2-aryl benzimidazole compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a 2-aryl benzimidazole compound and a preparation method thereof, a pharmaceutical composition taking the compound as an active component, and application of the 2-aryl benzimidazole compound in preparation of medicines for preventing or treating FBPase target related diseases. Specifically, the invention relates to a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a use method thereof and a method for preparing the compounds, and R1, R2, R3, R4, A and L are described in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and particularly relates to 2-arylbenzimidazole compounds represented by general formula (I) and pharmaceutical compositions thereof, preparation methods thereof, pharmaceutical compositions containing the compounds as active ingredients, and their use in preparing drugs for preventing or treating FBPase target-related diseases. Background Art

[0002] Type 2 diabetes mellitus (T2DM) is a chronic, debilitating metabolic disorder characterized by elevated blood glucose levels. Impaired insulin sensitivity, relative insulin deficiency, and increased endogenous glucose production (EGP) are some of the causes of elevated blood glucose levels. Long-term hyperglycemia is also associated with various microvascular and macrovascular complications, such as retinopathy and cataracts, nephropathy, neuropathy, and cardiovascular disease, which are considered to be one of the main factors of death in diabetic patients. According to the latest 2022 Diabetes Atlas report released by the International Diabetes Federation (IDF), 537 million adults worldwide have diabetes, and type 2 diabetes is still growing at an alarming rate worldwide. It has become an important direct factor in multiple complications such as peripheral neuropathy and peripheral arterial disease, as well as severe symptoms of COVID-19. It is estimated that the number of adults with diabetes will reach 643 million in 2030 and 783 million in 2045, becoming a major potential disease in low- and middle-income countries.

[0003] Existing hypoglycemic drugs generally lower blood glucose levels by avoiding peripheral insulin resistance and increasing insulin secretion. These mechanisms are associated with side effects such as hypoglycemia, weight gain, peripheral edema, gastrointestinal disorders, and fasting hyperglycemia. Fructose-1,6-bisphosphatase (FBPase) is a cytoplasmic rate-limiting enzyme in the gluconeogenesis process that has glycolipid co-regulatory effects. Its unique action mechanism and mechanism can effectively fill the market gap for drugs that lower fasting hyperglycemia and dual-function drugs. However, no FBPase inhibitor has yet passed clinical trials and has been approved for marketing. Therefore, the development of new, safer and more effective FBPase inhibitors remains a research hotspot for the treatment of T2DM. Summary of the Invention

[0004] The present invention provides a novel 2-arylbenzimidazole compound and a preparation method thereof, and a pharmaceutical composition thereof. The compound or pharmaceutical composition can effectively treat type II diabetes associated with FBPase.

[0005] The first aspect of the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in,

[0008] A is phenyl or a 5-6 membered heteroaryl group containing at least one atom selected from N, O or S;

[0009] L is -NHSO2- or -CONHSO2-;

[0010] R1 is selected from H, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl;

[0011] The substituents in R1 are independently selected from: F, Cl, Br, hydroxyl, carboxyl, -COOCH3, acetamido, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0012] R2 is selected from one or more H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0013] R3 is selected from one or more H, F, Cl, Br, C1-C3 alkyl, acetyl, acetamido, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0014] R4 is selected from one or more H, F, Cl, Br, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino.

[0015] Furthermore, the compound is represented by the general formula (II):

[0016]

[0017] Wherein, X is N or CH;

[0018] L, R1, R2, R3, and R4 are defined as in the first aspect.

[0019] Furthermore, the compound is represented by the general formula (III):

[0020]

[0021] wherein Y is N, O or S;

[0022] L, R1, R2, R3, and R4 are defined as in the first aspect.

[0023] Furthermore, the compound is represented by the general formula (IV):

[0024]

[0025] Wherein, X is N or CH;

[0026] L, R1, R2, R3, and R4 are defined as in the first aspect.

[0027] Furthermore, the compound is represented by the general formula (V):

[0028]

[0029] in,

[0030] R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0031] R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0032] R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl;

[0033] R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

[0034] Furthermore, the compound is represented by the general formula (VI):

[0035]

[0036] in,

[0037] R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0038] R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0039] R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl;

[0040] R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

[0041] Furthermore, the compound is represented by the general formula (VII):

[0042]

[0043] in,

[0044] R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0045] R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino;

[0046] R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl;

[0047] R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

[0048] In particular, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] The second aspect of the present invention provides a method for preparing the compound according to any one of the first aspects of the present invention, comprising the following steps: (1)

[0061]

[0062] I-1 and R3-substituted nitro aromatic formaldehyde are reacted in the presence of sodium metabisulfite in a suitable solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide) at 120-140°C to produce a benzimidazole aromatic nitro compound, which is then reduced in the presence of a metal (e.g., iron powder, zinc powder, etc.) in a suitable solvent (e.g., a mixed solvent of saturated ammonium chloride solution and ethanol) at 50-60°C to produce I-2.

[0063] I-2 is subjected to a condensation reaction with R4-substituted benzenesulfonyl chloride in an organic alkaline condition (e.g., pyridine) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile or acetone) to obtain a compound represented by formula (I);

[0064] or (2)

[0065]

[0066] I-1 and R3-substituted formyl aromatic methyl formate are reacted in the presence of sodium metabisulfite in a suitable solvent (e.g., N,N-dimethylformamide, N,N-dimethylacetamide) at 120-140°C to produce I-3;

[0067] I-3 is hydrolyzed in an inorganic alkaline solution (e.g., sodium hydroxide, lithium hydroxide, or potassium hydroxide) at 70-80°C in a suitable solvent (a mixed solvent consisting of water and tetrahydrofuran, dioxane, acetonitrile, or acetone) to produce I-4.

[0068] I-4 and R4-substituted benzenesulfonamide are reacted in the presence of a condensing agent (e.g., EDCI, CDI, DCC, HATU or HBTU, etc.) under alkaline conditions (e.g., triethylamine, diisopropylethylamine, DMAP or DBU, etc.) in a suitable solvent (e.g., dichloromethane, N,N-dimethylformamide or acetonitrile, etc.) by dehydration condensation to obtain the compound represented by formula (I);

[0069] Wherein, the definitions of R1, R2, R3, R4, A and L are as described in the first aspect of the invention.

[0070] The third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of the first aspects of the present invention or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0071] The fourth aspect of the present invention provides the use of any compound or pharmaceutically acceptable salt thereof according to the first aspect or the pharmaceutical composition according to the third aspect in the preparation of a medicament for preventing or treating FBPase target-related diseases, particularly type II diabetes and its complications, such as fasting hyperosmolar hyperglycemic state, ketoacidosis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic skin lesions, atherosclerosis, diabetic foot disease, and infection.

[0072] Various aspects and features of the present invention are further described below.

[0073] The various terms and phrases used in this invention have their general meanings as known to those skilled in the art. Nevertheless, the present invention intends to provide a more detailed description and explanation of these terms and phrases. If any term or phrase mentioned herein is inconsistent with the generally known meaning, the meaning as set forth in this invention shall prevail. The following are definitions of various terms used in this invention. These definitions apply to the terms used throughout this specification, unless otherwise specified in specific circumstances.

[0074] The term "substituted" means that any one or more hydrogen atoms on a specific atom in a given structure are replaced by a specific substituent, as long as the valence state of the specific atom is normal and the resulting compound is stable. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position. Among them, the substituents can be, but are not limited to, hydrogen, deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, thiol, amino (-NH2) arylamine, aminoalkyl, alkyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (=O) R a 、-OR b 、-COOR b 、-SO2R b 、-NR c R d 、-CONR c R d 、-SO2NR c R d 、-C(NR c R d ); where R a 、R b , Rc and Rd Each is independently hydrogen, cyano, amino, alkylamino, arylamino, alkylthio, alkoxy, aryloxy, hydroxy, mercapto, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylsulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, aminoalkylacyl or alkylacyl.

[0075] The carbon atom content of the various hydrocarbon-containing moieties is indicated by prefixes designating the minimum and maximum number of carbon atoms in the moiety. i -C J represents a moiety having an integer "i" (inclusive) to an integer "J" (inclusive) carbon atoms. Thus, for example, C1-C4 alkyl refers to an alkyl group having 1 to 4 (inclusive) carbon atoms, specifically methyl, ethyl, C3 alkyl, and C4 alkyl.

[0076] As used herein, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which may be linear or branched, and may include subgroups thereof. For example, when referring to "C1-C4 alkyl," it may also include sub-ranges of groups represented by C1-C3 alkyl, C1-C2 alkyl, C2-C4 alkyl, C3-C4 alkyl, etc., as well as specific groups such as methyl, ethyl, n-propyl, and isopropyl. The terms "alkoxy" and "alkylamino" are conventional expressions and refer to alkyl groups attached to the rest of the molecule via an oxygen atom or an amine group, respectively, wherein the alkyl group is as described herein. Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, n-propyloxy, and the like. Alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, n-propylamino, and the like.

[0077] As used herein, the terms "halo", "halogen", "halogen atom", "halo" and the like represent fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0078] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having a specified number of ring carbon atoms, and it may include its subgroups. For example, when referring to "3-6 membered cycloalkyl", it may also include sub-ranges represented by 3-5 membered cycloalkyl, 4-6 membered cycloalkyl, etc., as well as specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0079] As used herein, the term "heterocyclyl" refers to a cyclic heteroalkyl group having the specified number of ring atoms, including monocyclic or fused ring groups, having 4 to 10 ring atoms, one or two of which are heteroatoms selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms being carbon. These rings may also have one or more double bonds, however, these rings do not have a completely conjugated π electron system. Heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,2-dihydropyridinyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, piperazinyl, homopiperazinyl, 1,3-benzoxazinyl, oxazolidinyl, homopiperidinyl, and the like.

[0080] As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 3 heteroatoms as ring atoms, with the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. For example, "5-6 membered heteroaryl" includes 5-membered heteroaryl and 6-membered heteroaryl. 5-membered heteroaryl includes, but is not limited to, imidazolyl, furyl, thienyl, triazolyl, tetrazolyl, pyrazolyl (such as 2-pyrazolyl), thiazolyl, oxazolyl, and isoxazolyl. 6-membered heteroaryl includes pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and 1,3,5-triazinyl.

[0081] As used herein, the term "ring" refers to a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The term "ring" includes fused rings. The number of atoms in the ring is generally defined as the number of ring members. For example, a "3-6 membered ring" refers to a ring with 3-6 atoms arranged around it.

[0082] As used herein, the term "effective amount" refers to an amount of a drug that can achieve the desired treatment of a disease or condition described herein in a subject.

[0083] As described herein, the term "pharmaceutically acceptable" when describing, for example, a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to a subject, but also refers to a synthetic substance that has pharmaceutical use value, such as a salt formed as an intermediate when performing chiral resolution. Although the salt of this intermediate cannot be directly administered to a subject, the salt can play a role in obtaining the final product of the present invention.

[0084] As used herein, the term "pharmaceutical composition," which may also refer to a "composition," is useful for achieving the treatment of a disease or condition described herein in a subject, particularly a mammal.

[0085] "Treatment" for a disease includes:

[0086] (1) preventing the disease, i.e., preventing clinical symptoms of the disease in a mammal that does not experience or display symptoms of the disease,

[0087] (2) inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms,

[0088] (3) Alleviate the disease, that is, cause recovery of the disease or its clinical symptoms.

[0089] "Therapeutically effective amount" refers to the amount of a compound that is sufficient to achieve treatment of a disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, and the age, weight, sex, and other factors of the mammal. A therapeutically effective amount may also refer to any amount of a compound that is sufficient to achieve the desired beneficial effect, including preventing the disease, inhibiting the disease, or alleviating the disease as described in (1)-(3) above. For example, the amount of the compound may be between 0.1-250 mg / kg, or preferably, 0.5-100 mg / kg, or more preferably, 1-50 mg / kg, or even more preferably, 2-20 mg / kg. Preferably, the compound of said amount is administered to the mammal twice a day. More preferably, the compound of said amount is administered to the mammal once a day. More preferably, the compound of said amount is administered to the mammal once a week or once every two weeks.

[0090] As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives the compound of formula (I) or its pharmaceutical composition for treating the disease or condition described herein.

[0091] Yet another aspect of the present invention relates to pharmaceutical compositions comprising the compounds of the present invention as active ingredients. Such pharmaceutical compositions can be prepared according to methods known in the art. The compounds of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use.

[0092] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, rectal, etc.

[0093] The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0094] In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropyl alcohol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, etc.; the lubricant and solubilizing agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0095] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0096] To prepare a dosing unit as a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a cosolvent, and the mixture can be placed directly in a hard or soft capsule. Alternatively, the active ingredient compound of the present invention can be first mixed with a diluent, a binder, and a disintegrant to form granules or pellets, which can then be placed in a hard or soft capsule. The same diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0097] To prepare the compounds of the present invention as injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators commonly used in the art can be added. Examples of solubilizers or cosolvents include poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters include phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators include sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol, glucose, and the like can also be added as support agents.

[0098] Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

[0099] To achieve the intended use and enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the present invention may be administered by any known method. The compounds or compositions of the present invention may be taken alone or in combination with other therapeutic agents or symptomatic drugs. When the compounds of the present invention exhibit synergistic effects with other therapeutic agents, their dosage should be adjusted based on the actual situation. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figure 1 The bar graph shows the changes in blood glucose at the initial time, 30 minutes and 90 minutes after the oral pyruvate tolerance test (OPTT) in ICR mice. Figure 1 As can be seen, after administering equal amounts of sodium pyruvate to each group of ICR mice, metformin and compound 77 exhibited significant inhibitory activity on gluconeogenesis in mice, with comparable inhibitory levels. Metformin is metformin, serving as a positive control; Control is a blank control group. DETAILED DESCRIPTION

[0101] The present invention is further described by way of the following examples, which are not intended to limit the present invention in any way. While the present invention has been described in detail herein and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0102] For all of the following examples, standard procedures and purification methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectroscopy (MS).

[0103] Example 1

[0104]

[0105] 4-Chloro-N-(2-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 1)

[0106] first step:

[0107]

[0108] To a 100 mL single-necked bottle, add M-1 (cas: 74628-31-2, 300 mg, 1.58 mmol), o-nitrobenzaldehyde (cas: 552-89-6, 239 mg, 1.58 mmol), sodium metabisulfite (450 mg, 2.36 mmol), and DMF (30 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product, iron powder (434 mg, 7.78 mmol), saturated ammonium chloride solution (10 mL), and ethanol (20 mL) are added to a 100 mL single-necked bottle and heated at 50-60°C for 3 hours. The mixture was cooled, filtered through celite, and extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (eluted with a mixed solvent of petroleum ether / ethyl acetate) to give 395 mg of a reddish solid (M-2) in a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.84–7.75(m,1H),7.73–7.64(m,1H),7.30–7.23(m,3H),7.18(dd,J=7.6,1.6Hz,1H),6.8 9–6.79(m,2H),4.43–4.26(m,3H),2.39–2.27(m,2H),2.01–1.86(m,4H),1.78–1.70(m,1H),1.38–1.29(m,3H).

[0109] Step 2:

[0110]

[0111] M-2 (50 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and p-chlorobenzenesulfonyl chloride (cas: 98-60-2, 44 mg, 0.21 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixture) to obtain 43 mg of an off-white solid (Compound 1), with a yield of 54%. 1H NMR (400MHz, CDCl3) δ10.48 (s, 1H), 7.90–7.75 (m, 2H), 7.65 (dd, J = 6.8, 2.0Hz ,1H),7.59–7.51(m,2H),7.49–7.42(m,1H),7.36–7.33(m,2H),7.31–7.26(m, 2H),7.20–7.11(m,2H),4.20–4.08(m,1H),2.27–2.19(m,2H),1.99–1.86(m,2 H),1.74(s,1H),1.65–1.57(m,2H),1.33–1.24(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25 Calculated for O2N3ClS: 466.1351; found: 466.1359.

[0112] Example 2

[0113]

[0114] 4-Bromo-N-(2-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 2)

[0115]

[0116] M-2 (50 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and p-bromobenzenesulfonyl chloride (cas: 98-58-8, 54 mg, 0.21 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 44 mg of an off-white solid (Compound 2), with a yield of 50%. 1 H NMR(400MHz, CDCl3)δ10.55(s,1H),7.87–7.79(m,2H),7.64(dd,J=6.8,2.0 Hz,1H),7.49–7.42(m,3H),7.37–7.28(m,4H),7.27(d,J=2.4Hz,1H),7.24(d d,J=7.6,1.2Hz,1H),4.24–4.15(m,1H),2.31–2.17(m,2H),1.97–1.87(m,2H ),1.74(s,1H),1.66–1.53(m,2H),1.28–1.21(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25Calculated for O2N3BrS: 510.0845; found: 510.0862.

[0117] Example 3

[0118]

[0119] 4-Fluoro-N-(2-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 3)

[0120]

[0121] M-2 (50 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and p-fluorobenzenesulfonyl chloride (cas: 349-88-2, 41 mg, 0.21 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 34 mg of a white solid (Compound 3), in a 44% yield. 1 H NMR (400MHz, CDCl3) δ10.35 (s, 1H), 7.89–7.81 (m, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.72–7 .64(m,3H),7.49–7.40(m,1H),7.38–7.30(m,2H),7.30–7.27(m,1H),7.23(d,J=8.0H z,1H),6.91(t,J=8.4Hz,2H),4.23–4.17(m,1H),2.32–2.17(m,2H),1.90(d,J=10.8H z,2H),1.74(s,1H),1.66(d,J=12.8Hz,2H),1.30–1.24(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25 O2N3FS calculated value: 450.1646; measured value: 450.1638.

[0122] Example 4

[0123]

[0124] N-(2-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 4)

[0125]

[0126] M-2 (50 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and p-methoxybenzenesulfonyl chloride (cas: 98-68-0, 43 mg, 0.21 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 41 mg of an off-white solid (Compound 4), with a yield of 52%. 1 H NMR (400MHz, CDCl3) δ9.87(s,1H),7.91(d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.62(d,J=8.4Hz,3H),7.47(s,1H),7.39(s,2H),7.31(s,2H), 6.74(d,J=8.4Hz,2H),4.29–4.23(m,1H),3.77(s,3H),2.30–2.21(m,2H),1.93–1.86(m,4H),1.76(s,1H),1.30(s,3H).HR-MS(ESI):m / z[M+H] + C 26 H 28 O3N3S calculated value: 462.1846; measured value: 462.1842.

[0127] Example 5

[0128]

[0129] N-(2-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 5)

[0130]

[0131] M-2 (50 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and p-hydroxybenzenesulfonyl chloride (cas: 4025-67-6, 40 mg, 0.21 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixture) to obtain 31 mg of an off-white solid (Compound 5), with a yield of 40%. 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),10.09(s,1H),7.89–7.83(m,1H),7.76–7.69(m,1H),7.51–7.37(m,5H),7.33–7.24(m,3H),6.7 9–6.70(m,2H),4.01–3.94(m,1H),2.22–2.15(m,2H),1.85–1.77(m,4H),1.63–1.58(m,1H),1.34–1.13(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 26 O3N3S calculated value: 448.1689; measured value: 448.1691.

[0132] Example 6

[0133]

[0134] 4-Chloro-N-(2-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 6)

[0135] first step:

[0136]

[0137] Using M-3 (cas: 68817-71-0, 500 mg, 2.29 mmol) as starting material, a similar operation as in the first step of Example 1 was performed to obtain a crude product. Using the crude product as starting material, similar operations were performed in the first step and subsequent steps of Example 1 to obtain 505 mg of an off-yellow solid (M-4), with a yield of 69%. 1 H NMR(400MHz, CDCl3)δ7.85(dt,J=8.0,1.2Hz,1H),7.50–7.43(m,2H),7.36(ddd,J=8.0,7.2,1.6Hz,1H),7.32–7.26(m,3H),7 .25(d,J=3.2Hz,1H),7.12(ddd,J=8.0,7.2,1.6Hz,1H),6.79(ddd,J=8.0,7.2,1.2Hz,2H),6.46(ddd,J=8.0,7.2,1.2Hz,1H).

[0138] Step 2:

[0139]

[0140] Using M-4 (50 mg, 0.16 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 56 mg of a white solid (Compound 6) with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ11.51(s,1H),7.94(d,J=8.0Hz,1H),7.76(d,J=8.4Hz,1H),7.56–7.50(m,2H),7.47–7.40(m,3H),7.39–7.30(m,2H) ),7.20(d,J=8.0Hz,1H),7.12–7.06(m,2H),6.91–6.85(m,1H),6.79(dd,J=8.0,1.6Hz,1H),6.72(d,J=8.0Hz,2H).HR-MS(ESI):m / z[M+H] + C 25 H 18 Calculated for O2N3Cl2S: 494.0491; found: 494.0492.

[0141] Example 7

[0142]

[0143] 4-Fluoro-N-(2-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 7)

[0144]

[0145] Using M-4 (50 mg, 0.16 mmol) as starting material and adopting the similar operation as in Example 3, 49 mg of white solid (Compound 7) was obtained with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ11.49(s,1H),7.94(d,J=8.0Hz,1H),7.76(d,J=8.4Hz,1H),7.68–7.62 (m,2H),7.43–7.35(m,5H),7.20(d,J=8.0Hz,1H),6.83–6.76(m,6H).HR-MS(ESI):m / z[M+H] + C 25 H 18 O2N3ClFS calculated: 478.0787; found: 478.0790.

[0146] Example 8

[0147]

[0148] N-(2-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 8)

[0149]

[0150] Using M-4 (50 mg, 0.16 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 36 mg of an off-white solid (Compound 8) with a yield of 47%. 1 H NMR (400MHz, CDCl3) δ11.15(s,1H),7.96(d,J=8.0Hz,1H),7.74(d,J=8.4Hz,1H),7.56–7.35(m,6H),7.31(d,J=8.0Hz,1H), 7.20(d,J=8.0Hz,1H),6.87(t,J=8.0Hz,1H),6.81–6.72(m,3H),6.57(d,J=8.4Hz,2H),3.65(s,3H).HR-MS(ESI):m / z[M+H] + C 26 H 21 Calculated for O3N3ClS: 490.0987; found: 490.0992.

[0151] Example 9

[0152]

[0153] N-(2-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 9)

[0154]

[0155] Using M-4 (50 mg, 0.16 mmol) as starting material and adopting the similar operation as in Example 5, 39 mg of white solid (Compound 9) was obtained with a yield of 52%. 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),10.45(s,1H),7.91(d,J=8.0Hz,1H),7.52(t,J=9.6Hz,3H),7.40(q, J=9.6,8.0Hz,5H),7.28(d,J=8.0Hz,1H),7.07–6.96(m,4H),6.66(d,J=8.4Hz,2H).HR-MS(ESI):m / z[M+H] + C 25 H 19 Calculated for O3N3ClS: 476.0830; Found: 476.0836.

[0156] Example 10

[0157]

[0158] N-(4-(2-(2-((4-chlorophenyl)sulfinamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 10)

[0159] first step:

[0160]

[0161] Using M-5 (cas: 254435-22-8, 450 mg, 1.87 mmol) as starting material, a similar operation as in the first step of Example 1 was performed to obtain a crude product. Using the crude product as starting material, similar operations were performed in the first step and subsequent steps of Example 1 to obtain 525 mg of an off-white solid (M-6) with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ7.89–7.82(m,1H),7.66(d,J=8.4Hz,2H),7.48(s,1H),7.38–7.33(m,1H),7.31–7. 26(m,2H),7.24(d,J=2.0Hz,1H),7.13–7.04(m,1H),6.82–6.77(m,2H),6.46–6.39(m,1H),2.22(s,3H).

[0162] Step 2:

[0163]

[0164] Using M-6 (50 mg, 0.15 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 39 mg of an off-yellow solid (Compound 10) with a yield of 51%. 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.20(s,1H),7.89(d,J=8.0Hz,1H),7.68(d,J=8.4Hz,2H),7.62(d,J= 8.4Hz,2H),7.45–7.37(m,6H),7.26(d,J=8.0Hz,1H),7.08–6.97(m,4H),2.07(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 22 Calculated for O3N4ClS: 517.1096; found: 517.1109.

[0165] Example 11

[0166]

[0167] N-(4-(2-(2-((4-fluorophenyl)sulfinamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 11)

[0168]

[0169] Using M-6 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 58 mg of an off-yellow solid (Compound 11) with a yield of 77%. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.19(s,1H),7.89(d,J=7.6Hz,1H),7.75–7.64(m,4H) ,7.50–7.33(m,4H),7.29–7.20(m,3H),7.08–6.93(m,4H),2.07(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 22 O3N4FS calculated value: 501.1391; measured value: 501.1401.

[0170] Example 12

[0171]

[0172] N-(4-(2-(2-((4-methoxyphenyl)sulfinamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 12)

[0173]

[0174] Using M-6 (50 mg, 0.15 mmol) as starting material and adopting the similar operation as in Example 4, 40 mg of an off-yellow solid (Compound 12) was obtained with a yield of 54%. 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.20(s,1H),7.91(d,J=8.0Hz,1H),7.65(d,J=8.4Hz,2H),7.47– 7.41(m,6H),7.23(d,J=8.0Hz,1H),7.12–6.69(m,6H),3.70(s,3H),2.08(s,3H).HR-MS(ESI):m / z[M+H] + C 28 H 25O4N4S calculated value: 513.1603; measured value: 513.1591.

[0175] Example 13

[0176]

[0177] N-(4-(2-(2-((4-hydroxyphenyl)sulfinamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 13)

[0178]

[0179] Using M-6 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 36 mg of an off-yellow solid (Compound 13) in a yield of 48%. 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.44(s,1H),10.19(s,1H),7.91(d,J=8.0Hz,1H),7.65(d,J=8.4Hz,2H),7.55–7.40(m ,2H),7.36(t,J=8.4Hz,4H),7.23(d,J=8.0Hz,1H),7.02–6.88(m,4H),6.67–6.54(m,2H),2.07(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 23 O4N4S calculated value: 499.1435; measured value: 499.1436.

[0180] Example 14

[0181]

[0182] 4-Chloro-N-(2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 14)

[0183] first step:

[0184]

[0185] Using M-7 (cas: 5729-18-0, 600 mg, 2.58 mmol) as starting material, a crude product was obtained by similar procedures as in the first step of Example 1. Using the crude product as starting material, similar procedures were performed in the first step and subsequent steps of Example 1 to obtain 654 mg of an off-white solid (M-8), with a yield of 76%. 1H NMR(400MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.35–7.28(m,3H),7.26–7.16(m,3H),7.12(dd,J=8.0,1 .6Hz,1H),7.04(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,1H),6.73–6.65(m,1H),5.38(s,2H),4.84(s,1H).

[0186] Step 2:

[0187]

[0188] Using M-8 (50 mg, 0.15 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 48 mg of a white solid (Compound 14) in a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),7.77(d,J=7.6Hz,1H),7.56(d,J=8.0Hz,2H),7.48(d, J=7.6Hz,1H),7.44–7.22(m,10H),7.02(d,J=8.0Hz,2H),5.25(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 20 Calculated for O2N3Cl2S: 508.0648; found: 508.0653.

[0189] Example 15

[0190]

[0191] 4-Fluoro-N-(2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 15)

[0192]

[0193] Using M-8 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 38 mg of a white solid (Compound 15) in a yield of 52%. 1H NMR(400MHz, DMSO-d6)δ10.63(s,1H),7.78(dd,J=7.2,1.6Hz,1H),7.69–7.62(m,2H),7.51–7.45(m,1H),7.44 –7.39(m,2H),7.37–7.29(m,5H),7.26–7.19(m,3H),7.02(d,J=8.4Hz,2H),5.29(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 20 O2N3ClFS calculated value: 492.0943; measured value: 492.0949.

[0194] Example 16

[0195]

[0196] N-(2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 16)

[0197]

[0198] Using M-8 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 36 mg of an off-white solid (Compound 16) in a yield of 48%. 1 H NMR(400MHz, DMSO-d6)δ10.55(s,1H),7.81(d,J=8.0Hz,1H),7.50–7.43(m,4H),7.41–7.38(m,1H),7.37–7.26(m, 5H),7.24–7.16(m,1H),7.01(d,J=8.0Hz,2H),6.86–6.80(m,2H),5.23(s,2H),3.76(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 23 Calculated for O3N3ClS: 504.1143; found: 504.1142.

[0199] Example 17

[0200]

[0201] N-(2-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 17)

[0202]

[0203] Using M-8 (50 mg, 0.15 mmol) as starting material and adopting the similar operation as in Example 5, 32 mg of white solid (Compound 17) was obtained with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ10.53–10.45(m,2H),7.84–7.78(m,1H),7.46(d,J=4.0Hz,2H),7.40–7.27(m, 8H),7.22–7.16(m,1H),7.01(d,J=8.0Hz,2H),6.69–6.62(m,2H),5.24(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 21 Calculated for O3N3ClS: 490.0987; Found: 490.0987.

[0204] Example 18

[0205]

[0206] 4-Chloro-N-(3-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 18)

[0207] first step:

[0208]

[0209] To a 100 mL single-necked flask, add M-1 (500 mg, 2.63 mmol), m-nitrobenzaldehyde (cas: 99-61-6, 397 mg, 2.63 mmol), sodium metabisulfite (750 mg, 3.94 mmol), and DMF (40 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Using the crude product as the starting material, similar procedures to those in the first step and subsequent steps of Example 1 were followed to obtain 613 mg of an off-white solid (M-9), with a yield of 80%. 1H NMR (400MHz, CDCl3) δ7.84–7.78(m,1H),7.68–7.61(m,1H),7.30–7.22(m,3H),7.02(t,J=2.0Hz,1H),6.92(d,J=8.0Hz,1H),6.81( dd,J=8.0,2.4Hz,1H),4.47–4.39(m,1H),3.59(s,2H),2.36–2.30(m,2H),2.01–1.87(m,4H),1.80–1.70(m,1H),1.38–1.30(m,3H).

[0210] Step 2:

[0211]

[0212] Using M-9 (50 mg, 0.17 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 42 mg of an off-white solid (Compound 18) in a yield of 52%. 1 H NMR (400MHz, CDCl3) δ10.36 (s, 1H), 7.92 (d, J = 7.2Hz, 1H), 7.66 (d, J = 7.2Hz, 1H),7.53(d,J=8.0Hz,2H),7.45(s,1H),7.35(d,J=4.8Hz,2H),7.33–7.27(m, 3H),7.16(d,J=8.0Hz,2H),4.25(t,J=12.4Hz,1H),2.27(d,J=12.4Hz,2H),1 .89(d,J=10.8Hz,4H),1.76(s,1H),1.33–1.24(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25 Calculated for O2N3ClS: 466.1351; found: 466.1358.

[0213] Example 19

[0214]

[0215] 4-Bromo-N-(3-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 19)

[0216]

[0217] Using M-9 (50 mg, 0.17 mmol) as starting material and adopting the similar operation as in Example 2, 41 mg of white solid (Compound 19) was obtained with a yield of 47%. 1H NMR (400MHz, CDCl3) δ10.14(s,1H),7.95–7.83(m,1H),7.65(d,J=7.2Hz,1H),7.50–7.40(m,3H),7.38–7.33(m,4H),7.32–7.26(m,3 H),4.24(t,J=12.4Hz,1H),2.36–2.19(m,2H),1.88(d,J=10.8Hz,4H),1.81–1.71(m,1H),1.33–1.25(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25 Calculated for O2N3BrS: 510.0845; found: 510.0858.

[0218] Example 20

[0219]

[0220] 4-Fluoro-N-(3-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 20)

[0221]

[0222] Using M-9 (50 mg, 0.17 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 28 mg of a white solid (Compound 20) in a yield of 36%. 1 H NMR (400MHz, CDCl3) δ9.58(s,1H),7.96–7.89(m,1H),7.67(dd,J=8.8,4.8Hz,3H),7.47(s,1H),7.32(d,J=6.4Hz,5H),6.92(t,J=8.4H z,2H),4.28(d,J=12.4Hz,1H),2.29(d,J=12.4Hz,2H),1.92(d,J=10.8Hz,4H),1.77(s,1H),1.34–1.25(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 25 O2N3FS calculated value: 450.1646; measured value: 450.1649.

[0223] Example 21

[0224]

[0225] N-(3-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 21)

[0226]

[0227] Using M-9 (50 mg, 0.17 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 38 mg of a white solid (Compound 21) in a yield of 49%. 1 H NMR (400MHz, CDCl3) δ8.56(s,1H),7.87(d,J=5.6Hz,1H),7.64(d,J=9.6Hz,3H),7.44–7.27(m,6H),6.76(d,J=8.4Hz,2H), 4.30(s,1H),3.77(s,3H),2.29(d,J=11.6Hz,2H),1.91(d,J=11.6Hz,4H),1.76(s,1H),1.32(s,3H).HR-MS(ESI):m / z[M+H] + C 26 H 28 O3N3S calculated value: 462.1846; measured value: 462.1844.

[0228] Example 22

[0229]

[0230] N-(3-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 22)

[0231]

[0232] Using M-9 (50 mg, 0.17 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 34 mg of an off-white solid (Compound 22) in a yield of 45%. 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 10.39 (s, 1H), 7.92 (d, J = 6.8Hz, 1H), 7. 72–7.67(m,1H),7.65–7.58(m,2H),7.47(t,J=8.0Hz,1H),7.37–7.29(m,5H), 6.85(d,J=8.8Hz,2H),4.15(t,J=12.4Hz,1H),2.25–2.18(m,2H),1.83(d,J=1 0.8Hz,4H),1.64(d,J=12.4Hz,1H),1.30–1.21(m,3H).HR-MS(ESI):m / z[M+H] + C 25 H 26 O3N3S calculated value: 448.1689; measured value: 448.1691.

[0233] Example 23

[0234]

[0235] 4-Chloro-N-(3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 23)

[0236] first step:

[0237]

[0238] Using M-3 (770 mg, 3.52 mmol) as the starting material, the crude product was obtained by similar operations as in the first step of Example 18. Using the crude product as the starting material, the subsequent operations similar to the first step of Example 1 were performed to obtain 934 mg of an off-white solid (M-10), with a yield of 83%. 1 HNMR(400MHz, CDCl3)δ7.89(d,J=8.0Hz,1H),7.52–7.45(m,2H),7.42–7.27(m,4H),7.22( d,J=8.0Hz,1H),7.12(d,J=2.0Hz,1H),7.07–7.01(m,1H),6.74–6.66(m,2H),3.63(s,2H).

[0239] Step 2:

[0240]

[0241] Using M-10 (50 mg, 0.16 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 47 mg of a white solid (Compound 23) in a yield of 61%. 1H NMR(400MHz, CDCl3)δ8.01(s,1H),7.93–7.90(m,1H),7.61–7.56(m,2H),7.52–7.47(m,2H),7.46–7.43(m, 1H),7.42–7.37(m,1H),7.36–7.30(m,3H),7.27(d,J=2.0Hz,1H),7.24–7.17(m,5H).HR-MS(ESI):m / z[M+H] + C 25 H 18 Calculated for O2N3Cl2S: 494.0491; found: 494.0489.

[0242] Example 24

[0243]

[0244] 4-Fluoro-N-(3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 24)

[0245]

[0246] Using M-10 (50 mg, 0.16 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 36 mg of a white solid (Compound 24) in a yield of 47%. 1 H NMR(400MHz, CDCl3)δ8.74(s,1H),7.90(d,J=8.0Hz,1H),7.57(q,J=5.2Hz,3H),7.51–7.44(m,2H),7.4 0–7.28(m,3H),7.25–7.16(m,4H),7.10(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,2H).HR-MS(ESI):m / z[M+H] + C 25 H 18 O2N3ClFS calculated: 478.0787; found: 478.0788.

[0247] Example 25

[0248]

[0249] N-(3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 25)

[0250]

[0251] Using M-10 (50 mg, 0.16 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 36 mg of a white solid (Compound 25) in a yield of 47%. 1 H NMR(400MHz, CDCl3)δ8.74(s,1H),7.90(d,J=8.0Hz,1H),7.57(q,J=5.2Hz,3H),7.51–7.44(m,2H),7.4 0–7.28(m,3H),7.25–7.16(m,4H),7.10(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,2H).HR-MS(ESI):m / z[M+H] + C 26 H 21 Calculated for O3N3ClS: 490.0987; Found: 490.0987.

[0252] Example 26

[0253]

[0254] N-(3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 26)

[0255]

[0256] Using M-10 (50 mg, 0.16 mmol) as starting material and adopting the similar operation as in Example 5, 41 mg of off-white solid (Compound 26) was obtained with a yield of 54%. 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.20(s,1H),7.81–7.77(m,1H),7.63–7.58(m,2H),7.54–7.48(m ,2H),7.43–7.37(m,3H),7.35–7.26(m,2H),7.23–7.07(m,4H),6.87–6.81(m,2H).HR-MS(ESI):m / z[M+H] + C 25 H 19 Calculated for O3N3ClS: 476.0830; found: 476.0842.

[0257] Example 27

[0258]

[0259] N-(4-(2-(3-((4-chlorophenyl)sulfonamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 27)

[0260] first step:

[0261]

[0262] Using M-5 (500 mg, 2.07 mmol) as starting material, a crude product was obtained by similar operations as in the first step of Example 18. Using the crude product as starting material, similar operations were performed in the first step and subsequent steps of Example 1 to obtain 603 mg of an off-yellow solid (M-11), with a yield of 85%. 1 HNMR(400MHz, CDCl3)δ7.87–7.82(m,2H),7.71–7.65(m,2H),7.38–7.30(m,1H),7.26–7.22(m,3H),7.07(t,J =2.0Hz,1H),7.00(t,J=8.0Hz,1H),6.72(dt,J=8.0,1.2Hz,1H),6.69–6.60(m,1H),3.30(s,2H),2.22(s,3H).

[0263] Step 2:

[0264]

[0265] Using M-11 (50 mg, 0.15 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 35 mg of a yellow solid (Compound 27) in a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ10.68–10.58(m,1H),10.32(s,1H),7.87(d,J=8.0Hz,1H),7.83–7.76(m,2H),7.67(d,J=8.8Hz,2H),7.64–7.60(m,2 H),7.54(t,J=2.0Hz,1H),7.48–7.35(m,4H),7.30(d,J=7.2Hz,2H),7.23(s,1H),7.16(d,J=8.0Hz,1H),2.11(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 22 Calculated for O3N4ClS: 517.1096; found: 517.1108.

[0266] Example 28

[0267]

[0268] N-(4-(2-(3-((4-fluorophenyl)sulfonamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 28)

[0269]

[0270] Using M-11 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 28 mg of a yellow solid (Compound 28) in a yield of 38%. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),10.33(s,1H),7.85(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,2H),7.73(d,J=6.8Hz,2H),7 .53(s,1H),7.46(s,1H),7.42–7.35(m,5H),7.28(d,J=6.8Hz,2H),7.22–7.17(m,2H),2.10(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 22 O3N4FS calculated value: 501.1391; measured value: 501.1401.

[0271] Example 29

[0272]

[0273] N-(4-(2-(3-((4-methoxyphenyl)sulfonamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 29)

[0274]

[0275] Using M-11 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 37 mg of a yellow solid (Compound 29) in a yield of 50%. 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),10.33(s,1H),7.85(d,J=8.0Hz,1H),7.79(d,J=8.4Hz,2H),7.61(d,J=8.8Hz,2H),7.55(t,J=2.0Hz,1H),7.49– 7.42(m,2H),7.36(d,J=8.4Hz,2H),7.30–7.23(m,2H),7.15(d,J=8.0Hz,2 H),7.03(d,J=8.4Hz,2H),3.80(s,3H),2.10(s,3H).HR-MS(ESI):m / z[M+H] + C 28 H 25 O4N4S calculated value: 513.1591; measured value: 513.1605.

[0276] Example 30

[0277]

[0278] N-(4-(2-(3-((4-hydroxyphenyl)sulfonamido)phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide (Compound 30)

[0279]

[0280] Using M-11 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 30 mg of a yellow solid (Compound 30) in a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),10.35–10.26(m,2H),7.84–7.77(m,4H),7.57–7.49(m,4H),7.36(d,J=8 .8Hz,2H),7.26(d,J=8.4Hz,2H),7.16–7.07(m,2H),6.84(d,J=8.4Hz,2H),2.10(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 23 O4N4S calculated value: 499.1435; measured value: 499.1436.

[0281] Example 31

[0282]

[0283] 4-Chloro-N-(3-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 31)

[0284] first step:

[0285]

[0286] Using M-7 (500 mg, 2.15 mmol) as the starting material, the crude product was obtained by similar operations as in the first step of Example 18. Using the crude product as the starting material, the subsequent operations were similar to those in the first step of Example 1 to obtain 595 mg of a yellow solid (M-12) with a yield of 83%. 1 HNMR(400MHz, CDCl3)δ7.86(d,J=8.0Hz,1H),7.34–7.27(m,3H),7.25–7.15(m,3H),7.07–7.0 1(m,3H),6.93(dd,J=8.0,1.6Hz,1H),6.78(dd,J=8.0,2.4Hz,1H),5.44(s,2H),3.57(s,2H).

[0287] Step 2:

[0288]

[0289] Using M-12 (50 mg, 0.15 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 53 mg of a white solid (Compound 31) with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.72(dt,J=6.8,2.4Hz,3H),7.63–7.58(m,2H),7.51(t,J=2.4Hz,1H),7.47–7.43(m ,1H),7.42–7.35(m,2H),7.34–7.29(m,2H),7.28–7.21(m,3H),6.91(d,J=8.4Hz,2H),5.49(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 20 Calculated for O2N3Cl2S: 508.0648; found: 508.0658.

[0290] Example 32

[0291]

[0292] 4-Fluoro-N-(3-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 32)

[0293]

[0294] Using M-12 (50 mg, 0.15 mmol) as starting material and adopting the similar operation as in Example 3, 43 mg of white solid (Compound 32) was obtained with a yield of 59%. 1 H NMR(400MHz, DMSO-d6)δ10.56(s,1H),7.78(dd,J=8.8,5.2Hz,2H),7.74–7.69(m,1H),7.50(s,1H),7.46–7.42(m ,1H),7.41–7.30(m,6H),7.25(dd,J=6.4,3.2Hz,3H),6.91(d,J=8.0Hz,2H),5.48(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 20 O2N3ClFS calculated value: 492.0943; measured value: 492.0942.

[0295] Example 33

[0296]

[0297] N-(3-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 33)

[0298]

[0299] Using M-12 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 42 mg of a white solid (Compound 33) in a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.73–7.69(m,1H),7.69–7.64(m,2H),7.50(t,J=2.0Hz,1H),7.47–7.42(m,1H),7.39(t,J=8.0Hz ,1H),7.36–7.29(m,3H),7.26–7.17(m,3H),7.05–7.00(m,2H),6.90(d,J=8.0Hz,2H),5.47(s,2H),3.76(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 23 Calculated for O3N3ClS: 504.1143; found: 504.1151.

[0300] Example 34

[0301]

[0302] N-(3-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 34)

[0303]

[0304] Using M-12 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 35 mg of a white solid (Compound 34) in a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),10.31(s,1H),7.74–7.69(m,1H),7.59–7.53(m,2H),7.50(t,J=2.0Hz,1H),7.47–7.42(m,1H),7. 37(t,J=8.0Hz,1H),7.34–7.29(m,3H),7.28–7.20(m,3H),6.91(d,J=8.0Hz,2H),6.85–6.79(m,2H),5.48(s,2H).HR-MS(ESI):m / z[M+H] + C 26 H 21 Calculated for O3N3ClS: 490.0987; found: 490.0994.

[0305] Example 35

[0306]

[0307] 4-Chloro-N-(3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 35)

[0308] first step:

[0309]

[0310] Using M-13 (cas: 70918-95-5, 400 mg, 2.66 mmol) as the starting material, a similar operation as in the first step of Example 18 was performed to obtain a crude product. Using the crude product as the starting material, similar operations were performed in the first step and subsequent steps of Example 1 to obtain 535 mg of an off-yellow solid (M-14) with a yield of 80%. 1H NMR (400MHz, DMSO-d6) δ7.82–7.75(m,1H),7.67–7.60(m,1H),7.26–7.15(m,3H),6.83(t,J=2.0 Hz,1H),6.72(dd,J=8.0,2.0Hz,2H),5.36(s,2H),4.77(p,J=6.8Hz,1H),1.57(d,J=6.8Hz,6H).

[0311] Step 2:

[0312]

[0313] Using M-14 (50 mg, 0.20 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 68 mg of a white solid (Compound 35) with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),7.95–7.85(m,1H),7.78(d,J=8.0Hz,2H),7.73–7.66(m,3H),7.52(t,J=8.0Hz ,1H),7.41(d,J=7.6Hz,1H),7.40–7.31(m,4H),4.50(p,J=6.8Hz,1H),1.54(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 22 H 21 Calculated for O2N3ClS: 426.1038; found: 426.1039.

[0314] Example 36

[0315]

[0316] 4-Fluoro-N-(3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 36)

[0317]

[0318] Using M-14 (50 mg, 0.20 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 59 mg of a white solid (Compound 36) in a yield of 72%. 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),7.95–7.89(m,1H),7.86(dd,J=8.8,5.2Hz,2H),7.75–7.69(m,1H),7.51(t,J=8 .0Hz,1H),7.45–7.39(m,4H),7.37–7.31(m,3H),4.52(p,J=6.8Hz,1H),1.55(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 22 H 21 O2N3FS calculated value: 410.1333; measured value: 410.1334.

[0319] Example 37

[0320]

[0321] N-(3-(1-Isopropyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 37)

[0322]

[0323] Using M-14 (50 mg, 0.20 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 58 mg of an off-red solid (Compound 37) in a yield of 69%. 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),7.95–7.83(m,1H),7.72(d,J=8.8Hz,3H),7.48(t,J=8.0Hz,1H),7.38–7.2 8(m,5H),7.08(d,J=8.4Hz,2H),4.52(p,J=6.8Hz,1H),3.79(s,3H),1.54(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 24 O3N3S calculated value: 422.1533; measured value: 422.1531.

[0324] Example 38

[0325]

[0326] 4-Chloro-N-(3-(1-isobutyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 38)

[0327] first step:

[0328]

[0329] Using M-15 (cas: 78438-99-0, 400 mg, 2.44 mmol) as starting material, a crude product was obtained by similar procedures as in the first step of Example 18. Using the crude product as starting material, similar procedures were followed in the first step and subsequent steps of Example 1 to obtain 498 mg of an off-yellow solid (M-16) in a yield of 77%. 1 H NMR (400MHz, DMSO-d6) δ7.67–7.62(m,2H),7.29–7.15(m,3H),6.94(t,J=2.0Hz,1H),6.84(dt,J=7.6,1.2 Hz,1H),6.75–6.68(m,1H),5.49(s,2H),4.17(d,J=7.6Hz,2H),2.02–1.96(m,1H),0.66(d,J=6.8Hz,6H).

[0330] Step 2:

[0331]

[0332] Using M-16 (50 mg, 0.19 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 52 mg of a white solid (Compound 38) in a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),7.78(dd,J=8.0,5.6Hz,3H),7.75–7.69(m,1H),7.66–7.61(m,2H),7.49(t,J=4 .0Hz,3H),7.42–7.31(m,3H),4.09(d,J=7.6Hz,2H),1.83–1.74(m,1H),0.55(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 23 Calculated for O2N3ClS: 440.1194; found: 440.1177.

[0333] Example 39

[0334]

[0335] 4-Fluoro-N-(3-(1-isobutyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 39)

[0336]

[0337] Using M-16 (50 mg, 0.19 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 45 mg of a white solid (Compound 39) in a yield of 57%. 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.86–7.80(m,2H),7.68–7.62(m,2H),7.47–7.43(m,2H),7.42–7.37(m, 3H),7.30–7.21(m,3H),4.05(d,J=7.6Hz,2H),1.84–1.74(m,1H),0.53(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 23 O2N3FS calculated value: 424.1490; measured value: 424.1468.

[0338] Example 40

[0339]

[0340] N-(3-(1-isobutyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 40)

[0341]

[0342] Using M-16 (50 mg, 0.19 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 62 mg of a white solid (Compound 40) in a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.80(d,J=8.0Hz,1H),7.73(dd,J=8.0,2.4Hz,3H),7.52–7.45(m,3H),7.39(q,J=7.2Hz,2H),7.32(dt ,J=7.2,2.4Hz,1H),7.08–7.03(m,2H),4.10(d,J=7.6Hz,2H),3.78(s,3H),1.84–1.77(m,1H),0.56(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 24 H 26 O3N3S calculated value: 436.1689; measured value: 436.1677.

[0343] Example 41

[0344]

[0345] N-(3-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 41)

[0346]

[0347] Using M-16 (50 mg, 0.19 mmol) as starting material and adopting the similar operation as in Example 5, 54 mg of white solid (Compound 41) was obtained with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.30(s,1H),7.69–7.64(m,2H),7.61–7.57(m,2H),7.44–7.38(m,3H),7.30–7 .23(m,3H),6.85–6.80(m,2H),4.06(d,J=7.6Hz,2H),1.82–1.75(m,1H),0.55(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 24 O3N3S calculated value: 422.1533; measured value: 422.1522.

[0348] Example 42

[0349]

[0350] N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 42)

[0351] first step:

[0352]

[0353] Using M-17 (cas: 95-54-5, 400 mg, 3.70 mmol) as the starting material, a similar operation as in the first step of Example 18 was performed to obtain a crude product. Using the crude product as the starting material, similar operations were performed in the first step and subsequent steps of Example 1 to obtain 542 mg of an off-yellow solid (M-18) with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ7.61–7.50(m,2H),7.44(d,J=2.0Hz,1H),7.29(d,J=7.6Hz,1H),7.23–7.15(m,3H),6.72–6.66(m,1H),5.32(s,2H).

[0354] Step 2:

[0355]

[0356] Using M-18 (50 mg, 0.24 mmol) as starting material and adopting the similar operation as in Example 4, 48 mg of an off-red solid (Compound 42) was obtained with a yield of 53%. 1 H NMR(500MHz,DMSO-d6)δ10.63(s,1H),8.02(t,J=2.0Hz,1H),7.92(d,J=8.0Hz,1H),7.83–7.75(m,4H), 7.58–7.48(m,3H),7.32(dd,J=8.0,2.0Hz,1H),7.09–7.04(m,2H),3.78(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 18 O3N3S calculated value: 380.1063; measured value: 380.1057.

[0357] Example 43

[0358]

[0359] 4-Methoxy-N-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 43)

[0360] first step:

[0361]

[0362] Using M-19 (cas: 4760-34-3, 400 mg, 3.27 mmol) as starting material, a crude product was obtained by similar procedures as in the first step of Example 18. Using the crude product as starting material, similar procedures were followed in the first step and subsequent steps of Example 1 to obtain 475 mg of an off-white solid (M-20) in a yield of 65%. 1 H NMR(400MHz, DMSO-d6)δ7.64(dd,J=7.6,1.6Hz,1H),7.58(dd,J=7.6,1.2Hz,1H),7.30–7.16(m,3H),7. 04(d,J=2.0Hz,1H),6.93(dt,J=8.0,1.2Hz,1H),6.73(dt,J=8.0,1.6Hz,1H),5.33(s,2H),3.85(s,3H).

[0363] Step 2:

[0364]

[0365] Using M-20 (50 mg, 0.22 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 60 mg of a white solid (Compound 43) in a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),7.88(d,J=7.6Hz,1H),7.79(t,J=7.6Hz,3H),7.65(s,1H),7.56– 7.50(m,4H),7.42–7.35(m,1H),7.08(d,J=8.4Hz,2H),3.87(s,3H),3.80(s,3H).HR-MS(ESI):m / z[M+H] + C 21 H 20 O3N3S calculated value: 394.1220; measured value: 394.1230.

[0366] Example 44

[0367]

[0368] N-(3-chloro-5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 44)

[0369] first step:

[0370]

[0371] To a 100 mL single-necked flask, add M-3 (500 mg, 2.29 mmol), 3-chloro-5-nitrobenzaldehyde (cas: 22233-54-1, 425 mg, 2.29 mmol), sodium metabisulfite (653 mg, 3.44 mmol), and DMF (30 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Using the crude product as the starting material, similar procedures to those in the first step and subsequent steps of Example 1 were followed to obtain 381 mg of a white solid (M-21), with a yield of 47%. 1 H NMR(400MHz,DMSO-d6)δ7.80–7.74(m,1H),7.68–7.64(m,2H),7.50–7.46(m,2H),7.34–7.26(m,2H), 7.23–7.18(m,1H),6.77(t,J=2.0Hz,1H),6.61(t,J=2.0Hz,1H),6.49(t,J=1.6Hz,1H),5.60(s,2H).

[0372] Step 2:

[0373]

[0374] Using M-21 (50 mg, 0.14 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 46 mg of a white solid (Compound 44) ​​in a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),7.82–7.78(m,1H),7.67–7.60(m,4H),7.48–7.44(m,2H),7.35–7.2 6(m,3H),7.24–7.19(m,2H),7.14(t,J=2.0Hz,1H),7.11–7.07(m,2H),3.81(s,3H).HR-MS(ESI):m / z[M+H] + C 26 H 20 Calculated for O3N3Cl2S: 524.0597; found: 524.0600.

[0375] Example 45

[0376]

[0377] 4-Chloro-N-(3-chloro-5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 45)

[0378]

[0379] Using M-21 (50 mg, 0.14 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 32 mg of a white solid (Compound 45) in a yield of 43%. 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),7.83–7.78(m,1H),7.67(d,J=7.2Hz,5H),7.64(d,J=2.0Hz,1H),7.49–7.44(m,2H),7 .34(qd,J=7.2,1.6Hz,2H),7.27(p,J=1.6Hz,2H),7.21(dd,J=7.2,2.0Hz,1H),7.15(t,J=2.0Hz,1H).HR-MS(ESI):m / z[M+H] + C 25 H 17 Calculated for O2N3Cl3S: 528.0102; found: 528.0103.

[0380] Example 46

[0381]

[0382] N-(3-chloro-5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 46)

[0383]

[0384] Using M-21 (50 mg, 0.14 mmol) as starting material and adopting the similar operation as in Example 5, 33 mg of white solid (Compound 46) was obtained with a yield of 45%. 1 H NMR(400MHz, DMSO-d6)δ10.53(s,1H),10.48(s,1H),7.80(dd,J=7.2,2.0Hz,1H),7.66–7.62(m,2H),7.54–7.49(m,2H),7 .47–7.43(m,2H),7.37–7.28(m,3H),7.23–7.17(m,2H),7.12(t,J=2.0Hz,1H),6.91–6.85(m,2H).HR-MS(ESI):m / z[M+H] + C 25 H 18 Calculated for O₃N₃Cl₂S: 510.0440; Found: 510.0440.

[0385] Example 47

[0386]

[0387] 4-Chloro-N-(5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)thiophen-2-yl)benzenesulfonamide (Compound 47)

[0388] first step:

[0389]

[0390] To a 100 mL single-necked flask, add M-3 (500 mg, 2.29 mmol), 5-nitro-2-thiophenecarboxaldehyde (cas: 4521-33-9, 359 mg, 2.29 mmol), sodium metabisulfite (652 mg, 3.43 mmol), and DMF (30 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Using the crude product as the starting material, similar procedures to those in the first step and subsequent steps of Example 1 were followed to obtain 261 mg of a yellow solid (M-22), with a yield of 35%.1 H NMR (400MHz, DMSO-d6) δ7.78–7.69(m,2H),7.58(d,J=8.8Hz,3H),7.19(t,J=7.6Hz,1H) ,7.11(t,J=7.6Hz,1H),6.91(d,J=8.0Hz,1H),6.40–6.21(m,3H),5.74(d,J=4.0Hz,1H).

[0391] Step 2:

[0392]

[0393] Using M-22 (50 mg, 0.15 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 24 mg of an off-yellow solid (Compound 47) in a yield of 31%. 1 H NMR (400MHz, DMSO-d6) δ7.78–7.69(m,2H),7.58(d,J=8.8Hz,3H),7.19(t,J=7.6Hz,1H),7.11(t,J= 7.6Hz,1H),6.91(d,J=8.0Hz,1H),6.40–6.21(m,3H),5.74(d,J=4.0Hz,1H).HR-MS(ESI):m / z[M+H] + C 23 H 16 Calculated for O2N3Cl2S2: 500.0056; found: 500.0062.

[0394] Example 48

[0395]

[0396] N-(5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)thiophen-2-yl)-4-methoxybenzenesulfonamide (Compound 48)

[0397]

[0398] Using M-22 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 21 mg of an off-yellow solid (Compound 48) in a yield of 27%. 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.75–7.65(m,5H),7.62–7.55(m,2H),7.30–7.21(m,2H), 7.14–7.06(m,2H),7.01(d,J=8.0Hz,1H),6.52–6.35(m,2H),3.83(s,3H).HR-MS(ESI):m / z[M+H] + C 24 H 19 Calculated for O3N3ClS2: 496.0551; found: 496.0555.

[0399] Example 49

[0400]

[0401] N-(3-(1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-chlorobenzenesulfonamide (Compound 49)

[0402] first step:

[0403]

[0404] Using M-17 (500 mg, 4.62 mmol) as starting material, a crude product was obtained by similar procedures as in the first step of Example 44. Using the crude product as starting material, similar procedures as in the first step and subsequent steps of Example 1 were used to obtain 743 mg of an off-yellow solid (M-23) with a yield of 66%. 1 HNMR(400MHz,DMSO-d6)δ12.82(s,1H),7.63–7.51(m,2H),7.37(t,J=1.6Hz,1H), 7.29(t,J=1.6Hz,1H),7.19(d,J=6.4Hz,2H),6.69(t,J=1.6Hz,1H),5.66(s,2H).

[0405] Step 2:

[0406]

[0407] Using M-23 (50 mg, 0.21 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 37 mg of a white solid (Compound 49) in a yield of 43%. 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),7.99(t,J=1.6Hz,1H),7.91(t,J=1.6Hz,1H ),7.86–7.79(m,2H),7.71–7.57(m,4H),7.29–7.21(m,3H).HR-MS(ESI):m / z[M+H] + C 19 H 14 Calculated for O2N3Cl2S: 418.0178; found: 418.0190.

[0408] Example 50

[0409]

[0410] N-(3-(1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-fluorobenzenesulfonamide (Compound 50)

[0411]

[0412] Using M-23 (50 mg, 0.21 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 33 mg of a white solid (Compound 50) in a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),10.81(s,1H),7.99(s,1H),7.94–7.87(m,3H),7.68(d,J=7 .6Hz,1H),7.53(d,J=7.6Hz,1H),7.43(t,J=8.8Hz,2H),7.28–7.19(m,3H).HR-MS(ESI):m / z[M+H] + C 19 H 14 O2N3ClFS calculated value: 402.0474; measured value: 402.0487.

[0413] Example 51

[0414]

[0415] N-(3-(1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-methoxybenzenesulfonamide (Compound 51)

[0416]

[0417] Using M-23 (50 mg, 0.21 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 46 mg of a white solid (Compound 51) in a yield of 54%.1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),7.99(t,J=1.6Hz,1H),7.87(t,J=1.6Hz,1H),7.77(d,J=9.2H z,2H),7.68–7.57(m,2H),7.30–7.19(m,3H),7.12–7.05(m,2H),3.78(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 17 Calculated for O3N3ClS: 414.0674; found: 414.0690.

[0418] Example 52

[0419]

[0420] N-(3-(1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-hydroxybenzenesulfonamide (Compound 52)

[0421]

[0422] Using M-23 (50 mg, 0.21 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 24 mg of a white solid (Compound 52) in a yield of 29%. 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),10.55(s,1H),10.50(s,1H),7.97(t,J=1.6Hz,1H),7.85(t,J=1.6H z,1H),7.70–7.63(m,3H),7.56–7.50(m,1H),7.28–7.18(m,3H),6.89–6.84(m,2H).HR-MS(ESI):m / z[M+H] + C 19 H 15 Calculated for O3N3ClS: 400.0517; found: 400.0530.

[0423] Example 53

[0424]

[0425] 4-Chloro-N-(3-chloro-5-(4-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 53)

[0426] first step:

[0427]

[0428] Using M-24 (cas: 177477-60-0, 200 mg, 1.31 mmol) as starting material, a crude product was obtained by similar procedures as in the first step of Example 44. Using the crude product as starting material, similar procedures were followed in the first step and subsequent steps of Example 1 to obtain 268 mg of an off-white solid (M-25), with a yield of 71%. 1 H NMR (400MHz, DMSO-d6) δ7.23–7.13(m,2H),6.98(t,J=1.6Hz,1H),6.93(t,J=1.6Hz,1H),6.78–6.71(m,2H),5.68(s,2H),3.95(s,3H),3.83(s,3H).

[0429] Step 2:

[0430]

[0431] Using M-25 (100 mg, 0.35 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 104 mg of a white solid (Compound 53) in a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.88–7.81(m,2H),7.72–7.65(m,2H),7.60(t,J=1.6Hz,1H),7.52(t,J=1.6Hz,1H) ,7.29(t,J=2.0Hz,1H),7.26–7.16(m,2H),6.77(dd,J=7.6,1.2Hz,1H),3.95(s,3H),3.78(s,3H).HR-MS(ESI):m / z[M+H] + C 21 H 18 Calculated for O₃N₃Cl₂S: 462.0440; Found: 462.0450.

[0432] Example 54

[0433]

[0434] 4-Fluoro-N-(3-chloro-5-(4-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 54)

[0435]

[0436] Using M-25 (100 mg, 0.35 mmol) as starting material and adopting the similar operation as in Example 3, 97 mg of an off-red solid (Compound 54) was obtained with a yield of 62%.1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.95–7.87(m,2H),7.59(t,J=1.6Hz,1H),7.52(t,J=1.6Hz,1H),7.48–7.41(m,2H) ,7.29(t,J=2.0Hz,1H),7.26–7.16(m,2H),6.78(dd,J=7.6,1.2Hz,1H),3.95(s,3H),3.78(s,3H).HR-MS(ESI):m / z[M+H] + C 21 H 18 O3N3ClFS calculated value: 446.0736; found value: 446.0739.

[0437] Example 55

[0438]

[0439] N-(3-Chloro-5-(4-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methoxybenzenesulfonamide (Compound 55)

[0440]

[0441] Using M-25 (100 mg, 0.35 mmol) as starting material, a similar operation as in Example 4 was performed to obtain 94 mg of a white solid (Compound 55) in a yield of 59%. 1 H NMR(400MHz, DMSO-d6)δ10.70(s,1H),7.83–7.72(m,2H),7.58–7.48(m,2H),7.28(t,J=2.0Hz,1H),7.24 –7.19(m,2H),7.14–7.07(m,2H),6.77(d,J=7.6Hz,1H),3.94(s,3H),3.79(s,6H).HR-MS(ESI):m / z[M+H] + C 22 H 21 Calculated for O4N3ClS: 458.0936; found: 458.0940.

[0442] Example 56

[0443]

[0444] N-(3-chloro-5-(4-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 56)

[0445]

[0446] Using M-25 (100 mg, 0.35 mmol) as starting material, a similar procedure as in Example 5 was employed to obtain 76 mg of an off-white solid (Compound 56) in a yield of 49%. 1 H NMR(400MHz, DMSO-d6)δ10.70(s,1H),7.83–7.72(m,2H),7.58–7.48(m,2H),7.28(t,J=2.0Hz,1H),7.25 –7.17(m,2H),7.14–7.07(m,2H),6.77(d,J=7.6Hz,1H),3.94(s,3H),3.79(s,6H).HR-MS(ESI):m / z[M+H] + C 21 H 19 Calculated for O4N3ClS: 444.0779; found: 444.0783.

[0447] Example 57

[0448]

[0449] N-(3-Chloro-5-(4-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-hydroxybenzenesulfonamide (Compound 57)

[0450]

[0451] Compound 55 (50 mg, 0.11 mmol) was added to a 25 mL two-necked flask, sealed and protected with argon. Anhydrous dichloromethane (5 mL) was injected, and the mixture was placed in an ice-salt bath (-5°C) and stirred for 30 min. Boron tribromide / dichloromethane solution (1N, 0.33 mL, 0.33 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 3-5 h. Excess methanol was added to quench the reaction, and the mixture was concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to give 38 mg of a white solid (Compound 57), in an 82% yield. 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),10.54(s,1H),9.84(s,1H),7.71–7.63(m,2H),7.55–7.46(m,2H),7.26(t,J=2.0Hz,1H),7 .09(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.93–6.87(m,2H),6.61(dd,J=8.0,1.2Hz,1H),3.73(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 17 Calculated for O4N3ClS: 430.0623; found: 430.0613.

[0452] Example 58

[0453]

[0454] 4-Fluoro-N-(3-chloro-5-(4-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide (Compound 58)

[0455]

[0456] Using compound 54 (50 mg, 0.11 mmol) as starting material, a similar procedure as in Example 57 was employed to obtain 43 mg of an off-white solid (compound 58) in a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.84(s,1H),7.95–7.87(m,2H),7.58(t,J=1.6Hz,1H),7.50(t,J=1.6Hz,1H),7.45(t,J=8.8Hz ,2H),7.28(t,J=2.0Hz,1H),7.09(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.61(d,J=7.6Hz,1H),3.73(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 16 O3N3ClFS calculated value: 432.0579; measured value: 432.0600.

[0457] Example 59

[0458]

[0459] N-(3-(4-amino-1-methyl-1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-chlorobenzenesulfonamide (Compound 59)

[0460] first step:

[0461]

[0462] Using M-26 (300 mg, 1.26 mmol) as starting material, the crude product was obtained by similar operations as in the first step of Example 44. Using the crude product as starting material, the subsequent operations were similar to those in the first step of Example 1 to obtain 321 mg of an off-yellow solid (M-27) with a yield of 68%. 1 HNMR(400MHz,DMSO-d6)δ8.28(s,1H),7.63(d,J=7.6Hz,1H),7.28–7.19(m,2H),6.98 (dt,J=8.4,1.6Hz,2H),6.75(t,J=2.0Hz,1H),5.69(s,2H),3.85(s,3H),1.50(s,9H).

[0463] Step 2:

[0464]

[0465] Using M-27 (100 mg, 0.27 mmol) as starting material, a similar operation as in the second step of Example 1 was performed to obtain 93 mg of a white solid (M-28) with a yield of 63%. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.36(s,1H),7.86(d,J=8.4Hz,2H),7.72– 7.61(m,4H),7.53(d,J=1.6Hz,1H),7.32–7.22(m,3H),3.80(s,3H),1.50(s,9H).

[0466] Step 3:

[0467]

[0468] M-28 (50 mg, 0.09 mmol), TFA (0.90 mL), and dichloromethane (3 mL) were added to a 10 mL single-necked flask and stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with petroleum ether / ethyl acetate = 5 / 1, filtered, washed, and dried to obtain 39 mg of an off-white solid (Compound 59) in a yield of 97%. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.89–7.80(m,2H),7.72–7.66(m,2H),7.57(t,J=1.6Hz,1H),7.48(t,J=1.6Hz,1H),7.26(t, J=2.0Hz,1H),6.99(t,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),6.41(d,J=8.0Hz,1H),5.36(s,2H),3.70(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 17 Calculated for O2N4Cl2S: 447.0444; found: 447.0456.

[0469] Example 60

[0470]

[0471] N-(3-(4-amino-1-methyl-1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-fluorobenzenesulfonamide (Compound 60)

[0472] first step:

[0473]

[0474] Using M-27 (100 mg, 0.27 mmol) as starting material, a similar operation as in Example 3 was performed to obtain 81 mg of an off-white solid (M-29) with a yield of 57%. 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.35(s,1H),7.96–7.89(m,2H),7.67–7.61(m,2H), 7.52(t,J=1.6Hz,1H),7.45(t,J=8.8Hz,2H),7.30–7.22(m,3H),3.79(s,3H),1.50(s,9H).

[0475] Step 2:

[0476]

[0477] Using M-29 (50 mg, 0.09 mmol) as starting material, a similar operation as in the third step of Example 59 was performed to obtain 38 mg of an off-white solid (Compound 60) in a yield of 93%. 1H NMR(400MHz, DMSO-d6)δ10.85(s,1H),7.91(dd,J=8.8,5.2Hz,2H),7.56(s,1H),7.51–7.40(m,3H),7.26(s,1H),6. 99(t,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),6.41(d,J=8.0Hz,1H),5.35(s,2H),3.70(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 17 O2N4ClFS calculated value: 431.0739; found value: 431.0754.

[0478] Example 61

[0479]

[0480] N-(3-(4-amino-1-methyl-1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-methoxybenzenesulfonamide (Compound 61)

[0481] first step:

[0482]

[0483] Using M-27 (100 mg, 0.27 mmol) as starting material, similar procedures as in Example 4 were employed to obtain 99 mg of an off-white solid (M-30) with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),8.36(s,1H),7.81–7.75(m,2H),7.64(dd,J=7.2,1.6Hz,1H),7.59(t,J=1 .6Hz,1H),7.51(t,J=1.6Hz,1H),7.30–7.23(m,3H),7.13–7.09(m,2H),3.81(s,3H),3.79(s,3H),1.50(s,9H).

[0484] Step 2:

[0485]

[0486] Using M-30 (50 mg, 0.09 mmol) as starting material, a similar operation to the third step in Example 59 was performed to obtain 40 mg of an off-yellow solid (Compound 61) in a yield of 97%. 1H NMR (400MHz, DMSO-d6) δ10.69(s,1H),7.78(d,J=8.4Hz,2H),7.54–7.46(m,2H),7.27(s,1H),7.11(d,J=8.4Hz,2H),6.99(t ,J=7.6Hz,1H),6.72(d,J=8.0Hz,1H),6.41(d,J=7.6Hz,1H),5.37(s,2H),3.80(s,3H),3.70(s,3H).HR-MS(ESI):m / z[M+H] + C 21 H 20 Calculated for O3N4ClS: 443.0939; found: 443.0957.

[0487] Example 62

[0488]

[0489] N-(3-(4-amino-1-methyl-1H-benzo[d]imidazol-2-yl)-5-chlorophenyl)-4-hydroxybenzenesulfonamide (Compound 62)

[0490] first step:

[0491]

[0492] Using M-27 (100 mg, 0.27 mmol) as starting material, a similar operation as in Example 5 was performed to obtain 84 mg of an off-white solid (M-31) with a yield of 59%. 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),10.54(s,1H),8.36(s,1H),7.69–7.66(m,2H),7.65–7.63(m,1H),7. 58(t,J=1.6Hz,1H),7.51(t,J=1.6Hz,1H),7.27–7.22(m,3H),6.91–6.88(m,2H),3.79(s,3H),1.50(s,9H).

[0493] Step 2:

[0494]

[0495] Using M-31 (50 mg, 0.09 mmol) as starting material, a similar operation as in the third step of Example 59 was performed to obtain 39 mg of an off-yellow solid (Compound 62) in a yield of 95%. 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),10.54(s,1H),7.67(d,J=8.4Hz,2H),7.49–7.45(m,2H),7.24(s,1H),6.99(t,J=8.4H z,1H),6.90(d,J=8.0Hz,2H),6.71(d,J=8.0Hz,1H),6.41(d,J=8.0Hz,1H),5.35(s,2H),3.70(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 18 Calculated for O3N4ClS: 429.0783; found: 429.0801.

[0496] Example 63

[0497]

[0498] 3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 63)

[0499] first step:

[0500]

[0501] M-3 (500 mg, 2.29 mmol), methyl 3-formylbenzoate (cas: 52178-50-4, 376 mg, 2.29 mmol), sodium metabisulfite (652 mg, 3.43 mmol), and DMF (25 mL) were added to a 100 mL single-necked bottle and heated at 120-140°C for 4 hours. The mixture was cooled, filtered, concentrated, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solvent of petroleum ether / ethyl acetate) to obtain 456 mg of an off-yellow solid (M-32), in a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ8.21(t,J=1.6Hz,1H),7.99(dt,J=8.0,1.6Hz,1H),7.85–7.80(m,1H),7.72(dt,J= 8.0,1.6Hz,1H),7.69–7.64(m,2H),7.57–7.51(m,3H),7.38–7.29(m,2H),7.26–7.22(m,1H),3.85(s,3H).

[0502] Step 2:

[0503]

[0504] M-32 (400 mg, 1.10 mmol), sodium hydroxide (176 mg, 4.41 mmol), tetrahydrofuran (10 mL), and water (5 mL) were added to a 50 mL single-necked flask and heated at 70-80°C for 2 hours. After cooling, concentrated hydrochloric acid was added dropwise to adjust the pH to 7-7.5. The mixture was concentrated, and the residue was slurried with petroleum ether / ethyl acetate = 3 / 1, filtered, washed, and dried to obtain 354 mg of a white solid (M-33) in a 92% yield. 1 H NMR(400MHz,DMSO-d6)δ8.19(t,J=1.6Hz,1H),8.05–8.00(m,1H),7.89(d,J=8.4Hz,1H),7.75(s, 1H),7.68(d,J=8.4Hz,2H),7.58(dd,J=8.4,2.4Hz,3H),7.49–7.38(m,2H),7.33(d,J=8.0Hz,1H).

[0505] Step 3:

[0506]

[0507] M-33 (50 mg, 0.14 mmol), p-methoxybenzenesulfonamide (cas: 1129-26-6, 54 mg, 0.29 mmol), EDCI (42 mg, 0.22 mmol), DMAP (9 mg, 0.07 mmol), TEA (40 μL, 0.29 mmol), and dichloromethane (8 mL) were added to a 25 mL single-necked flask and stirred at room temperature for 4 hours. The system was extracted with dichloromethane and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 34 mg of a white solid (Compound 63), in a 44% yield. 1 H NMR(400MHz, DMSO-d6)δ12.56(s,1H),8.20(t,J=1.6Hz,1H),7.95–7.86(m,3H),7.82(dd,J=7.2,1.6Hz,1H),7.65–7.60(m,2H),7 .55–7.50(m,1H),7.50–7.42(m,3H),7.37–7.28(m,2H),7.27–7.22(m,1H),7.18–7.11(m,2H),3.85(s,3H).HR-MS(ESI):m / z[M+H] + C 27 H 21 Calculated for O4N3ClS: 518.0936; found: 518.0937.

[0508] Example 64

[0509]

[0510] 3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-chlorophenyl)sulfonyl)benzamide (Compound 64)

[0511]

[0512] M-33 (50 mg, 0.14 mmol), p-chlorobenzenesulfonamide (cas: 98-64-6, 55 mg, 0.29 mmol), EDCI (42 mg, 0.22 mmol), DMAP (9 mg, 0.07 mmol), TEA (40 μL, 0.29 mmol), and dichloromethane (8 mL) were added to a 25 mL single-necked flask and stirred at room temperature for 4 hours. The system was extracted with dichloromethane and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 26 mg of a white solid (Compound 64), in a 35% yield. 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=1.6Hz,1H),7.97(d,J=8.4Hz,2H),7.93–7.87(m,1H),7.84–7.80(m,1H),7.70(d,J=8.4Hz,2H),7. 65–7.60(m,2H),7.52(d,J=8.0Hz,1H),7.47(dd,J=8.0,6.0Hz,3H),7.38–7.29(m,2H),7.25(d,J=8.0Hz,1H).HR-MS(ESI):m / z[M+H] + C 26 H 18 Calculated for O₃N₃Cl₂S: 522.0440; Found: 522.0445.

[0513] Example 65

[0514]

[0515] 3-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-fluorophenyl)sulfonyl)benzamide (Compound 65)

[0516]

[0517] M-33 (50 mg, 0.14 mmol), p-fluorobenzenesulfonamide (cas: 402-46-0, 51 mg, 0.29 mmol), EDCI (42 mg, 0.22 mmol), DMAP (9 mg, 0.07 mmol), TEA (40 μL, 0.29 mmol), and dichloromethane (8 mL) were added to a 25 mL single-necked flask and stirred at room temperature for 4 hours. The system was extracted with dichloromethane and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 29 mg of a white solid (Compound 65), in a 40% yield. 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.04(s,2H),7.90(d,J=7.6Hz,1H),7.82(d,J=7.6Hz,1H),7.62(d, J=8.4Hz,2H),7.48(q,J=8.4Hz,6H),7.33(p,J=7.6Hz,2H),7.25(d,J=7.6Hz,1H).HR-MS(ESI):m / z[M+H] + C 26 H 18 O3N3ClFS calculated value: 506.0736; found value: 506.0743.

[0518] Example 66

[0519]

[0520] N-((4-chlorophenyl)sulfonyl)-3-(1-isobutyl-1H-benzo[d]imidazol-2-yl)benzamide (Compound 66)

[0521] first step:

[0522]

[0523] Using M-15 (1.00 g, 6.09 mmol) as starting material, a similar operation as in the first step of Example 63 was performed to obtain 1.75 g of a brown oil (M-34) with a yield of 93%. 1 H NMR(400MHz, DMSO-d6)δ8.34(t,J=1.6Hz,1H),8.12(tt,J=8.4,1.6Hz,2H),7.77–7.68(m,3H),7 .34–7.22(m,2H),4.22(d,J=7.6Hz,2H),3.91(s,3H),2.04–1.92(m,1H),0.66(d,J=6.8Hz,6H).

[0524] Step 2:

[0525]

[0526] Using M-34 (1.70 g, 5.51 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 1.54 g of a white solid (M-35) with a yield of 95%. 1 H NMR(400MHz, DMSO-d6)δ13.25(s,1H),8.30(t,J=1.6Hz,1H),8.14–8.05(m,2H),7.73–7.67 (m,3H),7.33–7.23(m,2H),4.21(d,J=7.6Hz,2H),2.02–1.91(m,1H),0.66(d,J=6.8Hz,6H).

[0527] Step 3:

[0528]

[0529] Using M-35 (50 mg, 0.17 mmol) as starting material, a similar operation as in Example 64 was performed to obtain 56 mg of a white solid (Compound 66) in a yield of 71%. 1 H NMR(400MHz, DMSO-d6)δ8.29(t,J=1.6Hz,1H),8.04(dt,J=8.0,1.6Hz,1H),7.95–7.86(m,3H),7.69(dd,J=8.0,1.6Hz,2H),7 .61–7.50(m,3H),7.33–7.25(m,2H),4.20(d,J=7.6Hz,2H),1.97–1.87(m,1H),0.64(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 24 H 23 Calculated for O3N3ClS: 468.1143; Found: 468.1148.

[0530] Example 67

[0531]

[0532] N-((4-Fluorophenyl)sulfonyl)-3-(1-isobutyl-1H-benzo[d]imidazol-2-yl)benzamide (Compound 67)

[0533]

[0534] Using M-35 (50 mg, 0.17 mmol) as starting material, a similar operation as in Example 65 was performed to obtain 57 mg of a white solid (Compound 67) in a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=1.6Hz,1H),8.07–7.95(m,3H),7.91(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,2H),7.59(t, J=7.6Hz,1H),7.39–7.23(m,4H),4.20(d,J=7.6Hz,2H),1.95–1.90(m,1H),0.64(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 24 H 23 O3N3FS calculated value: 452.1439; measured value: 452.1440.

[0535] Example 68

[0536]

[0537] 3-(1-Isobutyl-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 68)

[0538]

[0539] Using M-35 (50 mg, 0.17 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 54 mg of a white solid (Compound 68) in a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),8.27(d,J=1.6Hz,1H),8.05–7.88(m,4H),7.73–7.60(m,3H),7.33–7.22(m,2H),7. 09(d,J=8.8Hz,2H),4.20(d,J=7.6Hz,2H),3.83(s,3H),1.96–1.88(m,1H),0.63(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 25 H 26 O4N3S calculated value: 464.1639; measured value: 464.1639.

[0540] Example 69

[0541]

[0542] N-((4-chlorophenyl)sulfonyl)-3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)benzamide (Compound 69)

[0543] first step:

[0544]

[0545] Using M-13 (1.00 g, 6.66 mmol) as starting material, a similar operation as in the first step of Example 63 was performed to obtain 1.90 g of a brown oil (M-36) with a yield of 97%. 1 H NMR (400MHz, DMSO-d6) δ8.24(t,J=1.6Hz,1H),8.15(dt,J=7.6,1.6Hz,1H),7.98–7.93(m,1H),7.87–7.82(m,1H),7. 75(t,J=7.6Hz,1H),7.73–7.68(m,1H),7.31–7.23(m,2H),4.72(p,J=6.8Hz,1H),3.91(s,3H),1.61(d,J=6.8Hz,6H).

[0546] Step 2:

[0547]

[0548] Using M-36 (1.80 g, 6.12 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 1.64 g of a white solid (M-37) with a yield of 96%. 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.21(t,J=1.6Hz,1H),8.13(dt,J=7.6,1.6Hz,1H),7.92(dt,J=7.6,1.6 Hz,1H),7.87–7.82(m,1H),7.76–7.67(m,2H),7.31–7.22(m,2H),4.72(p,J=6.8Hz,1H),1.61(d,J=6.8Hz,6H).

[0549] Step 3:

[0550]

[0551] Using M-37 (50 mg, 0.18 mmol) as starting material, a similar procedure as in Example 64 was employed to obtain 62 mg of a white solid (Compound 69) in a yield of 77%. 1H NMR (400MHz, DMSO-d6) δ8.20(t,J=1.6Hz,1H),8.08(d,J=7.6Hz,1H),7.94–7.86(m,3H),7.78(d,J=7.6Hz,1H),7.73–7.68( m,1H),7.65–7.55(m,3H),7.30(dd,J=6.8,3.2Hz,2H),4.71(p,J=6.8Hz,1H),1.60(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 21 Calculated for O3N3ClS: 454.0987; Found: 454.0989.

[0552] Example 70

[0553]

[0554] N-((4-Fluorophenyl)sulfonyl)-3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)benzamide (Compound 70)

[0555]

[0556] Using M-37 (50 mg, 0.18 mmol) as starting material, a similar procedure as in Example 65 was employed to obtain 59 mg of a white solid (Compound 70) in a yield of 75%. 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.6Hz,1H),8.07(dt,J=7.6,1.6Hz,1H), 8.03–7.96(m,2H),7.89–7.83(m,1H),7.79(dt,J=7.6,1.6Hz,1H),7.73–7.6 7(m,1H),7.62(t,J=7.6Hz,1H),7.35(t,J=8.8Hz,2H),7.28(td,J=6.8,3.2 Hz,2H),4.70(p,J=6.8Hz,1H),1.60(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 23 H 21 O3N3FS calculated value: 438.1282; measured value: 438.1281.

[0557] Example 71

[0558]

[0559] 3-(1-Isopropyl-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 71)

[0560]

[0561] Using M-37 (50 mg, 0.18 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 54 mg of a white solid (Compound 71) in a yield of 67%. 1 H NMR(400MHz, DMSO-d6)δ12.68(s,1H),8.14(t,J=1.6Hz,1H),8.04(dt,J=7.6,1.6Hz,1H),7.97–7.91(m,2H),7.85(td,J=6.8,1.6Hz,2H), 7.73–7.65(m,2H),7.31–7.22(m,2H),7.17–7.10(m,2H),4.68(p,J=6.8Hz,1H),3.84(s,3H),1.59(d,J=6.8Hz,6H).HR-MS(ESI):m / z[M+H] + C 24 H 24 O4N3S calculated value: 450.1482; measured value: 450.1482.

[0562] Example 72

[0563]

[0564] 3-(1H-Benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 72)

[0565] first step:

[0566]

[0567] Using M-17 (1.00 g, 9.25 mmol) as starting material, a similar operation as in the first step of Example 63 was performed to obtain 1.47 g of a white solid (M-38) with a yield of 63%. 1 H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.81(t,J=1.6Hz,1H),8.47–8.43(m,1H),8.07(dt, J=8.0,1.6Hz,1H),7.76–7.67(m,2H),7.59–7.53(m,1H),7.29–7.18(m,2H),3.94(s,3H).

[0568] Step 2:

[0569]

[0570] Using M-38 (1.00 g, 3.96 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 888 mg of a white solid (M-39) with a yield of 94%. 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=2.0Hz,1H),8.27(d,J=7.6Hz,1H),8.05–7.97(m,1H),7.67–7.59(m,2H),7.57–7.51(m,1H),7.23–7.16(m,2H).

[0571] Step 3:

[0572]

[0573] Using M-39 (100 mg, 0.42 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 84 mg of a white solid (Compound 72) in a yield of 49%. 1 H NMR(400MHz, DMSO-d6)δ8.80(d,J=2.0Hz,1H),8.27(d,J=7.6Hz,1H),8.03–7.94(m,1H),7.70 –7.58(m,4H),7.54–7.48(m,1H),7.31–7.22(m,2H),7.09–7.06(m,2H).HR-MS(ESI):m / z[M+H] + C 21 H 18 O4N3S calculated value: 408.1013; measured value: 408.1025.

[0574] Example 73

[0575]

[0576] N-((4-Methoxyphenyl)sulfonyl)-3-(1-methyl-1H-benzo[d]imidazol-2-yl)benzamide (Compound 73)

[0577] first step:

[0578]

[0579] Using M-19 (1.00 g, 8.19 mmol) as starting material, a similar operation as in the first step of Example 63 was performed to obtain 1.50 g of an off-white solid (M-40) with a yield of 69%. 1H NMR (400MHz, DMSO-d6) δ8.43(t,J=2.0Hz,1H),8.18–8.11(m,2H),7.78–7.69(m,2H),7.67–7.62(m,1H),7.36–7.24(m,2H),3.92(s,6H).

[0580] Step 2:

[0581]

[0582] Using M-40 (1.40 g, 5.26 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 1.30 g of a white solid (M-41) with a yield of 98%. 1 H NMR (400MHz, DMSO-d6) δ13.37(s,1H),8.44(d,J=2.4Hz,1H),8.24–8.16(m,2H),7.87–7.75(m,3H),7.46(p,J=7.2Hz,2H),3.97(s,3H).

[0583] Step 3:

[0584]

[0585] Using M-41 (100 mg, 0.40 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 45 mg of a white solid (Compound 73) in a yield of 54%. 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.04(d,J=7.6Hz,1H),7.89(d,J=7.6Hz,1H),7.82(d,J=8.4Hz,2H),7.69(d,J=7.6Hz,1H),7. 62(d,J=8.0Hz,1H),7.55(t,J=7.6Hz,1H),7.33–7.25(m,2H),7.01–6.94(m,2H),3.88(s,3H),3.79(s,3H).HR-MS(ESI):m / z[M+H] + C 22 H 20 O4N3S calculated value: 422.1169; measured value: 422.1170.

[0586] Example 74

[0587]

[0588] 5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)-1H-pyrrole-2-carboxamide (Compound 74)

[0589] first step:

[0590]

[0591] M-3 (200 mg, 0.91 mmol), methyl 5-formylpyrrole-2-carboxylate (cas: 1197-13-3, 140 mg, 0.91 mmol), sodium metabisulfite (261 mg, 1.37 mmol), and DMF (15 mL) were added to a 50 mL single-necked bottle and heated at 120-140°C for 4 hours. The mixture was cooled, filtered, concentrated, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solvent of petroleum ether / ethyl acetate) to obtain 145 mg of an off-yellow solid (M-42) in a yield of 45%. 1 HNMR(400MHz,DMSO-d6)δ12.35(s,1H),7.80–7.75(m,1H),7.75–7.69(m,2H),7.60–7.51(m,2H),7.35– 7.24(m,2H),7.16–7.10(m,1H),6.74(dd,J=4.0,2.0Hz,1H),5.68(dd,J=4.0,2.0Hz,1H),3.77(s,3H).

[0592] Step 2:

[0593]

[0594] Using M-42 (100 mg, 0.28 mmol) as the starting material, a similar operation as in the second step of Example 63 was performed to obtain 91 mg of an off-white solid (M-43) with a yield of 95%. 1 H NMR(400MHz,DMSO-d6)δ12.57(s,1H),11.97(s,1H),7.79–7.72(m,3H),7.61–7.51(m,2H),7.3 7–7.22(m,2H),7.13(d,J=8.0Hz,1H),6.68(dd,J=4.0,2.4Hz,1H),5.68(dd,J=4.0,2.4Hz,1H).

[0595] Step 3:

[0596]

[0597] Using M-43 (50 mg, 0.15 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 14 mg of a gray solid (Compound 74) in a yield of 18%. 1 H NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.79–7.68 (m, 4H), 7.61–7. 56(m,2H),7.34–7.04(m,6H),5.53(d,J=3.6Hz,1H),3.82(s,3H).HR-MS(ESI):m / z[M+H] + C 25 H 20 Calculated for O4N4ClS: 507.0888; found: 507.0884.

[0598] Example 75

[0599]

[0600] 5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-chlorophenyl)sulfonyl)-1H-pyrrole-2-carboxamide (Compound 75)

[0601]

[0602] Using M-43 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 64 was performed to obtain 16 mg of an off-yellow solid (Compound 75) in a yield of 21%. 1 H NMR(400MHz, DMSO-d6)δ7.89(d,J=8.4Hz,2H),7.73(dd,J=8.4,3.2Hz,3H),7.63–7.51(m,4H),7. 30–7.23(m,2H),7.07(d,J=8.0Hz,1H),6.54(s,1H),5.52(d,J=3.6Hz,1H).HR-MS(ESI):m / z[M+H] + C 24 H 17 Calculated for O3N4Cl2S: 511.0393; Found: 511.0393.

[0603] Example 76

[0604]

[0605] 5-(1-(4-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-N-((4-fluorophenyl)sulfonyl)-1H-pyrrole-2-carboxamide (Compound 76)

[0606]

[0607] Using M-43 (50 mg, 0.15 mmol) as starting material, a similar operation as in Example 65 was performed to obtain 11 mg of an off-yellow solid (Compound 76) in a yield of 15%. 1 H NMR(400MHz,DMSO-d6)δ7.93(s,2H),7.75–7.70(m,3H),7.62–7.56(m,2H),7.33–7.24( m,4H),7.07(d,J=8.0Hz,1H),6.47(s,1H),5.50(d,J=3.6Hz,1H).HR-MS(ESI):m / z[M+H] + C 24 H 17 O3N4ClFS calculated value: 495.0688; found value: 495.0687.

[0608] Example 77

[0609]

[0610] 3-(1H-Benzo[d]imidazol-2-yl)-5-chloro-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 77)

[0611] first step:

[0612]

[0613] To a 100 mL single-necked flask, add M-17 (545 mg, 5.04 mmol), methyl 3-chloro-5-formylbenzoate (cas: 879542-48-0, 1.00 g, 5.04 mmol), sodium metabisulfite (1436 mg, 7.55 mmol), and DMF (30 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (eluted with a mixed solvent of petroleum ether / ethyl acetate) to afford 1.01 g of an off-white solid (M-44) in a 70% yield. 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.74(q,J=1.2Hz,1H),8.49(t,J=1.6Hz,1H),8.01(t,J =1.6Hz,1H),7.71(d,J=7.6Hz,1H),7.57(d,J=7.6Hz,1H),7.26(p,J=6.8Hz,2H),3.94(s,3H).

[0614] Step 2:

[0615]

[0616] Using M-44 (1.00 g, 3.49 mmol) as the starting material, a similar operation as in the second step of Example 63 was performed to obtain 818 mg of an off-yellow solid (M-45) with a yield of 86%. 1 H NMR (400MHz, DMSO-d6) δ13.60 (s, 1H), 13.36 (s, 1H), 8.74 (t, J = 1.6Hz, 1H), 8.5 0(dq,J=3.6,2.0Hz,1H),7.99(t,J=2.0Hz,1H),7.68–7.60(m,2H),7.25(s,2H).

[0617] Step 3:

[0618]

[0619] M-45 (50 mg, 0.18 mmol) was used as the starting material and the same operation as in the third step of Example 63 was performed to obtain 45 mg of an off-yellow solid (Compound 77) in a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),8.67(t,J=1.6Hz,1H),8.22(t,J=2.0Hz,1H),7.93(dd,J=2.0,1.2Hz,1 H),7.85–7.79(m,2H),7.60(s,2H),7.26–7.18(m,2H),6.98–6.92(m,2H),3.79(s,3H).HR-MS(ESI):m / z[M+H] + C 21 H 17 Calculated for O4N3ClS: 442.0623; Found: 442.0623.

[0620] Example 78

[0621]

[0622] 3-(1H-Benzo[d]imidazol-2-yl)-5-chloro-N-((4-chlorophenyl)sulfonyl)benzamide (Compound 78)

[0623]

[0624] M-45 (50 mg, 0.18 mmol) was used as the starting material and a similar procedure as in Example 64 was employed to obtain 32 mg of an off-white solid (Compound 78) in a 40% yield.1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),8.68(s,1H),8.23(s,1H),8.03–7.87(m,3H),7.61(s,2H),7.28–7.19(m,4H).HR-MS(ESI):m / z[M+H] + C 20 H 14 Calculated for O₃N₃Cl₂S: 446.0127; Found: 446.0127.

[0625] Example 79

[0626]

[0627] 3-(1H-Benzo[d]imidazol-2-yl)-5-chloro-N-((4-fluorophenyl)sulfonyl)benzamide (Compound 79)

[0628]

[0629] M-45 (50 mg, 0.18 mmol) was used as the starting material and a similar operation as in Example 65 was performed to obtain 25 mg of an off-yellow solid (Compound 79) in a yield of 32%. 1 H NMR(400MHz, DMSO-d6)δ13.13(s,1H),8.68(s,1H),8.22(t,J=2.0Hz,1H),7.96–7.87(m,3H),7.61(s,2H),7.27–7.20(m,4H).HR-MS(ESI):m / z[M+H] + C 20 H 14 O3N3ClFS calculated value: 430.0432; measured value: 430.0432.

[0630] Example 80

[0631]

[0632] 3-(1H-Benzo[d]imidazol-2-yl)-5-chloro-N-((3,4-dimethoxyphenyl)sulfonyl)benzamide (Compound 80)

[0633]

[0634] M-45 (50 mg, 0.18 mmol), 3,4-dimethoxybenzenesulfonamide (cas: 63624-27-1, 78 mg, 0.37 mmol), EDCI (53 mg, 0.28 mmol), DMAP (12 mg, 0.09 mmol), TEA (51 μL, 0.37 mmol), and dichloromethane (8 mL) were added to a 25 mL single-necked flask and stirred at room temperature for 4 hours. The system was extracted with dichloromethane and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 26 mg of a white solid (Compound 80), in a 30% yield. 1 H NMR (400MHz, DMSO-d6) δ13.06(s,1H),8.65(t,J=1.6Hz,1H),8.24(t,J=2.0Hz,1H),7.95–7.88(m,1H),7.87–7. 76(m,2H),7.62(s,1H),7.28–7.19(m,2H),6.98–6.92(m,2H),3.85(s,3H),3.76(s,3H).HR-MS(ESI):m / z[M+H] + C 22 H 19 Calculated for O5N3ClS: 472.0728; found: 472.0725.

[0635] Example 81

[0636]

[0637] 3-Chloro-5-(6-methoxy-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 81)

[0638] first step:

[0639]

[0640] Using M-46 (cas: 102-51-2, 350 mg, 2.52 mmol) as starting material, a similar operation as in the first step of Example 77 was performed to obtain 366 mg of an off-white solid (M-47) with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),8.69(s,1H),8.43(s,1H),7.97(s,1H),7. 56–7.49(m,1H),7.16–7.09(m,1H),6.91–6.84(m,1H),3.94(s,3H),3.82(s,3H).

[0641] Step 2:

[0642]

[0643] Using M-47 (300 mg, 0.95 mmol) as starting material, a similar operation as in the second step of Example 63 was adopted to obtain 252 mg of a white solid (M-48) with a yield of 88%. 1 H NMR(400MHz, CD3OD)δ8.48(t,J=1.6Hz,1H),8.17(t,J=2.0Hz,1H),8.05–7.93(m,1H), 7.50(d,J=8.8Hz,1H),7.11(d,J=2.4Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),3.86(s,3H).

[0644] Step 3:

[0645]

[0646] Using M-48 (50 mg, 0.17 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 31 mg of a white solid (Compound 81) in a yield of 40%. 1 H NMR (400MHz, CD3OD) δ8.47(t,J=1.6Hz,1H),8.20(t,J=2.0Hz,1H),7.96–7.92(m,1H),7.72–7.66(m,2H),7.61–7.5 3(m,1H),7.18–7.10(m,1H),7.09–7.03(m,2H),6.97–6.89(m,1H),3.87(s,3H),3.81(s,3H).HR-MS(ESI):m / z[M+H] + C 22 H 19 Calculated for O5N3ClS: 472.0728; Found: 472.0727.

[0647] Example 82

[0648]

[0649] 3-Chloro-5-(5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)benzamide (Compound 82)

[0650] first step:

[0651]

[0652] Using M-49 (cas: 27841-33-4, 430 mg, 2.56 mmol) as starting material, a similar operation as in the first step of Example 77 was performed to obtain 384 mg of an off-white solid (M-50) with a yield of 32%. 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),8.66(t,J=2.0Hz,1H),8.40(t,J=2.0Hz,1 H),7.94(t,J=2.0Hz,1H),7.16–7.07(m,2H),3.94(s,3H),3.83(d,J=4.0Hz,6H).

[0653] Step 2:

[0654]

[0655] Using M-50 (350 mg, 1.01 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 252 mg of a white solid (M-51) with a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ8.79–8.76(m,1H),8.74(s,1H),8.09–8.04(m,1H),7.22(s,2H),3.88(s,6H).

[0656] Step 3:

[0657]

[0658] Using M-51 (50 mg, 0.15 mmol) as starting material, a similar operation as in the third step of Example 63 was performed to obtain 26 mg of a white solid (Compound 82) in a yield of 35%. 1 H NMR (400MHz, CD3OD) δ8.67(t,J=2.0Hz,1H),8.42(t,J=2.0Hz,1H),7.94(t,J=2.0Hz,1H),7.72–7.66(m ,2H),7.18–7.10(m,2H),7.09–7.03(m,2H),3.84(d,J=4.0Hz,6H),3.80(s,3H).HR-MS(ESI):m / z[M+H] + C 23 H 21 Calculated for O₆N₃ClS: 502.0834; Found: 502.0830.

[0659] Example 83

[0660]

[0661] 5-(1H-Benzo[d]imidazol-2-yl)-N-((4-methoxyphenyl)sulfonyl)nicotinamide (Compound 83)

[0662] first step:

[0663]

[0664] To a 50 mL single-necked bottle, add M-17 (100 mg, 0.92 mmol), methyl 5-formylnicotinate (cas: 6221-06-3, 153 mg, 0.92 mmol), sodium metabisulfite (264 mg, 1.39 mmol), and DMF (15 mL). Heat at 120-140°C for 4 hours. Cool, filter, concentrate, and extract with ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (eluted with a mixed solvent of petroleum ether / ethyl acetate) to afford 208 mg of an off-yellow solid (M-52), in an 89% yield. 1 HNMR (400MHz, DMSO-d6) δ13.33(s,1H),9.58(d,J=2.0Hz,1H),9.15(t,J=2.0Hz,1H),9.02(t,J =2.0Hz,1H),7.73(d,J=7.6Hz,1H),7.59(d,J=7.6Hz,1H),7.27(p,J=7.2Hz,2H),3.97(s,3H).

[0665] Step 2:

[0666]

[0667] Using M-52 (180 mg, 0.71 mmol) as starting material, a similar operation as in the second step of Example 63 was performed to obtain 153 mg of an off-white solid (M-53) with a yield of 90%. 1 H NMR (400MHz, CD3OD) δ9.38(d,J=2.0Hz,1H),9.18(d,J=2.0Hz,1H),8.98(t,J=2.0Hz,1H),7.66(dd,J=6.0,3.2Hz,2H),7.31(dd,J=6.0,3.2Hz,2H).

[0668] Step 3:

[0669]

[0670] M-53 (100 mg, 0.42 mmol), p-methoxybenzenesulfonamide (157 mg, 0.84 mmol), CDI (102 mg, 0.63 mmol), DMAP (26 mg, 0.21 mmol), TEA (87 μL, 0.63 mmol), and dichloromethane (8 mL) were added to a 25 mL single-necked flask and stirred at room temperature for 4 hours. The system was extracted with dichloromethane and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixed solvent) to obtain 50 mg of an off-white solid (Compound 83) in a yield of 29%. 1 H NMR (400MHz, CD3OD) δ9.46(d,J=2.0Hz,1H),9.16(t,J=2.0Hz,1H),9.01(t,J=2.0Hz,1H),7 .74–7.62(m,4H),7.31–7.23(m,2H),7.09–7.03(m,2H),3.80(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 17 O4N4S calculated value: 409.0965; measured value: 409.0968.

[0671] Example 84

[0672]

[0673] N-(6-(6-chloro-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)-3,4-dimethoxybenzenesulfonamide (Compound 84)

[0674] first step:

[0675]

[0676] M-54 (cas: 95-83-0, 94 mg, 0.66 mmol), 6-nitro-2-pyridinecarboxaldehyde (cas: 131747-64-3, 100 mg, 0.66 mmol), sodium metabisulfite (188 mg, 0.99 mmol), and DMF (10 mL) were added to a 50 mL single-necked flask and heated at 120-140°C for 4 hours. The mixture was cooled, filtered, concentrated, and extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Using the crude product as the starting material, similar procedures were followed in the first step and subsequent steps of Example 1 to obtain 105 mg of an off-yellow solid (M-55), with a yield of 65%. 1H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.34(s,1H),7.56–7.44(m,3H),7.20–7.13(m,1H),6.82–6.73(m,1H),6.30(s,2H).

[0677] Step 2:

[0678]

[0679] M-55 (50 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), and 3,4-dimethoxybenzenesulfonyl chloride (cas: 23095-31-0, 58 mg, 0.25 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at room temperature for 3 hours. The pyridine was removed by concentration, and the residue was purified by silica gel column chromatography (eluted with a methanol / dichloromethane mixture) to obtain 40 mg of an off-white solid (Compound 84), in a 43% yield. 1 HNMR(400MHz,DMSO-d6)δ12.81(s,1H),11.40(s,1H),8.35(s,1H),7.71(d,J=2.0Hz,1H),7.56–7.46(m,3H) ,7.41–7.34(m,1H),7.22–7.13(m,2H),6.79–6.71(m,1H),3.87(s,3H),3.81(s,3H).HR-MS(ESI):m / z[M+H] + C 20 H 18 Calculated for O4N4ClS: 445.0732; found: 445.0728.

[0680] Experimental example: biological activity test

[0681] Experimental Example 1: Test of the Inhibitory Activity of the Compounds of the Invention on Human FBPase

[0682] Experimental principle: Human FBPase can react with phosphoglucose isomerase (PGI) and glucose-6-phosphate dehydrogenase (G6PDH) to catalyze the conversion of NADP + It is reduced to NADPH with specific absorption at 340 nm. Therefore, the absorbance of NADPH at 340 nm can be measured by spectrophotometry to evaluate the activity of the compound in inhibiting human FBPase in vitro.

[0683] Experimental method: Tris buffer (pH 7.5), 10 μM compound and 0.72 units of FBPase were mixed in a cuvette, incubated at 37°C for 60 min, and then 0.2 mM NADP was added. +The reaction was initiated with 0.01 unit PGI and 0.01 unit G6PDH and incubated at 37°C for 40 min. The absorbance at OD 340 nm was read using EnVision and data were collected to preliminarily evaluate the inhibitory effect of each compound at 10 μM.

[0684] Table 1. Inhibitory activity of the compounds of the present invention on human FBPase

[0685]

[0686]

[0687] Experimental Example 2: Oral pyruvate tolerance test (OPTT) of the compounds of the present invention on ICR mice

[0688] Experimental principle: Pyruvate is a substrate for gluconeogenesis. Oral administration of pyruvate to fasting animals can increase blood glucose levels through gluconeogenesis. Mice given different drugs show different upward and downward trends in blood glucose. Therefore, an oral pyruvate tolerance test in fasting ICR mice can be used to quickly screen for FBPase inhibitors with in vivo hypoglycemic activity.

[0689] Experimental Methods: ICR mice were grouped and fasted for 16 hours. Each drug was administered at 150 mg / kg BW. Blood was collected 1 hour later. Sodium pyruvate 2.0 g / kg BW was then administered orally. Blood was collected 30 and 90 minutes after administration. Blood samples were centrifuged at 6000 rpm for 1 minute at room temperature. 20 μL of the supernatant was mixed with 180 μL of GOD enzyme solution and reacted at 37°C for 40 minutes. OD values ​​were measured spectrophotometrically at 505 nm (using a sugar standard solution as a control). Mice in the blank group received 0.1 mL / 10 g BW of distilled water, while mice in the positive control group received 150 mg / kg BW of metformin.

[0690] Table 2. Effects of the compounds of the present invention and metformin on pyruvate tolerance in ICR mice (n=8)

[0691]

[0692] * P<0.05, **P<0.01 vs Control.

[0693] As shown in Table 2, compound 77 has the best activity in lowering fasting blood glucose in ICR mice, which is similar to that of metformin. The compounds of the present invention have strong FBPase inhibitory activity and are particularly suitable as hypoglycemic drugs for the treatment of type II diabetes.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, A is phenyl or a 5-6 membered heteroaryl group containing at least one atom selected from N, O or S; L is -NHSO2- or -CONHSO2-; R1 is selected from H, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl; The substituents in R1 are independently selected from: F, Cl, Br, hydroxyl, carboxyl, -COOCH3, acetamido, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or C1-C3 alkylamino; R2 is selected from one or more H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R3 is selected from one or more H, F, Cl, Br, C1-C3 alkyl, acetyl, acetamido, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R4 is selected from one or more H, F, Cl, Br, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (II): in, X is N or CH; L, R1, R2, R3, and R4 are as described in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (III): in, Y is N, O or S; L, R1, R2, R3, and R4 are as described in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (IV): in, X is N or CH; L, R1, R2, R3, and R4 are as described in claim 1.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (V): in, R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl; R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (VI): in, R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl; R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

7. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (VII): in, R1 is selected from H, methyl, ethyl, Substituted or unsubstituted Substituted or unsubstituted The substituent in R1 is selected from F, Cl, Br, C1-C3 alkyl, acetyl, acetylamino, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R2 is selected from H, F, Cl, Br, amino, C1-C3 alkyl, acetyl, acetamido, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, C1-C3 alkoxy, C1-C3 alkylamino; R3 is selected from H, F, Cl, Br, cyano, methyl, ethyl, isopropyl; R4 is selected from H, F, Cl, Br, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

9. A method for preparing a compound according to any one of claims 1 to 8, comprising the following steps: (1) The intermediate I-1 reacts with an R3-substituted nitroaromatic formaldehyde, followed by reduction to obtain I-2, which is then condensed with an R4-substituted benzenesulfonyl chloride to obtain the compound represented by formula (I); or (2) The intermediate I-1 reacts with R3-substituted formyl aromatic methyl formate to produce I-3, I-3 is hydrolyzed to produce I-4, and I-4 is condensed with R4-substituted benzenesulfonamide to produce the compound represented by formula (I); wherein R1, R2, R3, R4, A and L are as defined in claim 1.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for preventing or treating fructose 1,6-bisphosphatase target-related diseases.

12. The use according to claim 11, wherein the fructose 1,6-bisphosphatase target-related disease is type II diabetes and its complications, such as fasting hyperosmolar hyperglycemic state, ketoacidosis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic skin lesions, atherosclerosis, diabetic foot disease, and infection.

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