, DMSO) δ 8.47 (s, 1H, indole-2-H), 8.38 (s, 1H, CH=C), 8.01 (d, J = 7.7 Hz, 1H, indole-4-H), 7.68 (d, J = 8.0 Hz, 1H, indole-7-H), 7.59 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.36 (t, J = 7.5 Hz, 1H, indole-65-H), 7.32 (t, J = 7.4 Hz, 1H, indole-6-H), 6.69 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.32 (s, 2H, NH 2 ), 4.38 (q, J = 6.8 Hz, 2H, NCH 2 CH 3 ), 1.40 (t, J = 7.1 Hz, 3H, NCH 2 CH 3 ) ppm.

[0178] Example 45, Preparation of Intermediate I-5-9:

[0179]

[0180] Intermediate II (0.300 g, 1.26 mmol) and 1-butyl-1H-indole-3-carbaldehyde (0.304 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-9 (0.383 g, 0.908 mmol), yield: 72.1%, melting point: 195.0–196.7 °C; 1 HNMR (600 MHz, DMSO-d 6 ) δ 10.45 (s, 1H, NHCOCH 3 ), 8.51 (s, 1H, indole-2-H), 8.50 (s, 1H, CH=C), 8.05 (d, J = 7.5 Hz, 1H, indole-4-H), 7.94 (d, J = 8.3 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.3 Hz, 2H, SO 2-Ph-3,5-H), 7.70 (d, J = 6.8 Hz, 1H, indole-7-H), 7.41–7.31 (m, 2H, indole-5,6-H), 4.36 (s, 2H, NCH 2 CH 2 ), 2.10 (s, 3H, NHCOCH 3 ), 1.76 (s, 2H, CH 2 CH 2 CH 2 ), 1.32–1.21 (m, 2H, CH 2 CH 2 CH 3 ), 0.88 (t, J = 6.5 Hz, 3H, CH 2 CH 3 ) ppm.

[0181] Example 46. Preparation of Compound I-6-9:

[0182]

[0183] Compound I-5-9 (0.170 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain Compound I-6-9 (0.121 g, 0.320 mmol) with a yield of 79.4%; yellow solid; melting point: 168.9–170.7 °C; 1 1H NMR (600 MHz, DMSO) δ 8.45 (s, 1H, indole-2-H), 8.39 (s, 1H, CH═C), 8.01 (d, J = 7.7 Hz, 1H, indole-4-H), 7.68 (d, J = 7.9 Hz, 1H, indole-7-H), 7.61 (d, J = 8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.36 (t, J = 7.5 Hz, 1H, indole-6-H), 7.32 (t, J = 7.3 Hz, 1H, indole-5-H), 6.73 (d, J = 8.0 Hz, 2H, SO 2 -Ph-3,5-H), 6.51 (s, 2H, NH 2 ), 4.35 (t, J = 6.4 Hz, 2H, NCH 2 CH 2 CH 2 CH 3), 1.80–1.72 (m, 2H, NCH 2 CH 2 CH 2 CH 3 ), 1.26 (dt, J=14.3, 7.1 Hz, 2H, NCH 2 CH 2 CH 2 CH 3 ), 0.88 (t, J=7.2 Hz, 3H. NCH 2 CH 2 CH 2 CH 3 ) ppm。

[0184] Example 47, Preparation of Intermediate I-5-10:

[0185]

[0186] Intermediate II (0.300 g, 1.26 mmol), 1-pentyl-1H-indole-3-carbaldehyde (0.325 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-10 (0.432 g, 0.991 mmol), yield: 78.7%, melting point: 166.9–167.6 °C; 1 1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, NHCOCH 3 ), 8.51 (s, 1H, indole-2-H), 8.50 (s, 1H, CH=C), 8.05 (d, J=7.8 Hz, 1H, indole-4-H), 7.94 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J=8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.69 (d, J=8.0 Hz, 1H, indole-7-H), 7.36 (dt, J=21.7, 7.2 Hz, 2H, indole-5,6-H), 4.35 (t, J=7.0 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 2.10 (s, 3H, NHCOCH 3), 1.83–1.73 (m, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 1.29 (dd, J=14.1, 7.0 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 1.24 (dd, J=14.4, 7.5 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 0.82 (t, J=7.1 Hz, 3H, NCH 2 CH 2 CH 2 CH 2 CH 3 ) ppm.

[0187] Example 48, Preparation of Compound I-6-10:

[0188]

[0189] Compound I-5-10 (0.180 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-10 (0.136 g, 0.320 mmol), with a yield of 83.4%; yellow solid; melting point 148.6–149.5 °C; 1 1H NMR (600 MHz, DMSO) δ 8.45 (s, 1H, indole-2-H), 8.38 (s, 1H, CH=C), 8.01 (d, J=7.7 Hz, 1H, indole-4-H), 7.68 (s, 1H, indole-7-H), 7.59 (d, J=8.3 Hz, 2H, SO 2 -Ph-2,6-H), 7.36 (t, J=7.3 Hz, 1H, indole-6-H), 7.32 (t, J=7.1 Hz, 1H, indole-5-H), 6.70 (d, J=7.2 Hz, 2H, SO 2 -Ph-3,5-H), 4.34 (s, 2H, NCH 2 CH2 CH 2 CH 2 CH 3 ), 1.82–1.72 (m, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 1.33–1.26 (m, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 1.23 (d, J=5.9 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 3 ), 0.82 (dd, J=7.0, 5.4 Hz, 3H, NCH 2 CH 2 CH 2 CH 2 CH 3 ) ppm.

[0190] Example 49, Preparation of Intermediate I-5-11:

[0191]

[0192] Intermediate II (0.300 g, 1.26 mmol), 1-hexyl-1H-indole-3-carbaldehyde (0.346 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-11 (0.445 g, 0.990 mmol), yield: 78.6%, melting point: 136.8–138.4 °C; 1 H NMR (600 MHz, DMSO) δ 10.41 (s, 1H, NHCOCH 3 ), 8.48 (s, 2H, indole-2-H, CH=C), 8.03 (bs, 1H, indole-4-H), 7.92 (bs, 2H, SO 2 -Ph-2,6-H), 7.84 (bs, 2H, SO 2-Ph-3,5-H), 7.68 (bs, 1H, indole-7-H), 7.33 (bs, 2H, indole-5,6-H), 4.33 (bs, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2.07 (s, 3H, NHCOCH 3 ), 1.75 (bs, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.22 (bs, 6H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 0.80 (bs, 3H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) ppm.

[0193] Example 50. Preparation of Compound I-6-11:

[0194]

[0195] Compound I-5-11 (0.185 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-11 (0.138 g, 0.338 mmol) with a yield of 84.4%; yellow solid; melting point: 246.2–247.4 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.45 (s, 1H, indole-2-H), 8.39 (s, 1H, CH=C), 8.00 (d, J = 7.8 Hz, 1H, indole-4-H), 7.67 (d, J = 8.1 Hz, 1H, indole-7-H), 7.61 (d, J = 8.6 Hz, 2H, SO 2-Ph-2,6-H), 7.36 (t, J = 7.6 Hz, 1H, indole-6-H), 7.31 (t, J = 7.5 Hz, 1H, indole-5-H), 6.74 (d, J = 8.6 Hz, 2H, SO 2 -Ph-3,5-H), 5.44 (s, 2H, NH 2 ), 4.34 (t, J = 7.1 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.77 (p, J = 6.8 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.25 (s, 6H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 0.82 (t, J = 6.8 Hz, 3H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) ppm.

[0196] Example 51, Preparation of Intermediate I-5-12:

[0197]

[0198] Intermediate II (0.300 g, 1.26 mmol), 1-octyl-1H-indole-3-carbaldehyde (0.346 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-12 (0.444 g, 0.931 mmol), yield: 73.9%, melting point: 172.8–174.0 °C; 1 H NMR (600 MHz, DMSO) δ 10.44 (s, 1H, NHCOCH 3), 8.51 (s, 1H, indole-2-H), 8.49 (s, 1H, CH=C), 8.05 (d, J=6.6 Hz, 1H, indole-4-H), 7.93 (d, J=7.3 Hz, 2H, SO 2 -Ph-2,6-H), 7.85 (d, J=8.5 Hz, 2H, SO 2 -Ph-3,5-H), 7.70 (d, J=7.8 Hz, 1H, indole-7-H), 7.35 (dt, J=20.9, 6.7 Hz, 2H, indole-5,6-H), 4.35 (d, J=6.3 Hz, 2H, NCH 2 ), 2.09 (s, 3H, NHCOCH 3 ), 1.77 (m, 2H, NCH 2 CH 2 ), 1.29–1.12 (m, 10H, NCH 2 CH 2 (CH 2 ) 5 CH 3 ), 0.80 (d, J=6.6 Hz, 3H, CH 2 CH 3 ) ppm.

[0199] Example 52. Preparation of Compound I-6-12:

[0200]

[0201] Compound I-5-12 (0.185 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-12 (0.139 g, 0.320 mmol) with a yield of 82.6%; yellow solid; melting point: 189.2–190.6 °C; 1 1H NMR (600 MHz, DMSO) δ 8.45 (s, 1H, indole-2-H), 8.39 (s, 1H, CH=C), 8.01 (d, J=7.8 Hz, 1H, indole-4-H), 7.67 (d, J=8.1 Hz, 1H, indole-7-H), 7.60 (d, J=8.7 Hz, 2H, SO 2-Ph-2,6-H), 7.36 (t, J = 7.5 Hz, 1H, indole-6-H), 7.31 (t, J = 7.4 Hz, 1H, indole-5-H), 6.71 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 5.97 (s, 2H, NH 2 ), 4.34 (t, J = 6.8 Hz, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.76 (s, 2H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 1.21 (dd, J = 19.6, 11.8 Hz, 10H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 0.81 (t, J = 6.7 Hz, 3H, NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) ppm.

[0202] Example 53, Preparation of Intermediate I-5-13:

[0203]

[0204] Intermediate II (0.300 g, 1.26 mmol), 1-cyclopropylmethyl-1H-indole-3-carbaldehyde (0.301 g, 1.51 mmol), and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid Compound I-5-13 (0.398 g, 0.982 mmol), yield: 78.0%, melting point: 248.2–249.1 °C; 1 H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, NHCOCH 3 ), 8.63 (s, 1H, indole-2-H), 8.51 (s, 1H, CH=C), 8.06 (d, J = 7.7 Hz, 1H, indole-4-H), 7.95 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 7.74 (d, J = 7.6 Hz, 1H, indole-7-H), 7.36 (dt, J = 14.9, 7.1 Hz, 2H, indole-5,6-H), 4.23 (d, J = 6.9 Hz, 2H, NCH 2 ), 2.10 (s, 3H, NHCOCH 3 ), 1.35–1.26 (m, 1H, cyclopropane-1-H), 0.56 (d, J = 7.7 Hz, 2H, cyclopropane-H), 0.44 (d, J = 4.3 Hz, 2H, cyclopropane-H) ppm.

[0205] Example 54. Preparation of Compound I-6-13:

[0206]

[0207] Compound I-5-13 (0.170 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered off and the collected product was dried under vacuum to obtain Compound I-6-13 (0.117 g, 0.309 mmol), with a yield of 76.2%; yellow solid; melting point: 205.4–206.7 °C; 11H NMR (600 MHz, DMSO) δ 8.57 (s, 1H, indole-2-H), 8.40 (s, 1H, CH=C), 8.01 (d, J = 7.7 Hz, 1H, indole-4-H), 7.73 (d, J = 8.0 Hz, 1H, indole-7-H), 7.60 (d, J = 8.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.34 (dt, J = 23.6, 7.1 Hz, 2H, indole-5,6-H), 6.72 (d, J = 8.2 Hz, 2H, SO 2 -Ph-3,5-H), 6.29 (s, 2H, NH 2 ), 4.22 (d, J = 6.9 Hz, 2H, NCH 2 ), 1.31 (s, 1H, cyclopropane-H), 0.55 (d, J = 7.1 Hz, 2H, cyclopropane-H), 0.43 (d, J = 3.5 Hz, 2H, cyclopropane-H) ppm.

[0208] Example 55. Preparation of Intermediate I-5-14:

[0209]

[0210] Intermediate II (0.300 g, 1.26 mmol) and 1-cyclopentylmethyl-1H-indole-3-carbaldehyde (0.343 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-14 (0.417 g, 0.962 mmol), yield: 76.4%, melting point: 190.4–191.8 °C; 1 1H NMR (600 MHz, DMSO) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole-2-H), 8.50 (s, 1H, CH=C), 8.05 (d, J = 7.8 Hz, 1H, indole-4-H), 7.94 (d, J = 8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.9 Hz, 2H, SO 2-Ph-3,5-H), 7.73 (d, J = 7.9 Hz, 1H, indole-7-H), 7.40–7.30 (m, 2H, indole-5,6-H), 4.30 (d, J = 7.6 Hz, 2H, NCH 2 ), 2.38 (dt, J = 15.0, 7.5 Hz, 1H, cyclopentane-H), 2.10 (s, 3H, NHCOCH 3 ), 1.66–1.52 (m, 4H, cyclopentane-H), 1.53–1.44 (m, 2H, cyclopentane-H), 1.25 (dd, J = 11.5, 7.2 Hz, 2H, cyclopentane-H) ppm.

[0211] Example 56. Preparation of Compound I-6-14:

[0212]

[0213] Compound I-5-14 (0.185 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, after which heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-14 (0.133 g, 0.328 mmol) with a yield of 79.4%; yellow solid; melting point: 195.8–196.4 °C; 1 1H NMR (600 MHz, DMSO) δ 8.47 (s, 1H, indole-2-H), 8.39 (s, 1H, CH═C), 8.01 (d, J = 7.8 Hz, 1H, indole-4-H), 7.71 (d, J = 8.1 Hz, 1H, indole-7-H), 7.60 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.35 (t, J = 7.6 Hz, 1H, indole-6-H), 7.31 (t, J = 7.4 Hz, 1H, indole-5-H), 6.72 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.62 (s, 2H, NH 2 ), 4.29 (d, J = 7.5 Hz, 2H, NCH 2), 2.38 (dt, J = 14.8, 7.3 Hz, 1H, cyclopentane-H), 1.66–1.55 (m, 4H, cyclopentane-H), 1.49 (t, J = 9.2 Hz, 2H, cyclopentane-H), 1.24 (dd, J = 10.8, 7.1 Hz, 2H, cyclopentane-H) ppm。

[0214] Example 57. Preparation of Intermediate I-5-15:

[0215]

[0216] Intermediate II (0.300 g, 1.26 mmol) and 1-cyclohexylmethyl-1H-indole-3-carbaldehyde (0.343 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-15 (0.440 g, 0.985 mmol), yield: 78.2%, melting point: 223.4–224.1 °C; 1 H NMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3 ), 8.51 (s, 1H, indole-2-H), 8.46 (s, 1H, CH=C), 8.05 (d, J = 7.8 Hz, 1H, indole-4-H), 7.95 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.88 (d, J = 8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.71 (d, J = 8.0 Hz, 1H, indole-7-H), 7.35 (dt, J = 20.3, 7.2 Hz, 2H, indole-5,6-H), 4.21 (d, J = 7.1 Hz, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3), 1.81 (d, J = 3.2 Hz, 1H, cyclohexane-1-H), 1.63 (s, 2H, cyclohexane-H), 1.57 (s, 1H, cyclohexane-H), 1.49 (d, J = 12.2 Hz, 2H, cyclohexane-H), 1.15–1.05 (m, 3H, cyclohexane-H), 1.00 (t, J = 11.2 Hz, 2H, cyclohexane-H) ppm。

[0217] Example 58. Preparation of Compound I-6-15:

[0218]

[0219] Compound I-5-15 (0.190 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-15 (0.145 g, 0.347 mmol), with a yield of 84.2%; yellow solid; melting point: 160.3–161.5 °C; 1 H NMR (600 MHz, DMSO) δ 8.40 (s, 1H, indole-2-H), 8.39 (s, 1H, CH=C), 8.00 (d, J = 7.8 Hz, 1H, indole-4-H), 7.70 (d, J = 8.1 Hz, 1H, indole-7-H), 7.61 (d, J = 8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.35 (t, J = 7.6 Hz, 1H, indole-6-H), 7.31 (t, J = 7.4 Hz, 1H, indole-5-H), 6.73 (d, J = 8.3 Hz, 2H, SO 2 -Ph-3,5-H), 6.22 (s, 2H, NH 2 ), 4.20 (d, J = 6.9 Hz, 2H, NCH 2), 1.80 (d, J = 6.7 Hz, 1H, cyclohexane-H), 1.63 (s, 2H, cyclohexane-H), 1.57 (s, 1H, cyclohexane-H), 1.48 (d, J = 11.9 Hz, 2H, cyclohexane-H), 1.10 (d, J = 7.0 Hz, 3H, cyclohexane-H), 1.05–0.95 (m, 2H, cyclohexane-H) ppm。

[0220] Example 59. Preparation of Intermediate I-5-16:

[0221]

[0222] Intermediate II (0.300 g, 1.26 mmol) and 1-allyl-1H-indole-3-carbaldehyde (0.279 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave a yellow solid compound I-5-16 (0.412 g, 1.01 mmol), yield: 80.6%, melting point: 205.1–206.3 °C; 1 1H NMR (600 MHz, DMSO-d 6 6) δ 10.44 (s, 1H, NHCOCH 3 ), 8.51 (s, 2H, indole-2-H, CH=C), 8.06 (d, J = 7.3 Hz, 1H, indole-4-H), 7.94 (d, J = 8.4 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.1 Hz, 2H, SO 2 -Ph-3,5-H), 7.64 (d, J = 7.2 Hz, 1H, indole-7-H), 7.36 (dd, J = 15.3, 7.3 Hz, 2H, indole-5,6-H), 6.08–5.98 (m, 1H, CH 2 -CH=CH 2 ), 5.23 (d, J = 10.2 Hz, 1H, CH 2 -CH=CH 2 ), 5.16 (d, J = 17.1 Hz, 1H, CH 2 -CH=CH 2 ), 5.03 (s, 2H, CH 2 -CH=CH2 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0223] Example 60, Preparation of Compound I-6-16:

[0224]

[0225] Compound I-5-16 (0.165 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-16 (0.119 g, 0.326 mmol) with a yield of 80.1%; yellow solid; melting point: 191.6–192.3 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.46 (s, 1H, indole-2-H), 8.40 (s, 1H, CH=C), 8.01 (d, J = 7.7 Hz, 1H, indole-4-H), 7.62 (m, J = 14.1, 8.4 Hz, 3H, SO 2 -Ph-2,6-H, indole-6-H), 7.34 (dt, J = 19.0, 7.2 Hz, 2H, indole-5,7-H), 6.72 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.03 (ddd, J = 22.3, 10.6, 5.5 Hz, 1H, CH 2 -CH=CH 2 ), 5.23 (d, J = 10.2 Hz, 1H, CH 2 -CH=CH 2 ), 5.14 (d, J = 17.1 Hz, 2H, CH 2 -CH=CH 2 , NH 2 ), 5.03 (d, J = 5.3 Hz, 3H, CH 2 -CH=CH 2 , NH 2 ) ppm.

[0226] Example 61, Preparation of Intermediate I-5-17:

[0227]

[0228] Intermediate II (0.300 g, 1.26 mmol), 1-(3-methyl-2-en-1-yl)-1H-indole-3-carbaldehyde (0.322 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-17 (0.449 g, 1.03 mmol), yield: 82.1%, melting point: 212.6–214.0 °C; 1 H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, NHCOCH 3 ), 8.50 (s, 2H, indole-2-H, CH=C), 8.06 (d, J = 7.5 Hz, 1H, indole-4-H), 7.93 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.62 (d, J = 7.5 Hz, 1H, indole-7-H), 7.36 (dt, J = 14.9, 7.0 Hz, 2H, indole-5,6-H), 5.38 (s, 1H, C=CH), 4.95 (d, J = 5.8 Hz, 2H, NCH 2 ), 2.10 (s, 3H, NHCOCH 3 ), 1.82 (s, 3H, C=CH 3 ), 1.73 (s, 3H, C=CH 3 ) ppm.

[0229] Example 62: Preparation of compound I-6-17:

[0230]

[0231] Compound I-5-17 (0.185 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-6-17 (0.134 g, 0.343 mmol), with a yield of 80.4%; yellow solid; melting point: 197.6–198.9 °C; 11H NMR (600 MHz, DMSO) δ 8.44 (s, 1H, indole-2-H), 8.39 (s, 1H, CH=C), 8.01 (d, J = 7.8 Hz, 1H, indole-4-H), 7.61 (d, J = 8.7 Hz, 3H, indole-7-H, SO 2 -Ph-2,6-H), 7.36 (t, J = 7.6 Hz, 1H, indole-6-H), 7.32 (t, J = 7.5 Hz, 1H, indole-5-H), 6.73 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 6.65 (s, 2H, NH 2 ), 5.38 (t, J = 6.5 Hz, 1H, NCH 2 CH=C(CH 3 ) 2 ), 4.93 (d, J = 7.0 Hz, 2H, NCH 2 CH=C(CH 3 ) 2 ), 1.82 (s, 3H, NCH 2 CH=C(CH 3 ) 2 ), 1.73 (s, 3H, NCH 2 CH=C(CH 3 ) 2 ) ppm.

[0232] Example 63. Preparation of Intermediate I-5-18:

[0233]

[0234] Intermediate II (0.300 g, 1.26 mmol), 1-propynyl-1H-indole-3-carbaldehyde (0.322 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-18 (0.428 g, 1.06 mmol), yield: 84.2%, melting point: 265.6–266.4 °C; 1 1H NMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3), 8.62 (s, 1H, indole-2-H), 8.54 (s, 1H, CH=C), 8.08 (d, J=7.8 Hz, 1H, indole-4-H), 7.95 (d, J=8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J=8.6 Hz, 2H, SO 2 -Ph-3,5-H), 7.71 (d, J=8.1 Hz, 1H, indole-7-H), 7.42 (t, J=7.5 Hz, 1H, indole-6-H), 7.38 (t, J=7.4 Hz, 1H, indole-5-H), 5.36 (d, J=2.0 Hz, 2H, NCH 2 ), 3.60 (s, 1H, CCH), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0235] Example 64: Preparation of Compound I-6-18:

[0236]

[0237] Compound I-5-18 (0.185 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-18 (0.137 g, 0.378 mmol) with a yield of 82.4%; yellow solid; melting point: 194.8–196.2 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.56 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 8.02 (d, J=7.8 Hz, 1H, indole-4-H), 7.70 (d, J=8.1 Hz, 1H, indole-7-H), 7.62 (d, J=8.4 Hz, 2H, SO 2 -Ph-2,6-H), 7.40 (t, J=7.6 Hz, 1H, indole-6-H), 7.35 (t, J=7.5 Hz, 1H, indole-5-H), 6.75 (d, J=8.4 Hz, 2H, SO 2 -Ph-3,5-H), 5.55 (s, 2H, NH 2 ), 5.34 (s, 2H, NCH 2 ) ppm.

[0238] Example 65, Preparation of Intermediate I-5-19:

[0239]

[0240] Intermediate II (0.300 g, 1.26 mmol), 1-(2-hydroxyethyl)-1H-indole-3-carbaldehyde (0.286 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-19 (0.383 g, 0.934 mmol), yield: 74.2%, melting point: 242.0–243.7 °C; 1 1H NMR (600 MHz, DMSO) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole-2-H), 8.50 (s, 1H, CH═C), 8.05 (d, J = 7.6 Hz, 1H, indole-4-H), 7.94 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.70 (d, J = 7.9 Hz, 1H, indole-7-H), 7.39–7.29 (m, 2H, indole-5,6-H), 4.99 (t, J = 5.1 Hz, 1H, OH), 4.40 (t, J = 4.9 Hz, 2H, NCH 2 CH 2 OH), 3.75 (dd, J = 9.9, 5.0 Hz, 2H, NCH 2 CH 2 OH), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0241] Example 66, Preparation of Compound I-6-19:

[0242]

[0243] Compound I-5-19 (0.165 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion. Heating was stopped, and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation. The system was dropped into saturated sodium bicarbonate solution, and a solid precipitated. The solid was collected by filtration and dried under vacuum to obtain compound I-6-19 (0.118 g, 0.321 mmol) with a yield of 79.6%; yellow solid; melting point: 215.4–216.7 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.46 (s, 1H, indole-2-H), 8.38 (s, 1H, CH=C), 7.99 (d, J = 7.8 Hz, 1H, indole-4-H), 7.68 (d, J = 8.0 Hz, 1H, indole-7-H), 7.59 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.35 (t, J = 7.7 Hz, 1H, indole-6-H), 7.31 (t, J = 7.4 Hz, 1H, indole-5-H), 6.70 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 5.64 (s, 2H, NH 2 ), 4.39 (t, J = 5.2 Hz, 2H, NCH 2 CH 2 OH), 3.74 (t, J = 5.2 Hz, 2H, NCH 2 CH 2 OH) ppm.

[0244] Example 67. Preparation of Intermediate I-5-20:

[0245]

[0246] Intermediate II (0.300 g, 1.26 mmol), 1-(2-(dimethylamino)ethyl)-1H-indole-3-carbaldehyde (0.327 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and evaporated to dryness to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain a yellow solid compound I-5-20 (0.412 g, 0.943 mmol) with a yield of 74.9% and a melting point of 177.9–179.7 °C; 1 H NMR (600 MHz, DMSO-d 6)δ 10.45 (s, 1H, NHCOCH 3 ), 8.58 (s, 1H, indole-2-H), 8.49 (s, 1H, CH=C), 8.04 (d, J = 7.8 Hz, 1H, indole-4-H), 7.94 (d, J = 8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 7.70 (d, J = 8.0 Hz, 1H, indole-7-H), 7.37 (t, J = 7.5 Hz, 1H, indole-6-H), 7.33 (t, J = 7.4 Hz, 1H, indole-5-H), 4.43 (t, J = 6.1 Hz, 2H, NCH 2 CH 2 (CH 3 ) 2 ), 2.65 (t, J = 6.1 Hz, 2H, NCH 2 CH 2 (CH 3 ) 2 ), 2.17 (s, 6H, NCH 2 CH 2 (CH 3 ) 2 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0247] Example 68. Preparation of Compound I-6-20:

[0248]

[0249] Compound I-5-20 (0.165 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation. The system was dropped into saturated sodium bicarbonate solution, and a solid precipitated. The solid was filtered by suction and the collected product was dried under vacuum to obtain Compound I-6-20 (0.110 g, 0.269 mmol) with a yield of 71.2%; yellow solid; melting point: 189.4–191.7 °C; 1 1H NMR (600 MHz, DMSO-d 6)δ8.52(s,1H,indole-2-H),8.38(s,1H,CH=C),7.99(d,J=7.9Hz,1H,indole-4-H),7.68(d,J=8.1Hz,1H,indole-7-H),7.59(d,J=8.5Hz,2H,SO 2 -Ph-2,6-H),7.35(t,J=7.6Hz,1H,indole-6-H),7.31(t,J=7.5Hz,1H,indole-5-H),6.69(d,J=8.5Hz,2H,SO 2 -Ph-3,5-H),6.30(s,2H,NH 2 ),4.42(t,J=6.1Hz,2H,NCH 2 CH 2 (CH 3 ) 2 ),2.64(t,J=6.1Hz,2H,CH 2 CH 2 (CH 3 ) 2 ),2.17(s,6H,NCH 2 CH 2 (CH 3 ) 2 )ppm。

[0250] Example 69. Preparation of Intermediate I-5-21:

[0251]

[0252] Intermediate II (0.300 g, 1.26 mmol), 1-(2-morpholinoethyl)-1H-indole-3-carbaldehyde (0.390 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-21 (0.492 g, 1.03 mmol), yield: 81.6%, melting point: 234.0–236.0 °C; 1 H NMR (600 MHz, DMSO) δ10.44(s,1H,NHCOCH 3 ),8.66(s,1H,indole-2-H),8.50(s,1H,CH=C),8.03(d,J=7.8Hz,1H,indole-4-H),7.94(d,J=8.9Hz,2H,SO2 -Ph-2,6-H), 7.86 (d, J=8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.71 (d, J=7.9 Hz, 1H, indole-7-H), 7.35 (dt, J=19.3, 7.2 Hz, 2H, indole-5,6-H), 4.45 (t, J=5.6 Hz, 2H, indole-1-NCH 2 ), 3.53 (s, 4H, morpholino-CH), 2.68 (t, J=5.6 Hz, 2H, indole-1-NCH 2 CH 2 ), 2.42 (s, 4H, morpholino-CH), 2.10 (s, 3H, NHCOCH 3 ) ppm。

[0253] Example 70. Preparation of Compound I-6-21:

[0254]

[0255] Compound I-5-21 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, and then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-21 (0.135 g, 0.308 mmol) with a yield of 75.7%; yellow solid; melting point: 189.4–201.0 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.54 (s, 1H, indole-2-H), 8.40 (s, 1H, CH=C), 8.02 (d, J=7.9 Hz, 1H, indole-4-H), 7.89 (s, 1H, indole-7-H), 7.59 (d, J=8.4 Hz, 2H, SO 2 -Ph-2,6-H), 7.44–7.37 (m, 1H, indole-6-H), 7.38–7.32 (m, 1H, indole-5-H), 6.69 (d, J=8.5 Hz, 2H, SO 2 -Ph-3,5-H), 6.34 (s, 2H, NH 2 ), 4.90 (s, 2H, NCH 2 CH 2), 3.90 (d, J = 97.4 Hz, 4H, morpholino-CH), 3.61–3.40 (m, 4H, morpholino-CH), 3.14 (s, 2H, NCH 2 CH 2 ) ppm.

[0256] Example 71: Preparation of Intermediate I-5-22:

[0257]

[0258] Intermediate II (0.300 g, 1.26 mmol), 1-(2-fluorobenzyl)-1H-indole-3-carbaldehyde (0.390 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-22 (0.466 g, 0.985 mmol), yield: 78.2%, melting point: 202.5–203.6 °C; 1 1H NMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3 ), 8.63 (s, 1H, indole-2-H), 8.54 (s, 1H, CH=C), 8.07 (d, J = 6.8 Hz, 1H, indole-4-H), 7.95 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.6 Hz, 2H, SO 2 -Ph-3,5-H), 7.68 (d, J = 7.3 Hz, 1H, indole-7-H), 7.40–7.32 (m, 3H, indole-5,6-H, 2-F-Ph-4-H), 7.30 (t, J = 7.2 Hz, 1H, 2-F-Ph-3-H), 7.27–7.21 (m, 1H, 2-F-Ph-6-H), 7.17 (t, J = 7.5 Hz, 1H, 2-F-Ph-5-H), 5.70 (s, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0259] Example 72: Preparation of Compound I-6-22:

[0260]

[0261] Compound I-5-22 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, after which heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was collected by filtration and dried under vacuum to obtain compound I-6-22 (0.152 g, 0.352 mmol) with a yield of 85.4%; yellow solid; melting point: 196.2–197.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.57 (s, 1H, indole-2-H), 8.41 (s, 1H, CH=C), 8.02 (d, J = 7.6 Hz, 1H, indole-4-H), 7.66 (d, J = 7.9 Hz, 1H, indole-7-H), 7.61 (d, J = 8.2 Hz, 2H, SO 2 -Ph-2,6-H), 7.35 (dq, J = 23.4, 8.2, 7.8 Hz, 3H, indole-5,6-H, 2-F-Ph-4-H), 7.29 (q, J = 7.5, 6.7 Hz, 1H, 2-F-Ph-3-H), 7.23 (t, J = 9.4 Hz, 1H, 2-F-Ph-6-H), 7.16 (t, J = 7.5 Hz, 1H, 2-F-Ph-5-H), 6.73 (d, J = 8.5 Hz, 2H, SO 2 -Ph-3,5-H), 5.69 (s, 2H, NCH 2 ) ppm.

[0262] Example 73: Preparation of Intermediate I-5-23

[0263]

[0264] Intermediate II (0.300 g, 1.26 mmol), 1-(3-fluorobenzyl)-1H-indole-3-carbaldehyde (0.390 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation to obtain a crude product. The crude product was further purified by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) to obtain a yellow solid compound I-5-23 (0.479 g, 1.01 mmol) with a yield of 80.4% and a melting point of 232.4–233.6 °C; 1 HNMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3),8.69(s,1H,indole-2-H),8.54(s,1H,CH=C),8.11–8.02(m,1H,indole-4-H),7.96(d,J=8.8Hz,2H,SO 2 -Ph-2,6-H),7.88(d,J=8.8Hz,2H,SO 2 -Ph-3,5-H),7.66–7.61(m,1H,indole-7-H),7.41–7.36(m,1H,3-F-Ph-5-H),7.35(dd,J=9.9,5.8Hz,2H,indole-5,6-H),7.18(d,J=9.7Hz,1H,3-F-Ph-6-H),7.15–7.08(m,2H,3-F-Ph-2,4-H),5.68(s,2H,NCH 2 ,),2.11(s,3H,NHCOCH 3 )ppm。

[0265] Example 74. Preparation of Compound I-6-23:

[0266]

[0267] Compound I-5-23 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain Compound I-6-23 (0.151 g, 0.326 mmol) with a yield of 84.8%; yellow solid; melting point: 198.6–199.5 °C; 1 H NMR(600MHz,DMSO)δ8.63(s,1H,indole-2-H),8.42(s,1H,CH=C),8.02(dd,J=5.9,2.2Hz,1H,indole-4-H),7.62(dd,J=13.9,5.2Hz,3H,indole-7-H,SO 2-Ph-2,6-H), 7.37 (dd, J=14.2, 7.8 Hz, 1H, 3-F-Ph-5-H), 7.34–7.29 (m, 2H, indole-5,6-H), 7.17 (d, J=9.7 Hz, 1H, 3-F-Ph-6-H), 7.12 (dd, J=12.0, 5.1 Hz, 1H, 3-F-Ph-4-H), 7.08 (d, J=7.6 Hz, 1H, 3-F-Ph-2-H), 6.70 (d, J=8.8 Hz, 2H, SO 2 -Ph-3,5-H), 6.34 (s, 2H, NH 2 ), 5.66 (s, 2H, NCH 2 ) ppm.

[0268] Example 75. Preparation of Intermediate I-5-24:

[0269]

[0270] Intermediate II (0.300 g, 1.26 mmol), 1-(2,4-difluorobenzyl)-1H-indole-3-carbaldehyde (0.409 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-24 (0.490 g, 0.997 mmol), yield: 79.2%, melting point: 237.6–238.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.46 (s, 1H, NHCOCH 3 ), 8.61 (s, 1H, indole-2-H), 8.53 (s, 1H, CH=C), 8.06 (d, J=7.7 Hz, 1H, indole-4-H), 7.94 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J=8.8 Hz, 2H, SO 2-Ph-3,5-H), 7.68 (d, J = 7.7 Hz, 1H, indole-7-H), 7.41 (dd, J = 15.2, 8.4 Hz, 1H, indole-6-H), 7.39–7.32 (m, 2H, indole-5-H, 2,4-2F-Ph-6-H), 7.29 (dd, J = 14.1, 5.5 Hz, 1H, 2,4-2F-Ph-5-H), 7.07 (t, J = 7.5 Hz, 1H, 2,4-2F-Ph-3-H), 5.67 (s, 2H, NCH 2 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0271] Example 76. Preparation of Compound I-6-24:

[0272]

[0273] Compound I-5-24 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution. A solid precipitated, which was filtered by suction. The collected product was dried in vacuo to obtain Compound I-6-24 (0.146 g, 0.326 mmol), with a yield of 82.1%; yellow solid; melting point: 155.1–156.5 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.55 (s, 1H, indole-2-H), 8.41 (s, 1H, CH=C), 8.01 (d, J = 7.7 Hz, 1H, indole-4-H), 7.67 (d, J = 7.9 Hz, 1H, indole-7-H), 7.59 (d, J = 5.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.39 (q, J = 8.0 Hz, 1H, indole-6-H), 7.37–7.24 (m, 3H, indole-5-H, 2,4-2F-Ph-6-H), 7.06 (t, J = 8.3 Hz, 1H, 2,4-2F-Ph-3-H), 6.69 (d, J = 7.0 Hz, 2H, SO 2 -Ph-3,5-H), 5.66 (s, 2H, NCH 2 ) ppm.

[0274] Example 77. Preparation of Intermediate I-5-25:

[0275]

[0276] Intermediate II (0.300 g, 1.26 mmol), 1-(2-chlorobenzyl)-1H-indole-3-carbaldehyde (0.407 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-25 (0.493 g, 1.01 mmol), yield: 79.9%, melting point: 215.6–216.7 °C; 1 HNMR (600 MHz, DMSO) δ 10.46 (s, 1H, NH), 8.59 (s, 1H, indole-2-H), 8.55 (s, 1H, CH=C), 8.12–8.06 (m, 1H, indole-4-H), 7.95 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.61 (dd, J = 6.0, 3.0 Hz, 1H, indole-7-H), 7.53 (d, J = 7.9 Hz, 1H, 2-Cl-Ph-3-H), 7.39–7.33 (m, 3H, indole-5,6-H, 2-Cl-Ph-4-H), 7.29 (t, J = 7.5 Hz, 1H, 2-Cl-Ph-5-H), 7.04 (d, J = 7.6 Hz, 1H, 2-Cl-Ph-6-H), 5.72 (s, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0277] Example 78. Preparation of compound I-6-25:

[0278]

[0279] Compound I-5-25 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered off and the collected product was dried in vacuo to obtain compound I-6-25 (0.144 g, 0.321 mmol), with a yield of 80.7%; yellow solid; melting point: 250.0–251.7 °C; 11H NMR (600 MHz, DMSO-d 6 ) δ 8.53 (s, 1H, indole-2-H), 8.43 (s, 1H, CH=C), 8.06–8.02 (m, 1H, indole-4-H), 7.60 (td, J=7.9, 6.9, 3.4 Hz, 3H, SO 2 -Ph-2,6-H, indole-7-H), 7.52 (d, J=8.0 Hz, 1H, 2-Cl-Ph-3-H), 7.38–7.31 (m, 3H, indole-5,6-H, 2-Cl-Ph-4-H), 7.28 (t, J=7.5 Hz, 1H, 2-Cl-Ph-5-H), 7.02 (d, J=7.5 Hz, 1H, 2-Cl-Ph-6-H), 6.72 (dd, J=9.0, 2.7 Hz, 2H, SO 2 -Ph-3,5-H), 5.71 (s, 2H, NH 2 ) ppm。

[0280] Example 79. Preparation of Intermediate I-5-26:

[0281]

[0282] Intermediate II (0.300 g, 1.26 mmol), 1-(3-chlorobenzyl)-1H-indole-3-carbaldehyde (0.407 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-26 (0.520 g, 1.06 mmol), yield: 84.2%, melting point: 200.6–202.2 °C; 1 1H NMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3 ), 8.70 (s, 1H, indole-2-H), 8.53 (s, 1H, CH=C), 8.07 (dd, J=4.4, 3.2 Hz, 1H, indole-4-H), 7.96 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J=8.8 Hz, 2H, SO 2-Ph-3,5-H), 7.67–7.59 (m, 1H, indole-7-H), 7.43 (s, 1H, 3-Cl-Ph-2-H), 7.35 (dd, J=10.2, 4.4 Hz, 4H, indole-5,6-H, 3-Cl-Ph-4,5-H), 7.22 (d, J=2.7 Hz, 1H, 3-Cl-Ph-6-H), 5.67 (s, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0283] Example 80, Preparation of Compound I-6-26:

[0284]

[0285] Compound I-5-26 (0.195 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-6-26 (0.148 g, 0.331 mmol) with a yield of 83.2%; yellow solid; melting point: 176.1–177.2 °C; 1 1H NMR (600 MHz, DMSO) δ 8.64 (s, 1H, indole-2-H), 8.42 (d, J=1.5 Hz, 1H, CH=C), 8.02 (d, J=7.0 Hz, 1H, indole-4-H), 7.62 (t, J=6.8 Hz, 3H, indole-7-H, SO 2 -Ph-2,6-H), 7.42 (s, 1H, 3-Cl-Ph-2-H), 7.35 (d, J=4.8 Hz, 2H, 3-Cl-Ph-4,6-H), 7.32 (dd, J=11.7, 6.5 Hz, 2H, indole-5,6-H), 7.20 (d, J=4.2 Hz, 1H, 3-Cl-Ph-5-H), 6.75 (d, J=18.3 Hz, 2H, SO 2 -Ph-3,5-H), 5.66 (s, 2H, NCH 2 ) ppm.

[0286] Example 81, Preparation of Intermediate I-5-27:

[0287]

[0288] Intermediate II (0.300 g, 1.26 mmol), 1-(2,4-dichlorobenzyl)-1H-indole-3-carbaldehyde (0.460 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-27 (0.528 g, 1.01 mmol), yield: 79.9%, melting point: 280.1–281.3 °C; 1 H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, NHCOCH 3 ), 8.60 (s, 1H, indole-2-H), 8.54 (s, 1H, CH=C), 8.09 (dd, J=6.1, 2.7 Hz, 1H, indole-4-H), 7.95 (d, J=8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J=8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.70 (d, J=1.6 Hz, 1H, 2,4-2Cl-Ph-5-H), 7.59 (dd, J=5.9, 2.8 Hz, 1H, indole-7-H), 7.40–7.29 (m, 3H, indole-5,6-H, 2,4-2Cl-Ph-3-H), 7.01 (d, J=8.4 Hz, 1H, 2,4-2Cl-Ph-6-H), 5.71 (s, 2H, NCH 2 ), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0289] Example 82. Preparation of compound I-6-27:

[0290]

[0291] Compound I-5-27 (0.215 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried in vacuo to obtain compound I-6-27 (0.166 g, 0.343 mmol), with a yield of 83.7%; yellow solid; melting point: 250.0–251.7 °C; 1 H NMR (600 MHz, DMSO-d 6)δ8.65(s,1H,indole-2-H),8.42(s,1H,CH=C),8.03(d,J=6.9Hz,1H,indole-4-H),7.66(s,1H,2,4-2Cl-Ph-3-H),7.63(d,J=8.6Hz,3H,SO 2 -Ph-2,6-H,indole-7-H),7.58(d,J=8.3Hz,1H,2,4-2Cl-Ph-5-H),7.32(dd,J=6.3,3.5Hz,2H,indole-5,6-H),7.21(d,J=8.3Hz,1H,2,4-2Cl-Ph-6-H),6.75(d,J=8.7Hz,2H,SO 2 -Ph-3,5-H),5.66(s,2H,CH 2 )ppm。

[0292] Example 83. Preparation of Intermediate I-5-28:

[0293]

[0294] Intermediate II (0.300 g, 1.26 mmol), 1-(3,4-dichlorobenzyl)-1H-indole-3-carbaldehyde (0.460 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-28 (0.554 g, 1.06 mmol), yield: 83.9%, melting point: 237.6–239.2 °C; 1 H NMR (600 MHz, DMSO) δ10.46(s,1H,NHCOCH 3 ),8.70(s,1H,indole-2-H),8.53(s,1H,CH=C),8.14–8.01(m,1H,indole-4-H),7.95(d,J=8.9Hz,2H,SO 2 -Ph-2,6-H),7.87(d,J=8.9Hz,2H,SO 2-Ph-3,5-H), 7.67 (s, 1H, 3,4-2Cl-Ph-2-H), 7.65–7.61 (m, 1H, indole-7-H), 7.58 (d, J=8.3 Hz, 1H, 3,4-2Cl-Ph-5-H), 7.34 (p, J=6.2 Hz, 2H, indole-5,6-H), 7.22 (dd, J=8.3, 1.7 Hz, 1H, 3,4-2Cl-Ph-6-H), 5.66 (s, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0295] Example 84, Preparation of Compound I-6-28:

[0296]

[0297] Compound I-5-28 (0.215 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried in vacuo to obtain Compound I-6-28 (0.166 g, 0.345 mmol), with a yield of 84.1%; yellow solid; melting point: 215.2–216.5 °C; 1 1H NMR (600 MHz, DMSO) δ 8.65 (s, 1H, indole-2-H), 8.42 (s, 1H, CH=C), 8.02 (dd, J=6.2, 1.9 Hz, 1H, indole-4-H), 7.66 (s, 1H, 3,4-2Cl-Ph-5-H), 7.61 (t, J=7.1 Hz, 3H, SO 2 -Ph-2,6-H, 3,4-2Cl-Ph-2-H), 7.58 (d, J=8.3 Hz, 1H, 3,4-2Cl-Ph-6-H), 7.36–7.29 (m, 2H, indole-5,6-H), 7.21 (dd, J=8.3, 1.6 Hz, 1H, indole-7-H), 6.71 (d, J=8.7 Hz, 2H, SO 2 -Ph-3,5-H), 5.77 (s, 2H, NH 2 ), 5.66 (s, 2H, NCH 2 ) ppm.

[0298] Example 85, Preparation of Intermediate I-5-29:

[0299]

[0300] Intermediate II (0.300 g, 1.26 mmol), 1-(4-nitrobenzyl)-1H-indole-3-carbaldehyde (0.423 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-29 (0.494 g, 0.986 mmol), yield: 78.3%, melting point: 209.2–210.5 °C; 1 H NMR (600 MHz, DMSO) δ 10.46 (s, 1H, NHCOCH 3 ), 8.74 (s, 1H, indole-2-H), 8.55 (s, 1H, CH=C), 8.19 (d, J = 8.6 Hz, 2H, 4-NO 2 -Ph-3,5-H), 8.11–8.05 (m, 1H, indole-4-H), 7.96 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.61–7.53 (m, 1H, indole-7-H), 7.49 (d, J = 8.6 Hz, 2H, 4-NO 2 -Ph-2,6-H), 7.34 (p, J = 8.9 Hz, 2H, indole-5,6-H), 5.85 (s, 2H, NCH 2 ), 2.11 (s, 3H, NHCOCH 3 ) ppm.

[0301] Example 86. Preparation of compound I-6-29:

[0302]

[0303] Compound I-5-29 (0.200 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by TLC until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered off and the collected product was dried in vacuo to obtain compound I-6-29 (0.158 g, 0.345 mmol), yield 86.4%; yellow solid; melting point 263.2–264.8 °C; 11H NMR (600 MHz, DMSO) δ 8.69 (s, 1H, indole-2-H), 8.45 (s, 1H, CH=C), 8.19 (d, J = 8.2 Hz, 2H, 4-NO 2 -Ph-3,5-H), 8.04 (d, J = 4.3 Hz, 1H, indole-4-H), 7.64 (d, J = 6.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.57 (d, J = 4.5 Hz, 1H, indole-7-H), 7.48 (d, J = 8.3 Hz, 2H, 4-NO 2 -Ph-2,6-H), 7.36–7.29 (m, 2H, indole-5,6-H), 6.76 (d, J = 7.4 Hz, 2H, SO 2 -Ph-3,5-H), 5.84 (s, 2H, NCH 2 ) ppm.

[0304] Example 87. Preparation of Compound I-5-30:

[0305]

[0306] Intermediate II (0.300 g, 1.26 mmol), 1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-3-carbaldehyde (0.423 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid Compound I-5-30 (0.457 g, 0.96 mmol), yield: 76.2%, melting point: 220.1–222.0 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole-2-H), 8.47 (s, 1H, CH=C), 8.03 (d, J = 8.8 Hz, 1H, indole-4-H), 7.95 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.7 Hz, 2H, SO 2-Ph-3,5-H), 7.59 (d, J = 8.4 Hz, 1H, indole-7-H), 7.36–7.30 (m, 2H, indole-5,6-H), 5.33 (s, 2H, NCH 2 ), 3.59 (t, J = 6.8 Hz, 2H, pyrrolidine-H), 3.31 (t, J = 7.1 Hz, 4H, pyrrolidine-H, H 2 O) 2.10 (s, 3H, NHCOCH 3 ), 1.96 (p, J = 6.9 Hz, 2H, pyrrolidine-H), 1.80 (p, J = 6.9 Hz, 2H, pyrrolidine-H) ppm。

[0307] Example 88: Preparation of Compound I-5-31:

[0308]

[0309] Intermediate II (0.300 g, 1.26 mmol), 1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-indole-3-carbaldehyde (0.423 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid Compound I-5-31 (0.489 g, 1.00 mmol), yield: 79.1%, melting point: 231.1–232.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.43 (s, 1H, NHCOCH 3 ), 8.51 (s, 1H, indole-2-H), 8.46 (s, 1H, CH=C), 8.02 (d, J = 8.1 Hz, 1H, indole-4-H), 7.94 (d, J = 9.0 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.9 Hz, 2H, SO 2 -Ph-3,5-H), 7.53 (d, J = 7.4 Hz, 1H, indole-7-H), 7.36–7.30 (m, 2H, indole-5,6-H), 5.44 (s, 2H, NCH 2), 3.50 (s, 2H, piperidin-H), 3.42 (t, J = 5.6 Hz, 2H, piperidin-H), 2.10 (s, 3H, CH 3 ), 1.62 (s, 4H, piperidin-H), 1.46 (s, 2H, piperidin-H) ppm.

[0310] Example 89. Preparation of Compound I-5-32:

[0311]

[0312] Intermediate II (0.300 g, 1.26 mmol), 1-(2-morpholin-2-oxoethyl)-1H-indole-3-carbaldehyde (0.411 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid Compound I-5-32 (0.464 g, 0.943 mmol), yield: 74.8%, melting point: 261.2–262.8 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole-2-H), 8.46 (s, 1H, CH=C), 8.03 (d, J = 8.5 Hz, 1H, indole-4-H), 7.94 (d, J = 8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.86 (d, J = 8.6 Hz, 2H, SO 2 -Ph-3,5-H), 7.57 (d, J = 7.2 Hz, 1H, indole-7-H), 7.37–7.31 (m, 2H, indole-5,6-H), 5.46 (s, 2H, NCH 2 ), 3.70 (d, J = 4.5 Hz, 2H, morpholino-H), 3.58 (dt, J = 17.7, 4.8 Hz, 4H, morpholino-H), 3.44 (d, J = 5.1 Hz, 2H, morpholino-H), 2.10 (s, 3H, NHCOCH 3 ) ppm.

[0313] Example 90. Preparation of Compound I-5-33:

[0314]

[0315] Intermediate II (0.300 g, 1.26 mmol), N,N - diethyl - 2 - (3 - formyl - 1H - indol - 1 - yl) acetamide (0.390 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I - 5 - 33 (0.479 g, 1.00 mmol), yield: 79.5%, melting point: 273.6–274.8 °C; 1 H NMR (600 MHz, DMSO - d 6 ) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole - 2 - H), 8.49 (s, 1H, CH=C), 8.03 (d, J = 8.7 Hz, 1H, indole - 4 - H), 7.94 (d, J = 8.9 Hz, 2H, SO 2 -Ph - 2,6 - H, 7.87 (d, J = 8.8 Hz, 2H, SO 2 -Ph - 3,5 - H), 7.49 (d, J = 7.0 Hz, 1H, indole - 7 - H), 7.36–7.30 (m, 2H, indole - 5,6 - H), 5.42 (s, 2H, NCH 2 ), 3.46 (q, J = 7.1 Hz, 2H, N(CH 2 CH 3 ) 2 ), 3.28 (t, J = 7.1 Hz, 2H, N(CH 2 CH 3 ) 2 ), 2.10 (s, 3H, NHCOCH 3 ), 1.25 (t, J = 7.1 Hz, 3H, N(CH 2 CH 3 ) 2 ), 1.03 (t, J = 7.1 Hz, 3H, N(CH 2 CH 3 ) 2 ) ppm.

[0316] Example 91: Preparation of Compound I - 5 - 34:

[0317]

[0318] Intermediate II (0.300 g, 1.26 mmol), 2-(3-formyl-1H-indol-1-yl)-N,N-diisopropylethylamine (0.432 g, 1.51 mmol), and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-34 (0.487 g, 0.96 mmol), yield: 76.4%, melting point: 285.8–286.5 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.44 (s, 1H, NHCOCH 3 ), 8.52 (s, 1H, indole-2-H), 8.46 (s, 1H, CH=C), 8.03 (d, J = 7.9 Hz, 1H, indole-4-H), 7.95 (d, J = 8.9 Hz, 2H, SO 2 -Ph-2,6-H, 7.87 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 7.46 (d, J = 7.6 Hz, 1H, indole-7-H), 7.33 (p, J = 6.9 Hz, 2H, indole-5,6-H), 5.38 (s, 2H, NCH 2 ), 4.07 (p, J = 6.7 Hz, 1H, N(CH(CH 3 ) 2 ) 2 ), 3.52 (p, J = 6.8 Hz, 1H, N(CH(CH 3 ) 2 ) 2 ), 2.10 (s, 3H, CH 3 ), 1.25 (d, J = 6.7 Hz, 12H, N(CH(CH 3 ) 2 ) 2 ) ppm.

[0319] Example 92: Preparation of Compound I-5-35:

[0320]

[0321] Intermediate II (0.300 g, 1.26 mmol), ethyl 2-(3-formyl-1H-indol-1-yl)acetate (0.349 g, 1.51 mmol), and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid Compound I-5-35 (0.422 g, 0.94 mmol), yield: 74.2%, melting point: 226.5–227.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.45 (s, 1H, NHCOCH 3 ), 8.57 (s, 1H, indole-2-H), 8.53 (s, 1H, CH=C), 8.04 (d, J = 8.2 Hz, 1H, indole-4-H), 7.95 (d, J = 8.5 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 7.60 (d, J = 7.2 Hz, 1H, indole-7-H), 7.36 (dd, J = 11.3, 6.0 Hz, 2H, indole-5,6-H), 5.40 (s, 2H, NCH 2 ), 4.17 (q, J = 7.0 Hz, 2H, COOCH 2 CH 3 ), 2.10 (s, 3H, NHCOCH 3 ), 1.21 (t, J = 7.1 Hz, 3H, COOCH 2 CH 3 ) ppm.

[0322] Example 93. Preparation of Compound I-5-36:

[0323]

[0324] Intermediate II (0.300 g, 1.26 mmol), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.370 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-36 (0.428 g, 0.92 mmol), yield: 73.0%, melting point: 186.4–187.6 °C; 1 H NMR(600MHz,DMSO-d 6 )δ10.49(s,1H,NHCOCH 3 ),8.70(s,1H,indole-2-H),8.60(s,1H,CH=C),8.12(d,J=8.4Hz,1H,indole-4-H),8.07(d,J=8.0Hz,1H,indole-7-H),7.99(d,J=8.5Hz,2H,SO 2 -Ph-2,6-H),7.90(d,J=8.8Hz,2H,SO 2 -Ph-3,5-H),7.49(t,J=7.8Hz,1H,indole-6-H),7.43(t,J=7.4Hz,1H,indole-5-H),2.11(s,3H,CH 3 ),1.65(s,9H,C(CH 3 ) 3 )ppm.

[0325] Example 94: Preparation of Compound I-5-37:

[0326]

[0327] Intermediate II (0.300 g, 1.26 mmol), tert-butyl 3-formyl-1H-indole-1-carboxylate (0.392 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-5-37 (0.431 g, 0.90 mmol), yield: 71.4%, melting point: 131.4–132.6 °C; 1 H NMR(600MHz,DMSO-d 6) δ 10.45 (s, 1H, NHCOCH 3 ), 8.55 (s, 1H, indole-2-H), 8.53 (s, 1H, CH=C), 8.05 (d, J = 7.5 Hz, 1H, indole-4-H), 7.95 (d, J = 8.7 Hz, 2H, SO 2 -Ph-2,6-H), 7.87 (d, J = 8.7 Hz, 2H, SO 2 -Ph-3,5-H), 7.57 (d, J = 7.8 Hz, 1H, indole-7-H), 7.39–7.36 (m, 1H, indole-6-H), 7.34 (d, J = 7.3 Hz, 1H, indole-5-H), 5.29 (s, 2H, NCH 2 ), 2.10 (s, 3H, NHCOCH 3 ), 1.42 (s, 9H, C(CH 3 ) 3 ) ppm.

[0328] Example 95. Preparation of Intermediate I-7-1:

[0329]

[0330] Intermediate II (0.300 g, 1.26 mmol), benzofuran-2-carbaldehyde (0.221 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-7-1 (0.494 g, 0.986 mmol), yield: 78.3%, melting point: 242.7–243.8 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, NHCOCH 3 ), 8.49 (s, 1H, C=CH), 7.99 (s, 1H, benzofuran-8-H), 7.95 (d, J = 9.0 Hz, 2H, SO 2 -Ph-2,6-H), 7.91 (d, J = 9.1 Hz, 2H, SO 2-Ph-3,5-H), 7.88 (d, J = 7.9 Hz, 1H, benzofuran-3-H), 7.68 (d, J = 8.4 Hz, 1H, benzofuran-6-H), 7.58 (t, J = 7.7 Hz, 1H, benzofuran-4-H), 7.40 (t, J = 7.6 Hz, 1H, benzofuran-5-H), 2.12 (s, 3H, NHCOCH 3 ).

[0331] Example 96. Preparation of Compound I-8-1:

[0332]

[0333] Compound I-7-1 (0.150 g, 0.41 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask. Then, 0.2 mL of concentrated hydrochloric acid was added dropwise, and the mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. Ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction, and the collected product was dried under vacuum to obtain Compound I-8-1 (0.121 g, 0.37 mmol) with a yield of 91.1%; yellow solid; melting point: 198.7–200.2 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.34 (s, 1H, C=CH), 7.91 (s, 1H, benzofuran-8-H), 7.86 (d, J = 7.9 Hz, 1H, benzofuran-3-H), 7.67 (d, J = 8.4 Hz, 1H, benzofuran-6-H), 7.60 (d, J = 8.6 Hz, 2H, SO 2 -Ph-2,6-H), 7.56 (t, J = 7.9 Hz, 1H, benzofuran-4-H), 7.38 (t, J = 7.5 Hz, 1H, benzofuran-5-H), 6.74 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 6.52 (s, 2H, NH 2 ).

[0334] Example 97. Preparation of Intermediate I-7-2:

[0335]

[0336] Intermediate II (0.300 g, 1.26 mmol), benzothiophene-2-carbaldehyde (0.245 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain the crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-7-2 (0.401 g, 1.05 mmol), yield: 83.2%, melting point: 282.3–283.6 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.52 (s, 1H, NHCOCH 3 ), 8.97 (s, 1H, C=CH), 8.63 (s, 1H, benzothiophene-2-H), 8.17 (dd, J=15.0, 8.1 Hz, 2H, benzothiophene-4-H, benzothiophene-7-H), 8.03 (d, J=8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.91 (d, J=9.0 Hz, 2H, SO 2 -Ph-3,5-H), 7.63–7.57 (m, 1H, benzothiophene-6-H), 7.55 (t, J=7.1 Hz, 1H, benzothiophene-5-H), 2.11 (s, 3H, NHCOCH 3 ).

[0337] Example 98. Preparation of compound I-8-2:

[0338]

[0339] Compound I-7-2 (0.150 g, 0.40 mmol) and 5 mL of ethanol were added to a 25 mL round-bottom flask, and then 0.2 mL of concentrated hydrochloric acid was added dropwise. The mixture was refluxed at 90 °C for 8 h. The reaction was monitored by thin-layer chromatography until completion, then heating was stopped and the mixture was cooled to room temperature. The ethanol was removed by rotary evaporation, and the system was dropped into saturated sodium bicarbonate solution to precipitate a solid. The solid was filtered by suction and the collected product was dried under vacuum to obtain compound I-8-2 (0.118 g, 0.35 mmol), yield: 88.3%; yellow solid; melting point: 279.7–280.3 °C; 1 H NMR (600 MHz, DMSO-d 6)δ 8.88 (s, 1H, C=CH), 8.50 (s, 1H, benzothiophene-2-H), 8.14 (t, J = 8.8 Hz, 2H, benzothiophene-4-H, benzothiophene-7-H), 7.66 (d, J = 8.8 Hz, 2H, SO 2 -Ph-2,6-H), 7.58 (t, J = 7.5 Hz, 1H, benzothiophene-6-H), 7.53 (t, J = 7.5 Hz, 1H, benzothiophene-5-H), 6.72 (d, J = 8.8 Hz, 2H, SO 2 -Ph-3,5-H), 6.48 (s, 2H, NH 2 ).

[0340] Example 99, Preparation of Intermediate I-7-3:

[0341]

[0342] Intermediate II (0.300 g, 1.26 mmol), 1H-benzo[d]imidazole-2-carbaldehyde (0.221 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-7-3 (0.321 g, 0.876 mmol), yield: 69.6%, melting point: 280.7–282.3 °C; 1 1H NMR (600 MHz, DMSO-d 6 ) δ 13.37 (s, 1H, benzimidazole-1-H), 10.54 (s, 1H, NHCOCH 3 ), 8.33 (s, 1H, CH=C)), 7.97 (d, J = 9.0 Hz, 2H, SO 2 -Ph-2,6-H), 7.92 (d, J = 9.0 Hz, 2H, SO 2 -Ph-3,5-H), 7.74 (s, 2H, benzimidazole-4,7-H), 7.37 (s, 2H, benzimidazole-5,6-H), 2.12 (s, 3H, NHCOCH 3 ).

[0343] Example 100, Preparation of Intermediate I-7-4:

[0344]

[0345] Intermediate II (0.300 g, 1.26 mmol), benzothiazole-2-carbaldehyde (0.423 g, 1.51 mmol) and piperidine (0.030 g, 0.36 mmol) were reacted in an ethanol solution at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated to obtain a crude product. Further purification by silica gel column chromatography (eluent: dichloromethane / methanol, 30 / 1–10 / 1, V / V) gave the yellow solid compound I-7-4 (0.376 g, 0.980 mmol), yield: 77.9%, melting point: 284.2–285.5 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.55 (s, 1H, NHCOCH 3 ), 8.76 (s, 1H, CH=C), 8.32 (d, J = 8.4 Hz, 1H, benzothiazole-4-H), 8.19 (d, J = 7.4 Hz, 1H, benzothiazole-7-H), 8.02 (d, J = 8.9 Hz, 2H, SO 2 -Ph-2,6-H), 7.93 (d, J = 9.0 Hz, 2H, SO 2 -Ph-3,5-H), 7.70–7.62 (m, 2H, benzothiazole-5,6-H), 2.12 (s, 3H, NHCOCH 3 ).

[0346] Note: Ph represents a benzene ring.

[0347] Example 101, In Vitro Antimicrobial Activity of Cyanoethenylsulfonanilide Compounds

[0348] Using the serial dilution method of the clinical experimental standards formulated by the National Committee of the United States (Clinical and Laboratory Standards Institute, CLSI), the minimum inhibitory concentration (MIC) of the cyanoethenylsulfonanilide compounds prepared in Examples 13 to 100 against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii) was detected. The compound to be tested was dissolved in a small amount of dimethyl sulfoxide, and then diluted with water to prepare a solution with a concentration of 1.28 mg / mL, and then diluted with the culture medium to 256 μg / mL. After culturing at 35 °C for 24 to 72 hours, the culture plate was shaken well on the oscillator, and the MIC was measured at a wavelength of 490 nm. The results are shown in Tables 1 and 2.

[0349] Table 1. In vitro antibacterial activities (MIC, μg / mL) of the cyanoethenylsulfonanilide five-membered heterocyclic compounds prepared in Examples 13 to 28

[0350]

[0351]

[0352] Table 2. In vitro antibacterial activities (MIC, μg / mL) of the cyanoethenylsulfonanilide benzheterocyclic compounds prepared in Examples 29 to 100

[0353]

[0354]

[0355]

[0356] As can be seen from Table 1, the cyanoethenylsulfonanilide five-membered heterocyclic compounds in the present invention exhibit certain inhibitory effects on the tested bacteria, especially showing anti-MRSA activity. The phenylthiazole-substituted compound I-3-5 (MIC = 0.5 μg / mL) exhibits significant antibacterial activity against MRSA, which is significantly better than the reference drug norfloxacin (MIC = 8 μg / mL). As can be seen from Table 2, most of the newly synthesized cyanoethenylsulfonanilide benzheterocyclic compounds have good biological activities against the tested bacteria, especially Acinetobacter baumannii and Escherichia coli ATCC 25922. The hydroxyethyl derivative I-6-19 exhibits high antibacterial activities against Escherichia coli ATCC 25922 and Acinetobacter baumannii, with MIC values both being 0.5 μg / mL, which is 8 times that of the reference drug norfloxacin (MIC values are both 4 μg / mL). In addition, the antibacterial activities of some compounds can be comparable to or even stronger than that of the reference drug norfloxacin.

[0357] Example 102, Pharmaceutical Use of Cyanoethenylsulfonanilide Compounds

[0358] According to the above antimicrobial activity test results, the cyanoethenylsulfonanilide compounds of the present invention have good antibacterial activities and can be made into antibacterial drugs for clinical use. These drugs can be either single-agent preparations, such as those made from a cyanoethenylsulfonanilide compound of one structure and pharmaceutically acceptable excipients; or compound preparations, such as those made from a cyanoethenylsulfonanilide compound of one structure and existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphofluconazole, itraconazole, etc.) and pharmaceutically acceptable excipients, or those made from several cyanoethenylsulfonanilide compounds of different structures and pharmaceutically acceptable excipients. The dosage form types include but are not limited to tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal absorption patches and other dosage forms, as well as various sustained-release, controlled-release preparations and nano-preparations.

[0359] 1. Preparation of Compound I-1-1 Tablets

[0360] Formulation: 10 g of Compound I-1-1, 50 g of corn starch, 187 g of lactose, 3.0 g of magnesium stearate, an appropriate amount of ethanol solution with a volume percentage concentration of 70%, and a total of 1000 tablets are prepared.

[0361] Preparation method: Dry the corn starch at 105 °C for 5 hours and reserve it; mix Compound I-1-1 with lactose and corn starch evenly, make soft materials with 70% ethanol solution, pass through a sieve to make wet granules, then add magnesium stearate and press tablets to obtain; each tablet weighs 250 mg and the active ingredient content is 10 mg.

[0362] 2. Preparation of Compound I-1-6 Capsules

[0363] Prescription: 25 g of Compound I-1-6, 12.5 g of modified starch (120 mesh), 7.5 g of microcrystalline cellulose (100 mesh), 2.5 g of low-substituted hydroxypropyl cellulose (100 mesh), 2.0 g of talc powder (100 mesh), 1.25 g of sweetener, 0.25 g of orange essence, appropriate amount of pigment, appropriate amount of water, to make 1000 capsules.

[0364] Preparation method: After micronizing and pulverizing the prescribed amount of Compound I-1-6 into extremely fine powder, mix it evenly with the prescribed amount of modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc powder, sweetener, orange essence and pigment, make soft material with water, granulate through a 12–14 mesh sieve, dry at 40–50 °C, sieve and size the granules, and fill into empty capsules to obtain; each tablet weighs 50 mg and the active ingredient content is 25 mg.

[0365] 3. Preparation of Compound I-3-3 Granules

[0366] Prescription: 26 g of Compound I-3-3, 120 g of dextrin, 280 g of sucrose.

[0367] Preparation method: Mix Compound I-3-3, dextrin and sucrose evenly, granulate by wet method, dry at 60 °C, and pack to obtain.

[0368] 4. Preparation of Compound I-3-5 Injection

[0369] Prescription: 10 g of Compound I-3-5, 500 mL of propylene glycol, 500 mL of injection water, to make 1000 mL in total.

[0370] Preparation method: Weigh Compound I-3-5, add propylene glycol and injection water, stir to dissolve, then add 1 g of activated carbon, stir well and let stand for 15 minutes, filter and remove carbon with a 5 μm titanium rod, and then filter and refine successively with microporous membranes with pore sizes of 0.45 μm and 0.22 μm, and finally fill and seal in 10 mL ampoules, sterilize in flowing steam at 100 °C for 45 minutes to obtain.

[0371] 5. Preparation of Compound I-4-3 Powder for Injection

[0372] Preparation method: The sterile powder of Intermediate I-4-3 is packed under sterile conditions to obtain.

[0373] 6. Preparation of Compound I-5-15 Eye Drops

[0374] Prescription: 3.78 g of Compound I-5-15, 0.9 g of sodium chloride, appropriate amount of boric acid buffer solution, add distilled water to 1000 mL.

[0375] Preparation method: Weigh compound I-5-15 and sodium chloride, add them to 500 mL of distilled water. After complete dissolution, adjust the pH to 6.5 with boric acid buffer solution, add distilled water to 1000 mL, stir evenly, filter through a microporous membrane, fill, seal, and sterilize with flowing steam at 100 °C for 1 hour to obtain the product.

[0376] 7. Preparation of Compound I-5-17 Liniment

[0377] Prescription: 4 g of compound I-5-17, 7.5 g of potassium soap, 5 g of camphor, add distilled water to 100 mL.

[0378] Preparation method: Dissolve camphor in ethanol solution with a volume percentage concentration of 95% for standby; heat and liquefy potassium soap for standby. Weigh compound I-5-17, add it to the potassium soap solution and camphor ethanol solution under continuous stirring, then gradually add distilled water. After complete emulsification, add distilled water to the full volume to obtain the product.

[0379] 8. Preparation of Compound I-5-21 Suppository

[0380] Prescription: 4 g of compound I-5-21, 14 g of gelatin, 70 g of glycerol, add distilled water to 100 mL, making 100 pieces in total.

[0381] Preparation method: Weigh gelatin and glycerol, add distilled water to 100 mL, heat and melt in a water bath at 60 °C until it becomes a paste, then add compound I-5-21, stir evenly. When it is nearly solidified, pour it into a vaginal suppository mold, cool and solidify to obtain the product.

[0382] 9. Preparation of Compound I-6-1 Ointment

[0383] Prescription: 0.5 - 2 g of compound I-6-1, 6 - 8 g of cetyl alcohol, 8 - 10 g of white vaseline, 8 - 19 g of liquid paraffin, 2 - 5 g of monoglyceride, 2 - 5 g of polyoxyethylene (40) stearate, 5 - 10 g of glycerol, 0.1 g of ethylparaben, add distilled water to 100 g.

[0384] Preparation method: Heat and completely melt cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate, mix them evenly, keep the temperature at 80 °C for standby; add ethylparaben to glycerol and distilled water, heat to 85 °C for dissolution, then add the oil phase under continuous stirring. After emulsification, add compound I-6-1, stir and cool to obtain the product.

[0385] 10. Preparation of Compound I-6-19 and Fluconazole Compound Powder for Injection

[0386] Prescription: 50 g of compound I-6-19, 50 g of fluconazole, 1 g of sodium benzoate, making 100 bottles in total.

[0387] Preparation method: Weigh the prescribed amounts of Compound I-6-19, fluconazole, and sodium benzoate, mix them evenly under aseptic conditions, and dispense into 100 bottles to obtain the product.

[0388] 11. Preparation of Compound I-6-25 Aerosol

[0389] Prescription: 2.5 g of Compound I-6-25, 3 g of Span 20, 4 g of talcum powder (100 mesh), and trifluoromonochloromethane added to an appropriate amount.

[0390] Preparation method: Place Compound I-6-25, Span 20, and talcum powder in a vacuum drying oven and dry for several hours. Cool to room temperature in a desiccator, pulverize into fine powder with a jet mill, then mix evenly according to the prescription amounts, pour into a sealed container, and add trifluoromonochloromethane to the specified amount to obtain the product.

[0391] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the present technical solution, and all of them should be covered by the scope of the claims of the present invention.

Claims

1. Cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts, being any one of the following compounds: Wherein, When R 5 = H: I-5-1, I-6-1: R 6 = H, R 7 = H, R 8 = H, R 9 = H; I-5-2, I-6-2: R 6 = CI, R 7 = H, R 8 = H, R 9 = H I-5-3I-6-3:R 6 = H, R 7 = NO 2 ,R 8 = H, R 9 = H; I-5-4, I-6-4:R 6 = H, R 7 = H, R 8 = F, R 9 = H I-5-5, I-6-5: R 6 = H, R 7 = H, R 8 = Br, R 9 = H; I-5-6, I-6-6: R 6 = H, R 7 = H, R 8 = H, R 9 = CH 3 2. The cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts according to claim 1, Characterized in that, The pharmaceutically acceptable salts are hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate or acetate.

3. Use of the cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 2 in the preparation of antibacterial drugs.

4. The use according to claim 3, wherein the bacteria are selected from one or more of Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa or Acinetobacter baumannii.

5. The use according to claim 4, Characterized in that, The Staphylococcus aureus is methicillin-resistant Staphylococcus aureus, Staphylococcus aureus ATCC 25923 or Staphylococcus aureus ATCC 29213, the Escherichia coli is Escherichia coli ATCC 25922, and the Pseudomonas aeruginosa is Pseudomonas aeruginosa ATCC 27853.

6. A preparation containing the cyanoethenylsulfonanilide compounds and their pharmaceutically acceptable salts according to any one of claims 1 to 2.

7. The preparation according to claim 6, Characterized in that, The preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.

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