Benzimidazole compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a benzimidazole compound, a preparation method thereof and application of the benzimidazole compound in preparation of medicines for treating or preventing infectious diseases caused by mycobacterium tuberculosis. Specifically, the invention relates to a compound as shown in formula (I), pharmaceutically acceptable salts thereof and a pharmaceutical composition containing the compound, and A, R1, R2, R3 and R4 are described in the specification. The invention aims to prepare a new compound with mycobacterium tuberculosis polyketide synthase 13 inhibitory activity, and the new compound can be used as a potential new medicine for treating or preventing infection caused by mycobacterium tuberculosis. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to a benzimidazole compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing an anti-tuberculosis mycobacterium drug. Background Art

[0002] Tuberculosis (TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. In the face of the severe situation of tuberculosis, the field still needs to research and develop anti-tuberculosis drugs with new targets and novel structures.

[0003] Mycobacterium tuberculosis polyketide synthase 13 (Pks13) belongs to the polyketide synthase family and plays the final assembly role in the biosynthesis of tuberculin acid. It is composed of five domains, including the keto synthase domain (KS), the acyltransferase domain (AT), two acyl carrier protein domains (ACP) and the thioesterase domain (TE). The five domains correspond to different catalytic activities, which are responsible for the processing and transfer of the two precursor carbon chains of mycolic acid and mediate the Claisen condensation reaction to complete the assembly of mycolic acid. Inhibiting Pks13 can effectively inhibit the biosynthesis of mycolic acid and kill Mycobacterium tuberculosis. Therefore, Pks13 is a promising target for anti-tuberculosis drugs. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a Mycobacterium tuberculosis polyketide synthase 13 inhibitor with a novel structure.

[0005] In order to solve the technical problem of the present invention, the present invention provides the following technical solution:

[0006] The first aspect of the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in,

[0009] R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy;

[0010] R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group;

[0011] R3 is hydrogen or C1-C3 alkyl;

[0012] R4 is

[0013] R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0014] A is R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0015] The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0016] The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino.

[0017] In some aspects, the compound of formula I is selected from the compounds of formula (I-1):

[0018]

[0019] in,

[0020] R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy;

[0021] R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group;

[0022] R3 is hydrogen or C1-C3 alkyl;

[0023] R4 is

[0024] R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0025] R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0026] The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0027] The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino.

[0028] In some aspects, the compound of formula I is selected from the compound of formula (I-2):

[0029]

[0030] in,

[0031] R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy;

[0032] R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group;

[0033] R3 is hydrogen or C1-C3 alkyl;

[0034] R4 is

[0035] R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0036] R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0037] The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0038] The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino.

[0039] In some aspects, the compound of formula I is selected from the compound of formula (I-3):

[0040]

[0041] in,

[0042] R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy;

[0043] R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group;

[0044] R3 is hydrogen or C1-C3 alkyl;

[0045] R4 is

[0046] R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0047] R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0048] The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0049] The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino.

[0050] In some aspects, the compound of formula I is selected from the compound of formula (I-4):

[0051]

[0052] in,

[0053] R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy;

[0054] R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group;

[0055] R3 is hydrogen or C1-C3 alkyl;

[0056] R4 is

[0057] R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0058] R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0059] The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino;

[0060] The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino.

[0061] According to any one of the compounds and pharmaceutically acceptable salts of the first aspect of the present invention, wherein:

[0062] R1 is selected from hydrogen, hydroxy, F, Cl, Br, methoxy or methyl;

[0063] R2 is methyl, ethyl, isopropyl,

[0064] R3 is selected from hydrogen or methyl;

[0065] R4 is selected from

[0066] R6 is selected from hydrogen, F, Cl, Br, hydroxy, methoxy or methyl.

[0067] The pharmaceutically acceptable salts described in the present invention are salts formed between the compounds of the present invention and an acid selected from the following: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, fumaric acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.

[0068] The compound according to any one of the first aspects of the present invention is the target compound of the present invention prepared in the examples (represented by a structural formula or described by a systematic name) or a pharmaceutically acceptable salt thereof.

[0069] According to any one of the compounds of the first aspect of the present invention, it is a compound selected from the following:

[0070]

[0071]

[0072]

[0073]

[0074] 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 synthesis method: (1)

[0076]

[0077] The raw material a is condensed with an amino compound under alkaline conditions such as potassium carbonate to obtain an intermediate b, b is reduced to obtain c, c reacts with hydroxyacetic acid to obtain a benzimidazole compound d, the hydroxyl group in d is converted into chlorine under the action of dichloride to obtain e, and then the intermediate e is subjected to a substitution reaction with a corresponding piperazine compound under the action of potassium carbonate to obtain an intermediate g, and then reduction, acylation and substitution reactions are performed to obtain a product represented by formula (I-1); (2)

[0079]

[0080] Compound c reacts with methyl trichloroacetimidate to obtain benzimidazole compound j, and then intermediate j reacts with the corresponding piperazine compound under the action of potassium carbonate to obtain intermediate k, which is then subjected to reduction, acylation and substitution reactions to obtain the product shown in formula (I-2); (3)

[0082]

[0083] The intermediate e reacts with the corresponding piperazinone compound under the action of potassium carbonate to obtain the intermediate s, which is then subjected to reduction, acylation and substitution to obtain the product shown in formula (I-3); (4)

[0085]

[0086] Compound c is cyclized with an aldehyde compound in the presence of Na2S2O5 and DMF to give a benzimidazole compound v, which is then subjected to reduction, acylation and substitution to give a product of formula (I-4).

[0087] The third aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of any compound of the first aspect of the present invention and a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0088] The fourth aspect of the present invention provides use of the compound and pharmaceutically acceptable salt thereof according to any one of the first aspect of the present invention, or the pharmaceutical composition according to any one of the third aspect of the present invention for treating and preventing infectious diseases caused by Mycobacterium tuberculosis.

[0089] The features of any aspect of the present invention or any item of any aspect are also applicable to any other aspect or any item of any other aspect, as long as they do not contradict each other. Of course, when applicable to each other, the corresponding features can be appropriately modified if necessary. In the present invention, for example, when referring to "any item of the first aspect of the present invention", the "any item" refers to any sub-aspect of the first aspect of the present invention, and when other aspects are referred to in a similar manner, they also have similar meanings. Detailed description of the invention:

[0091] Various aspects and features of the present invention are further described below.

[0092] The various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail. The following are the definitions of various terms used in the present invention, which apply to the terms used in the entire specification of this application, unless otherwise specified in specific circumstances.

[0093] 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 substituted at each position in the same or different manner. Among them, the substituents can be, but are not limited to, hydrogen, halogen, cyano, nitro, hydroxyl, amino (-NH2) arylamine, aminoalkyl, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, 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 , R c and R dEach is independently hydrogen, cyano, amino, alkylamino, arylamino, alkylthio, alkoxy, aryloxy, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylsulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, aminoalkylacyl or alkylacyl.

[0094] 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 It refers to a moiety having an integer "i" (inclusive) to an integer "j" (inclusive) carbon atoms. Thus, for example, C1-C3 alkyl refers to an alkyl group having 1 to 3 (inclusive) carbon atoms, particularly methyl, ethyl and C3 alkyl.

[0095] As used herein, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which is a straight or branched alkyl group, and which may include its subgroups, such as when referring to "C1-C3 alkyl", it may also include sub-ranges of groups represented by C1-C2 alkyl, C2-C3 alkyl, and specific groups such as methyl, ethyl, n-propyl, isopropyl. The terms "alkoxy" and "alkylamino" are customary expressions and refer to alkyl groups connected to the rest of the molecule through 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, isopropoxy, n-propoxy, and the like. Alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, n-propylamino, and the like.

[0096] As used herein, the terms "halo", "halogen", "halogen atom", "halo" and the like represent fluorine, chlorine, bromine or iodine.

[0097] As used herein, the term "effective amount" refers to the amount of a drug that can achieve the desired treatment of a disease or condition described herein in a subject.

[0098] As used 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 having pharmaceutical use value.

[0099] As described herein, the term "pharmaceutical composition", which may also be a "composition", can be used to achieve treatment of the diseases or disorders described herein in a subject, particularly a mammal.

[0100] "Treatment" for illness includes:

[0101] (1) preventing the disease, that is, preventing the clinical symptoms of the disease from occurring in a mammal that is exposed to or susceptible to the disease but does not experience or show symptoms of the disease,

[0102] (2) inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms,

[0103] (3) Alleviate the disease, that is, cause recovery of the disease or its clinical symptoms.

[0104] "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. The therapeutically effective amount may also refer to any amount of a compound that is sufficient to achieve the desired beneficial effect, including preventing, inhibiting, or alleviating the disease as described in (1)-(3) above. For example, the amount of the compound may be between 1-300 mg / kg, or preferably, 10-200 mg / kg, or more preferably, 20-100 mg / kg. Preferably, the amount of the compound is administered to the mammal twice a day. More preferably, the amount of the compound is administered to the mammal once a day. More preferably, the amount of the compound is administered to the mammal once a week or once every two weeks.

[0105] As described herein, the term "disease and / or condition" refers to a physical state of the subject, which is related to the disease and / or condition described in the present invention. For example, the disease and / or condition described in the present invention refers to Mycobacterium tuberculosis infectious disease.

[0106] Another aspect of the present invention also relates to a pharmaceutical composition having the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use.

[0107] The compounds of the present invention or pharmaceutical compositions containing the same can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0108] The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0109] The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0110] 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, isopropanol, 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 dodecyl sulfate, etc.; the lubricant and solubilizing agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0111] 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.

[0112] In order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a cosolvent, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The 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.

[0113] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0114] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0115] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation. DETAILED DESCRIPTION

[0116] The present invention can be described in detail by the following examples, but it is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious 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 present invention.

[0117] For all of the following examples, standard manipulations and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structures of the compounds were determined by H NMR ( 1 HNMR) and / or mass spectrometry (MS). The H NMR spectrum shift (δ) is given in parts per million (ppm). The NMR spectrum is measured using a Mercury-400 or Brucker-500 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (ACETONE-d6) or deuterated chloroform (CDCl3) as solvent and tetramethylsilane (TMS) as internal standard. Column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel as carrier.

[0118] Preparation Example

[0119] Preparation Example 1 Preparation of Intermediate g2

[0120]

[0121] Step 1: Preparation of f2 2-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0122] 2-(Chloromethyl)-1H-benzo[d]imidazole (84 mg, 0.5 mmol), raw material e1 (134 mg, 0.65 mmol), anhydrous potassium carbonate (138 mg, 1 mmol) were used as raw materials, 10 mL of DMF was used as solvent, and stirred at 100°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, an appropriate amount of water was added, and ethyl acetate was extracted three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After silica gel column chromatography (methanol / dichloromethane = 2.5%), intermediate f2 was obtained as a yellow solid of 138 mg, with a yield of 82%. 1 HNMR(400MHz,DMSO-D6)δ12.34(s,1H),8.08–8.00(m,2H),7.60–7.54(m,1H),7.48–7.40(m,1H), 7.19–7.10(m,2H),7.04–7.01(m,2H),3.79(s,2H),3.49(t,J=5.2Hz,4H),2.61(t,J=5.2Hz,4H).

[0123] Step 2: Preparation of f3 1-isobutyl-2-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0124] Take a sealed tube, add intermediate f2 (100 mg, 0.3 mmol), isobutyl bromide (60 μl, 0.6 mmol), anhydrous potassium carbonate (83 mg, 0.6 mmol), 10 mL DMF, heat to 100 ° C, and stir for 8 h. After the reaction is completed by TLC monitoring, add appropriate amount of water to the reaction solution, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane = 2%), intermediate f3 is obtained as a yellow solid 70 mg, with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ8.11(d,J=9.6Hz,2H),7.80–7.73(m,1H),7.39–7.35(m,1H),7.31–7.22(m,2H),6.81(d,J=9.6Hz,2H) ,4.13(d,J=7.6Hz,2H),3.89(s,2H),3.41(t,J=5.2Hz,4H),2.71(t,J=5.2Hz,4H),2.38–2.31(m,1H),0.98(d,J=6.8Hz,6H).

[0125] Step 3: Preparation of intermediate g2 4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)aniline

[0126] Take intermediate f3 (70 mg, 0.18 mmol) as raw material, dissolve in 5 mL of dichloromethane, add Pd / C (14 mg, 20%), place a hydrogen balloon, ventilate three times, stir at room temperature overnight, filter, concentrate the filtrate to obtain g2, 65 mg of white solid, yield 99%. 1 H NMR (400MHz, CDCl3) δ7.86–7.65(m,1H),7.42–7.32(m,1H),7.28–7.23(m,2H),6.82(d,J=8.4Hz,2H),6.64(d,J=8.8Hz,2H),4. 15(d,J=7.6Hz,2H),3.90(s,2H),3.06(s,4H),2.73(s,4H),2.40–2.31(m,1H),0.98(s,3H),0.96(s,3H).LC-MS(ESI):m / z[M+H] + :364.23.

[0127] Preparation Example 2 Preparation of Intermediate g3

[0128]

[0129] Step 1: Preparation of j1 N-cyclohexyl-2-nitroaniline

[0130] Take a 100mL single-mouth bottle, add o-fluoronitrobenzene (375μl, 3.54mmol), cyclohexylamine (405μl, 3.54mmol), anhydrous potassium carbonate (977mg, 7.08mmol), 15mL DMF, heat to 100℃, and stir for 5h. After TLC monitoring, add appropriate amount of water to the reaction solution, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (ethyl acetate / petroleum ether = 10%), intermediate j1 is obtained as a yellow oil 730mg, with a yield of 93.7%. 1 H NMR (500MHz, CDCl3) δ8.22–8.05(m,2H),7.44–7.34(m,1H),6.86(d,J=9.0Hz,1H),6.61–6.56(m,1H),3 .52(d,J=10.0Hz,1H),2.06(d,J=11.0Hz,2H),1.83–1.79(m,2H),1.68–1.64(m,1H),1.49–1.23(m,5H).

[0131] Step 2: Preparation of k1 N1-cyclohexylbenzene-o-phenylenediamine

[0132] Take a 50mL single-mouth bottle, add intermediate j1 (400mg, 1.82mmol), dissolve it in 10mL dichloromethane, then add Pd / C (40mg, 10%), place a hydrogen balloon, ventilate three times, and stir at room temperature overnight. After the reaction is completed by TLC monitoring, filter and concentrate the filtrate to obtain intermediate k1, 320mg of brown oil, with a yield of 92%. 1 H NMR(500MHz,DMSO-D6)δ6.53(dd,J=7.5,1.5Hz,1H),6.49-6.42(m,2H),6.39-6.35(m,1H),4.43(s,2H),4.04(s, 1H),3.15(s,1H),1.97-1.93(m,2H),1.75-1.70(m,2H),1.63-1.58(m,1H),1.37-1.28(m,2H),1.25–1.05(m,3H).

[0133] Step 3: Preparation of a2 (1-cyclohexyl-1H-benzo[d]imidazol-2-yl)methanol

[0134] Intermediate k1 (327 mg, 1.72 mmol), glycolic acid (157 mg, 2.06 mmol) as raw materials, 20% HCl as solvent, placed in a microwave reactor, 130 ° C, 200 W, 2 atmospheres, react for 30 minutes and then take out. After TLC monitoring, adjust the pH to 9 with 15% NaOH solution, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. Silica gel column chromatography (methanol / dichloromethane = 3%) to obtain intermediate a2, 380 mg of brown oil, yield 96%. 1 H NMR (400MHz, CDCl3) δ7.71–7.62(m,1H),7.60–7.52(m,1H),7.25–7.17(m,2H),4.97(s,1H),4.87(s,2H),4.49 –4.40(m,1H),2.25–2.14(m,2H),2.07–1.90(m,4H),1.88–1.75(m,1H),1.57-1.44(m,2H),1.39–1.26(m,1H).

[0135] Step 4: Preparation of b3 2-(Chloromethyl)-1-cyclohexyl-1H-benzimidazole [d] imidazole

[0136] Intermediate a2 (300 mg, 1.3 mmol) was used as raw material and DCM was used as solvent. Sulfonyl chloride (1.5 mL, 20.3 mmol) was slowly added under ice bath and stirred at room temperature for 1 h. After the reaction was completed under TLC monitoring, the reaction solution was concentrated to obtain intermediate b3 as a yellow solid (310 mg) with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.99–7.93(m,1H),7.84–7.76(m,1H),7.58–7.51(m,2H),5.39(s,2H),4.63–4.47(m,1H),2.34–2. 23(m,2H),2.19–2.15(m,2H),2.08(d,J=13.6Hz,2H),1.91(d,J=13.2Hz,1H),1.57(q,J=13.2Hz,2H),1.48–1.31(m,1H).

[0137] Step 5: Preparation of f4 1-cyclohexyl-2-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0138] Intermediate b3 (216 mg, 0.87 mmol), e1 (249 mg, 1.2 mmol), anhydrous potassium carbonate (241 mg, 1.74 mmol) were used as raw materials, 20 mL of DMF was used as solvent, the temperature was raised to 100 ° C and stirred for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, an appropriate amount of water was added, and ethyl acetate was extracted three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Intermediate f4 was obtained by silica gel column chromatography (methanol / dichloromethane = 2.5%), 252 mg of yellow solid, and the yield was 69%. 1 H NMR (400MHz, CDCl3) δ8.11(d,J=9.2Hz,2H),7.83–7.68(m,1H),7.63–7.48(m,1H),7.33–7.13(m,2H),6.81(d,J=9.2Hz,2H),4.64–4.47(m,1H) ),3.89(s,2H),3.37(t,J=5.2Hz,4H),2.68(t,J=5.2Hz,4H),2.39–2.13(m,2H),2.07–1.91(m,4H),1.82(d,J=12.0Hz,1H),1.56–1.28(m,3H).

[0139] Step 6: Preparation of intermediate g3 4-(4-[(1-cyclohexyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)aniline

[0140] Take intermediate f4 (150 mg, 0.35 mmol) as raw material, dissolve in 5 mL of dichloromethane, add Pd / C (25 mg, 20%), place a hydrogen balloon, ventilate three times, and stir at room temperature overnight. After the reaction is completed by TLC monitoring, filter and concentrate the filtrate to obtain intermediate g3, an off-white solid, 136 mg, and a yield of 100%. 1 H NMR (400MHz, CDCl3) δ7.84–7.70(m,1H),7.63–7.52(m,1H),7.24–7.16(m,2 H),6.79(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),4.70–4.44(m,1H),3.87(s ,2H),3.02(t,J=4.8Hz,4H),2.73–2.60(m,4H),2.34–2.14(m,2H),2.0–1.9 2(m,4H),1.80(d,J=12.0Hz,1H),1.54–1.30(m,3H).LC-MS(ESI):m / z[M+H] + :390.25.

[0141] Preparation Example 3 Preparation of Intermediate g4

[0142]

[0143] Step 1: Preparation of f5 1-methyl-2-((4-(2-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0144] Using raw material b1 (110 mg, 0.6 mmol), raw material e2 (125 mg, 0.6 mmol), anhydrous potassium carbonate (166 mg, 1.2 mmol) as raw materials and 5 mL DMF as solvent, a preparation method similar to intermediate f2 was adopted to obtain intermediate f5, a yellow solid of 135 mg, with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ8.12(d,J=2.0Hz,1H),8.10(d,J=2.0Hz,1H),7.79–7.71(m,1H),7.39–7.35(m,1H),7.34–7.27( m,2H),6.82(d,J=2.0Hz,1H),6.80(d,J=2.0Hz,1H),3.90(s,3H),3.89(s,2H),3.44–3.35(m,4H),2.77–2.63(m,4H).

[0145] Step 2: Preparation of intermediate g4 2-(4-[(1-methyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)aniline

[0146] Intermediate f5 (120 mg, 0.35 mmol) was used as the starting material, and a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g4, a white solid, 70 mg, with a yield of 62%. 1 H NMR (400MHz, DMSO-D6) δ7.58(dd,J=8.0,1.2Hz,1H),7.55–7.50(m,1H),7.26–7.21(m,1H),7.19–7.15(m,1H),6.88–6.84(m,1H),6.81–6.76(m,1H) ,6.65(dd,J=7.6,1.6Hz,1H),6.52(dd,J=7.6,1.6Hz,1H),4.70(s,2H),3 .87(s,3H),3.85(s,2H),2.79(s,4H),2.63(s,4H).LC-MS(ESI):m / z[M+H] + :322.10.

[0147] Preparation Example 4 Preparation of Intermediate g5

[0148]

[0149] Step 1: Preparation of f6 1-methyl-2-((4-(3-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0150] Using raw material b1 (181 mg, 1 mmol), raw material e3 (207 mg, 1 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) as raw materials and 5 mL DMF as solvent, a preparation method similar to intermediate f2 was adopted to obtain intermediate f6, 240 mg of yellow solid, with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ7.76 (dd, J=6.8, 1.6Hz, 1H), 7.69 (t, J=2.4Hz, 1H), 7.67–7.62 (m, 1H) ,7.38–7.25(m,4H),7.20–7.13(m,1H),3.90(s,5H),3.30–3.23(m,4H),2.76–2.68(m,4H).

[0151] Step 2: Preparation of intermediate g5 3-(4-[(1-methyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)aniline

[0152] Using f6 (135 mg, 0.42 mmol) as raw material, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g5, a white solid, 131 mg, with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.75(d,J=7.6Hz,1H),7.36(d,J=7.2Hz,1H),7.33–7.23(m,2H),7.03(t,J=8.0Hz,1H),6.34(dd,J=8.4, 2.4Hz,1H),6.27–6.18(m,2H),3.90(s,3H),3.89(s,2H),3.14(d,J=5.2Hz,4H),2.69(t,J=5.2Hz,4H).LC-MS(ESI):m / z[M+H] + :322.06.

[0153] Preparation Example 5 Preparation of Intermediate g6

[0154]

[0155] Step 1: Preparation of b4 1-cyclohexyl-2-(trichloromethyl)-1H-benzo[d]imidazole

[0156] Take a 50mL single-mouth bottle, add intermediate k1 (500mL, 2.6mmol), methyl 2,2,2-trichloroacetimidate (464mg, 2.6mmol), 2mL acetone, and stir at room temperature for 1h. After the reaction is completed by TLC monitoring, filter and wash the filter cake with water 3 times to obtain intermediate b4, a white solid of 700mg, with a yield of 85%. 1 H NMR (400MHz, DMSO-D6) δ7.94(d,J=8.4Hz,1H),7.80(d,J=8.0Hz,1H),7.45–7.30(m,2H),5. 02–4.83(m,1H),2.40-2.27(m,2H),1.94(t,J=13.2Hz,4H),1.71(s,1H),1.55–1.30(m,3H).

[0157] Step 2: Preparation of f7 (1-cyclohexyl-1H-benzo[d]imidazol-2-yl)(4-(4-nitrophenyl)piperazine-1-yl)methanone

[0158] Take a 100mL single-mouth bottle, add b4 (700mg, 2.2mmol), raw material e1 (911mg, 4.4mmol), anhydrous potassium carbonate (1215mg, 8.8mmol), acetonitrile / water = 3 / 1 (30mL), set up a reflux condenser, reflux and stir for 8h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, add appropriate amount of water, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (ethyl acetate / petroleum ether = 40%), intermediate f7 is obtained as a yellow solid 750mg, with a yield of 79%. 1 H NMR(400MHz, CDCl3)δ8.12(d,J=9.2Hz,2H),7.82–7.75(m,1H),7.64(dd,J=6.8,2.4Hz,1H) ,7.31(tt,J=7.2,5.6Hz,2H),6.84(d,J=9.6Hz,2H),4.63–4.50(m,1H),4.05–3.97(m,2H), 3.96–3.88(m,2H),3.60–3.57(m,2H),3.55–3.47(m,2H),2.29–2.19(m,2H),2.06–1.99(m, 2H),1.98–1.88(m,2H),1.79(d,J=12.8Hz,1H),1.56–1.41(m,2H),1.33(t,J=12.8Hz,1H).

[0159] Step 3: Preparation of intermediate g6 (4-(4-aminophenyl)piperazine-1-yl)(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)methanone

[0160] Using f7 (700 mg, 1.6 mmol) as raw material, Pd / C (140 mg, 20%) and DCM as solvent, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g6, a white solid of 600 mg, with a yield of 93%. 1 H NMR(400MHz,DMSO-D6)δ7.83(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.35–7.22 (m,2H),6.72(d,J=8.4Hz,2H),6.51(d,J=8.4Hz,2H),4.68(s,2H),4.43–4.22(m, 1H),3.84(s,2H),3.54(s,2H),3.01(s,2H),2.88(s,2H),2.23–2.10(m,2H),1.9 2–1.83(m,4H),1.68(d,J=11.2Hz,1H),1.48–1.28(m,3H).LC-MS(ESI):m / z[M+H] + :404.26.

[0161] Preparation Example 6 Preparation of Intermediate g7

[0162]

[0163] Step 1: Preparation of e6 4-(4-nitrophenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester

[0164] Take a 50mL two-necked bottle, add p-bromonitrobenzene (47mg, 0.23mmol), Boc piperazinone (50mg, 0.25mmol), Brettphos (13mg, 0.023mmol), allylpalladium chloride (9mg, 0.023mmol), cesium carbonate (225mg, 0.69mmol), cyclopentyl methyl ether (5mL), argon protection, ventilate 3 times, reflux condenser, heat to 100℃, stir for 3h. After the reaction is completed, monitor the reaction by TLC, and concentrate the reaction solution. Silica gel column chromatography (methanol / dichloromethane = 2%) gives intermediate e6, yellow solid 65mg, yield 86%. 1 H NMR (400MHz, CDCl3) δ8.27(d,J=9.2Hz,2H),7.54(d,J=9.2Hz,2H),4.29(s,2H),3.83(s,4H),1.51(s,9H).

[0165] Step 2: Preparation of e7 1-(4-nitrophenyl)piperazine-2-one

[0166] Take a 50mL single-mouth bottle, add intermediate e6 (60mg, 0.19mmol), then add hydrochloric acid / ethyl acetate solution (8mL), stir at room temperature for 1h. After the reaction is completed by TLC monitoring, filter and obtain intermediate e7, 25mg of white solid, yield 59%. 1 HNMR (400MHz, DMSO-D6) δ10.15(brs,2H),8.30(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),4.01(t,J=5.6Hz,2H),3.91(s,2H),3.55(t,J=5.6Hz,2H).

[0167] Step 3: Preparation of f8 4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl))methyl)-1-(4-nitrophenyl)piperazin-2-one

[0168] Using intermediate e7 (180 mg, 0.8 mmol), intermediate b3 (200 mg, 0.8 mmol), anhydrous potassium carbonate (221 mg, 1.6 mmol) as raw materials and 20 mL DMF as solvent, a preparation method similar to intermediate f2 was used to obtain intermediate f8, a yellow solid (273 mg), with a yield of 79%. 1 H NMR (400MHz, CDCl3) δ8.28–8.21(m,2H),7.80–7.73(m,1H),7.64–7.58(m,1H),7.54(d,J=8.4Hz,2H),7.27–7.24(m,2H),4.47(t,J=12.4Hz,1H),3. 97(s,2H),3.72–3.70(m,2H),3.53(s,2H),2.95(d,J=5.2Hz,2H),2.38–2 .20(m,2H),2.05–1.91(m,4H),1.85(d,J=12.8Hz,1H),1.53–1.31(m,3H).

[0169] Step 4: Preparation of intermediate g7 1-(4-aminophenyl)-4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-2-one

[0170] Using f8 (200 mg, 0.46 mmol) as raw material and DCM as solvent, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g7, an off-white solid of 128 mg, with a yield of 70%. 1H NMR (400MHz, CDCl3) δ7.76(s,1H),7.60(s,1H),7.27–7.23(m,2H),7.01(d,J=8.0Hz,2H),6.67(d,J=8.0Hz,2H),4.57–4.53(m,1H),3.94(s,2H),3 .54(s,2H),3.45(s,2H),2.84(s,2H),2.31–2.22(m,2H),1.98(t,J=17.6 Hz,4H),1.85(d,J=12.8Hz,1H),1.56–1.31(m,3H).LC-MS(ESI):m / z[M+H] + :404.27.

[0171] Preparation Example 7 Preparation of Intermediate g8

[0172]

[0173] Step 1: Preparation of f9 1-cyclohexyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole

[0174] Take a 100mL single-mouth bottle, add intermediate k1 (387mg, 2.03mmol), p-nitrobenzaldehyde (307mg, 2.03mmol), sodium pyrosulfite (580mg, 3.05mmol), 20mL DMF, heat to 100°C, and stir for 4h. After TLC monitoring, add appropriate amount of water to the system, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (ethyl acetate / petroleum ether = 35%), intermediate f9 is obtained as a yellow solid 476mg, with a yield of 73%. 1 HNMR(400MHz, CDCl3)δ8.40(d,J=8.4Hz,2H),7.86(d,J=8.0Hz,3H),7.71–7.69(m,1H),7.35–7.31(m, 2H), 4.30 (t, J = 12.4Hz, 1H), 2.37 (d, J = 12.4Hz, 2H), 1.99 (d, J = 13.6Hz, 4H), 1.80 (s, 1H), 1.35 (s, 3H).

[0175] Step 2: Preparation of intermediate g8 4-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)aniline

[0176] Using intermediate f9 (150 mg, 0.47 mmol) and Pd / C (30 mg, 20%) as raw materials, a preparation method similar to that of intermediate g2 was adopted to obtain raw material g8, a white solid, 112 mg, with a yield of 82%. 1H NMR (400MHz, CDCl3) δ7.79(d,J=7.6Hz,1H),7.63(d,J=7.2Hz,1H),7.44(d,J=8.0Hz,2H),7.25–7.20(m,2H),6.79(d,J=8.0Hz,2H),4 .40(t,J=12.4Hz,1H),3.93(s,1H),2.33(d,J=12.4Hz,2H),1.96–1.92(m,4H),1.76(s,1H),1.36–1.31(m,3H).LC-MS(ESI):m / z[M+H] + :291.99.

[0177] Preparation Example 8 Preparation of Intermediate g9

[0178]

[0179] Step 1: Preparation of j2 N-cyclopentyl-2-nitroaniline

[0180] Take a 100mL single-mouth bottle, add o-fluoronitrobenzene (375μl, 3.54mmol), cyclopentylamine (350μl, 3.54mmol), anhydrous potassium carbonate (977mg, 7.08mmol), 15mL DMF, heat to 100℃, and stir for 5h. After the reaction is completed by TLC monitoring, add appropriate amount of water to the reaction solution, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (ethyl acetate / petroleum ether = 10%), intermediate j2 is obtained as a yellow oil 690mg, with a yield of 94%. 1 HNMR(400MHz, CDCl3)δ8.15(dd,J=8.4,1.6Hz,1H),8.13–8.07(m,1H),7.45–7.36(m,1H),6.88(d,J=8.8Hz,1H ),6.60(dd,J=8.4,7.2Hz,1H),3.96(q,J=6.0Hz,1H),2.17–2.02(m,2H),1.84–1.73(m,2H),1.72–1.54(m,4H).

[0181] Step 2: Preparation of K4 N1-cyclopentylbenzene-o-phenylenediamine

[0182] Take a 50mL single-mouth bottle, add intermediate j2 (500mg, 2.42mmol), dissolve it in 10mL dichloromethane, then add Pd / C (50mg, 10%), place a hydrogen balloon, ventilate three times, and stir at room temperature overnight. After the reaction is completed by TLC monitoring, filter and concentrate the filtrate to obtain intermediate k4, 382mg of brown oil, with a yield of 89%. 1H NMR (400MHz, DMSO-D6) δ6.55–6.48(m,2H),6.47–6.36(m,2H),4.67(s,3H),3.80–3.54(m,1H),1.95–1.88(m,2H),1.67(s,2H),1.61–1.39(m,4H).

[0183] Step 3: Preparation of a5 (1-cyclopentyl-1H-benzo[d]imidazol-2-yl)methanol

[0184] Using intermediate k4 (200 mg, 1.14 mmol) and glycolic acid (104 mg, 1.36 mmol) as raw materials and 20% HCl (2 mL) as solvent, a preparation method similar to intermediate a2 was adopted to obtain intermediate a5, 210 mg of yellow oil, with a yield of 85%. 1 H NMR (400MHz, DMSO-D6) δ7.60 (dd, J=7.2, 2.0Hz, 1H), 7.54 (dd, J=7.2, 2.0Hz, 1H), 7.23–7.13 (m, 2H), 5. 60(s,1H),5.08(p,J=9.2Hz,1H),4.72(s,2H),2.13–2.06(m,4H),2.0–1.92(m,2H),1.78–1.68(m,2H).

[0185] Step 4: Preparation of b6 2-Chloromethyl-1-cyclopentyl-1H-benzo[d]imidazole

[0186] Intermediate a5 (180 mg, 0.83 mmol) was used as raw material and DCM as solvent. A preparation method similar to that of intermediate b3 was adopted to obtain intermediate b6 as a yellow solid (185 mg). The yield was 95%. 1 H NMR(400MHz, CDCl3)δ7.97–7.90(m,1H),7.64(dt,J=7.2,3.6Hz,1H),7.56–7.51(m,2H),5.43(s,2H ),5.11(t,J=8.8Hz,1H),2.42(s,2H),2.34–2.21(m,2H),2.15(d,J=8.4Hz,2H),2.01–1.84(m,2H).

[0187] Step 5: Preparation of f10 1-cyclopentyl-2-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0188] Using intermediate b6 (150 mg, 0.64 mmol), intermediate e1 (172 mg, 0.83 mmol), anhydrous potassium carbonate (177 mg, 1.28 mmol) as raw materials and 10 mL DMF as solvent, a preparation method similar to intermediate f2 was used to obtain intermediate f10, a yellow solid of 189 mg, with a yield of 73%. 1 H NMR(400MHz, DMSO-D6)δ8.10–7.99(m,2H),7.61(dd,J=7.2,2.0Hz,1H),7.58–7.49(m,1H),7.19(m,2H),7.05–6.96(m,2H),5.24– 5.15(m,1H),3.88(s,2H),3.45–3.39(m,4H),2.54(t,J=5.2Hz,4H),2.12(q,J=7.6Hz,4H),2.00–1.97(m,2H),1.80–1.68(m,2H).

[0189] Step 6: Preparation of intermediate g9 4-(4-[(1-cyclopentyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)aniline

[0190] Using f10 (100 mg, 0.25 mmol) as raw material, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g9, an off-white solid, 82 mg, with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.82–7.73(m,1H),7.49–7.41(m,1H),7.26–7.20(m, 2H),6.84–6.76(m,2H),6.71–6.58(m,2H),5.21(p,J=9.2Hz,1H),3.91(s, 2H),3.03(t,J=4.8Hz,4H),2.67(t,J=4.8Hz,4H),2.28–2.19(m,2H),2.18 –2.09(m,2H),2.08–1.98(m,2H),1.86–1.75(m,2H).LC-MS(ESI):m / z[M+H] + :376.22.

[0191] Preparation Example 9 Preparation of Intermediate g10

[0192]

[0193] Step 1: Preparation of a7 (1-(cyclohexylmethyl)-1H-benzo[d]imidazol-2-yl)methanol

[0194] Take a 250mL single-mouth bottle, add (1H-benzo[d]imidazol-2-yl)methanol (2000mg, 13.6mmol), bromomethylcyclohexane (3.8mL, 27.2mmol), anhydrous potassium carbonate (6000mg, 40.8mmol), 30mL DMF, set up a reflux condenser, heat to 100°C, and stir for 7h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, add appropriate amount of water, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane = 3%), intermediate a7 is obtained as a yellow oil 2.9g, with a yield of 88%. 1 H NMR (400MHz, DMSO-D6) δ7.56(dd,J=15.6,8.0Hz,2H),7.29–7.07(m,2H),5.60–5.50(m,1H),4.71(d,J=5.6Hz ,2H),4.13(d,J=7.6Hz,2H),2.00–1.80(m,1H),1.72–1.56(m,3H),1.50(d,J=11.2Hz,2H),1.21–0.91(m,5H).

[0195] Step 2: Preparation of b8 2-(Chloromethyl)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole

[0196] Intermediate a7 (2000 mg, 8.2 mmol) was used as raw material and DCM as solvent. A preparation method similar to that of intermediate b3 was adopted to obtain intermediate b8, 1.55 g of off-white solid, with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ8.04–7.86(m,1H),7.67–7.46(m,3H),5.32(s,2H),4.30(d,J=7.6H z,2H),2.02(s,1H),1.77(s,2H),1.72(s,1H),1.65(d,J=12.0Hz,2H),1.27–1.09(m,5H).

[0197] Step 3: Preparation of f11 1-(cyclohexylmethyl)-2-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0198] Using intermediate b8 (1000 mg, 3.8 mmol), raw material e1 (830 mg, 4 mmol), anhydrous potassium carbonate (1100 mg, 8 mmol) as raw materials and 20 mL DMF as solvent, a preparation method similar to intermediate f2 was adopted to obtain intermediate f11, a yellow solid of 1.15 g, with a yield of 70%. 1H NMR (500MHz, DMSO-D6) δ8.05(d,J=9.5Hz,2H),7.64–7.49(m,2H),7.28–7.13(m,2H),7.02(d,J=9.5Hz,2H),4.16(d,J=7.5Hz,2H),3 .82(s,2H),3.44(t,J=5.0Hz,4H),2.61(t,J=5.0Hz,4H),2.02(s,1H),1.66(s,2H),1.59(s,1H),1.53(s,2H),1.12(d,J=8.0Hz,5H).

[0199] Step 4: Preparation of intermediate g10 4-(4-((1-(cyclohexylmethyl))-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)aniline

[0200] Using f11 (366 mg, 0.85 mmol) as raw material, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g10, an off-white solid, 270 mg, with a yield of 79%. 1 H NMR (400MHz, DMSO-D6) δ7.63–7.47(m,2H),7.29–7.02(m,2H),6.66(d,J=8.4Hz,2H),6.48(d,J=8.4Hz,2H),4.62(s,1H),4.14(d,J =7.2Hz,2H),3.79(s,2H),2.89(s,4H),2.58(s,4H),2.05(s,1H),1.70–1.44(m,5H),1.11(d,J=7.7Hz,5H).LC-MS(ESI):m / z[M+H] + :404.27.

[0201] Preparation Example 10 Preparation of Intermediate g13

[0202]

[0203] Step 1: Preparation of f14 1-cyclohexyl-2-((4-(2-nitrophenyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0204] Using intermediate b3 (340 mg, 1.4 mmol), intermediate e2 (283 mg, 1.4 mmol), anhydrous potassium carbonate (387 mg, 2.8 mmol) as raw materials and 20 mL of DMF as solvent, a preparation method similar to intermediate f2 was used to obtain intermediate f14, a yellow solid of 250 mg, with a yield of 43%. 1H NMR (400MHz, CDCl3) δ7.77–7.73(m,2H),7.62–7.54(m,1H),7.49–7.41(m, 1H),7.25–7.17(m,2H),7.10(d,J=8.0Hz,1H),7.02(t,J=7.6Hz,1H),4.65– 4.44(m,1H),3.88(s,2H),3.13–2.94(m,4H),2.67(t,J=4.8Hz,4H),2.30– 2.20(m,2H),2.06–1.88(m,4H),1.82(d,J=12.4Hz,1H),1.51–1.39(m,3H).

[0205] Step 2: Preparation of intermediate g13 2-(4-[(1-cyclohexyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)aniline

[0206] Using intermediate f14 (200 mg, 0.48 mmol) and Pd / C (20 mg, 10%) as raw materials and DCM as solvent, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g13, 160 mg of off-white solid, with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ7.74(s,1H),7.67–7.52(m,1H),7.25–7.17(m,2H),7.04–6.85(m,2H),6.74–6.70(m,2H),4.65(m,1H),3.90(s,4H),3.00 –2.83(m,4H),2.68(s,4H),2.27(qd,J=12.8,4.0Hz,2H),2.03–1.06(m,4H),1.84(d,J=12.4Hz,1H),1.61–1.31(m,3H).LC-MS(ESI):m / z[M+H] + :390.27.

[0207] Preparation Example 11 Preparation of Intermediate g14

[0208]

[0209] Step 1: Preparation of e8 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0210] Take a 100mL single-mouth bottle, add 4-fluoro-2-methoxy-1-nitrobenzene (2000mg, 11.7mmol), piperazinone (2600mg, 14mmol), anhydrous potassium carbonate (3200mg, 23.4mmol), 50mL DMF. Heat to 100℃ and stir for 3h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, add appropriate amount of water to the system, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to precipitate 2300mg of yellow solid, and obtain intermediate e8 with a yield of 59%. 1 H NMR(400MHz, CDCl3)δ8.00(d,J=9.6Hz,1H),6.44–6.40(m,1H),6.34(d,J=2.4H z,1H),3.95(s,3H),3.61(t,J=5.2Hz,4H),3.39(t,J=5.2Hz,4H),1.49(s,9H).

[0211] Step 2: Preparation of e9 1-(3-methoxy-4-nitrophenyl)piperazine

[0212] Take intermediate e8 (2000 mg, 5.9 mmol), trifluoroacetic acid (16 mL) as raw materials, 10 mL of dichloromethane as solvent, and stir at room temperature for 1 h. After the reaction is completed by TLC monitoring, the reaction solution is concentrated to obtain an oily substance, and an appropriate amount of water is added. The pH is adjusted to neutral with a saturated NaHCO3 solution, and the dichloromethane is extracted three times. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Intermediate e9 is obtained as a yellow solid of 1300 mg, with a yield of 94%. 1 H NMR (400MHz, DMSO-D6) δ7.88(d,J=9.6Hz,1H),6.57(d,J=9.6Hz,1H),6.49(s,1H),3.90(s,3H),3.36(s,4H),2.80(s,4H).

[0213] Step 3: Preparation of f15 (1-cyclohexyl-2-((4-(3-methoxy-4-nitrophenyl))piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0214] Using intermediate e9 (338 mg, 1.42 mmol), intermediate b3 (295 mg, 1.18 mmol), anhydrous potassium carbonate (326 mg, 2.36 mmol) as raw materials and 20 mL of DMF as solvent, a preparation method similar to intermediate f2 was used to obtain intermediate f15, a yellow solid of 460 mg, with a yield of 86%. 1H NMR(500MHz,DMSO-D6)δ7.88(d,J=9.5Hz,1H),7.73(dd,J=8.0,1.0Hz,1H),7.60–7.54(m ,1H),7.22–7.11(m,2H),6.58(dd,J=9.5,2.5Hz,1H),6.53(d,J=2.5Hz,1H),4.60(t,J=12 .5Hz,1H),3.89(s,3H),3.87(s,2H),3.40(t,J=5.0Hz,4H),2.55(t,J=5.0Hz,4H),2.20( tt,J=12.0,6.5Hz,2H),1.88(d,J=8.5Hz,4H),1.70(d,J=11.0Hz,1H),1.51–1.35(m,3H).

[0215] Step 4: Preparation of intermediate g14 4-(4-[(1-cyclohexyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)-2-methoxyaniline

[0216] Using f15 (440 mg, 0.98 mmol) as raw material and DCM as solvent, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g14, 360 mg of off-white solid, with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.79–7.71(m,1H),7.63–7.55(m,1H),7.24–7.21(m,2H) ,6.64(d,J=8.4Hz,1H),6.51(s,1H),6.39(d,J=8.4Hz,1H),4.60(t,J=13.2Hz ,1H),3.89(s,2H),3.83(s,3H),3.04(s,4H),2.70(s,4H),2.29–2.20(m,2H), 1.96(s,4H),1.81(d,J=12.4Hz,1H),1.53–1.31(m,3H).LC-MS(ESI):m / z[M+H] + :420.33.

[0217] Preparation Example 12 Preparation of Intermediate g15

[0218]

[0219] Step 1: Preparation of e10 4-(2-methoxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0220] Take a 100mL single-mouth bottle, add 2-fluoro-5-nitroanisole (2000mg, 11.7mmol), piperazinone (2600mg, 14mmol), anhydrous potassium carbonate (3200mg, 23.4mmol), 50mL DMF. Heat to 100℃ and stir for 3h. After the reaction is completed by TLC monitoring, concentrate the reaction solution, add appropriate amount of water to the system, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to precipitate 2100mg of yellow solid to obtain intermediate e10 with a yield of 53%. 1 H NMR (400MHz, DMSO-D6) δ7.83(d,J=8.8Hz,1H),7.70(s,1H),7.02(dd,J=8.8,2.0Hz,1H),3.91(s,3H),3.46(s,4H),3.14(s,4H),1.42(s,9H).

[0221] Step 2: Preparation of e11 1-(2-methoxy-4-nitrophenyl)piperazine

[0222] Intermediate e10 (2000 mg, 5.9 mmol) was used as raw material, and hydrochloric acid / ethyl acetate solution (15 mL) was added to obtain intermediate e11, 1.1 g of yellow solid, with a yield of 84%. 1 H NMR (400MHz, DMSO-D6) δ9.03(brs,2H),7.85(d,J=9.0Hz,1H),7.73(s,1H),7.10(d,J=8.9Hz,1H),3.93(s,3H),3.39(s,4H),3.26(s,4H).

[0223] Step 3: Preparation of f16 (1-cyclohexyl-2-((4-(2-methoxy-4-nitrophenyl))piperazin-1-yl)methyl)-1H-benzo[d]imidazole

[0224] Intermediate e11 (338 mg, 1.42 mmol), intermediate b3 (295 mg, 1.18 mmol), anhydrous potassium carbonate (326 mg, 2.36 mmol) were used as raw materials and 20 mL of DMF was used as solvent. Intermediate f16 was obtained by a similar preparation method to intermediate f2. The yellow solid was 380 mg and the yield was 72%. LC-MS (ESI): m / z [M+H] + :450.24.

[0225] Step 4: Preparation of intermediate g15 4-(4-[(1-cyclohexyl-1H-benzo[d]imidazol-2-yl])methyl)piperazin-1-yl)-m-methoxyaniline

[0226] Using f16 (370 mg, 0.82 mmol) as raw material and DCM as solvent, a preparation method similar to that of intermediate g2 was adopted to obtain intermediate g15, an off-white solid (270 mg), with a yield of 79%. 1 H NMR(500MHz,DMSO-D6)δ7.72(d,J=7.0Hz,1H),7.57(d,J=7.0Hz,1H),7.22–7.10(m,2H),6.5 7(d,J=8.5Hz,1H),6.21(d,J=2.5Hz,1H),6.05(dd,J=8.5,2.5Hz,1H),4.73(s,2H),4.60(t,J =12.0Hz,1H),3.82(s,2H),3.67(s,3H),2.77(s,4H),2.50(s,4H),2.26–2.10(m,2H),1.88(t ,J=10.5Hz,4H),1.71(d,J=10.0Hz,1H),1.50-1.30(h,J=12.9Hz,3H).LC-MS(ESI):m / z[M+H] + :420.34.

[0227] Preparation Example 13 Preparation of Intermediate g16

[0228]

[0229] Step 1: Preparation of f17 1-isobutyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole

[0230] Using 2-(4-nitrophenyl)-1H-benzo[d]imidazole (500 mg, 2.1 mmol), isobutane bromide (575 mg, 4.2 mmol), anhydrous potassium carbonate (1445 mg, 10.5 mmol), and 20 mL of DMF as solvent, a similar preparation method to intermediate f3 was used to obtain intermediate f17, a yellow solid (400 mg), with a yield of 65%. 1 H NMR (400MHz, DMSO-D6) δ8.39(d,J=8.8Hz,2H),8.11(d,J=8.8Hz,2H),7.73(d,J=9.2Hz, 2H),7.39–7.22(m,2H),4.26(d,J=7.6Hz,2H),1.96–1.85(m,1H),0.64(d,J=6.8Hz,6H).

[0231] Step 2: Preparation of intermediate g16 4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)aniline

[0232] Using f17 (200 mg, 0.68 mmol) and Pd / C (20 mg, 10%) as raw materials, a preparation method similar to that of intermediate g2 was adopted to obtain raw material g16, a white solid, 160 mg, with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.82–7.74(m,1H),7.49(d,J=8.4Hz,2H),7.41–7.32(m,1H),7.26(d,J=8.8Hz,2H),6. 76(d,J=8.0Hz,2H),4.07(d,J=7.6Hz,2H),2.25–2.00(m,1H),0.75(d,J=6.8Hz,6H).LC-MS(ESI):m / z[M+H] + :266.12.

[0233] Preparation Example 14 Preparation of Intermediate b5

[0234]

[0235] Step 1: Preparation of k3 5-methoxy-N1-methylbenzene-1,2-diamine

[0236] Using 4-methoxy-N-methyl-2-nitroaniline (500 mg, 27 mmol) as raw material, catalytic hydrogenation method was used to obtain intermediate k3, black liquid 420 mg, yield 100%. 1 H NMR (500MHz, CDCl3) δ6.62 (d, J = 8.5Hz, 1H), 6.36 (s, 2H), 3.74 (s, 3H), 3.31 (s, 3H), 2.83 (s, 3H).

[0237] Step 2: Preparation of a4 (5-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)methanol

[0238] Intermediate k3 (340 mg, 2.23 mmol) and glycolic acid (204 mg, 2.68 mmol) were used as raw materials and 2.5 mL of 20% HCl was used as solvent. A similar preparation method to that of intermediate a2 was used to obtain intermediate a4 as a yellow-white oil (394 mg). The yield was 92%. 1 HNMR (400MHz, DMSO-D6) δ7.41(d,J=8.8Hz,1H),7.10(d,J=2.4Hz,1H),6.87(dd,J=8. 8,2.4Hz,1H),5.52(t,J=5.6Hz,1H),4.67(d,J=5.6Hz,2H),3.78(s,3H),3.77(s,3H).

[0239] Step 3: Preparation of intermediate b5 2-(chloromethyl)-5-methoxy-1-methyl-1H-benzo[d]imidazole

[0240] Using a4 (300 mg, 1.56 mmol) as raw material and DCM as solvent, a preparation method similar to that of intermediate b3 was adopted to obtain raw material b5, 315 mg of black solid, with a yield of 96%. 1 H NMR (400MHz, DMSO-D6) δ7.81(d,J=9.2Hz,1H),7.26(d,J=2.4Hz,1H),7.20(dd,J =9.2,2.4Hz,1H),5.29(s,2H),3.99(s,3H),3.86(s,3H).LC-MS(ESI):m / z[M+H] + :210.01.

[0241] Preparation Example 15 Preparation of Intermediate i2

[0242]

[0243] Step 1: Preparation of i1 tert-butyl 4-(4-(phenylsulfonamido)phenyl)piperazine-1-carboxylate

[0244] Take a 200mL single-mouth bottle, add 1-Boc-4-(4-aminophenyl)piperazine (2000mg, 7.2mmol), benzenesulfonyl chloride (916μl, 7.2mmol), triethylamine (2mL, 14.4mmol), 30mL dichloromethane to dissolve, and stir overnight at room temperature. After TLC monitoring, add appropriate amount of water to the reaction solution, extract three times with dichloromethane, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane=1%), intermediate i1 is obtained as a yellow-white solid of 1.8g, with a yield of 60%. 1 H NMR(400MHz,DMSO-D6)δ9.84(s,1H),7.73–7.65(m,2H),7.63–7.56(m,1H),7.55–7.48(m,2H), 6.98–6.87(m,2H),6.84–6.74(m,2H),3.40(t,J=5.2Hz,4H),2.98(t,J=5.2,4H),1.40(s,9H).

[0245] Step 2: Preparation of intermediate i2 N-(4-(piperazin-1-yl))phenyl)benzenesulfonamide

[0246] Take a 100mL single-mouth bottle, add i1 (1800mg, 4.3mmol), trifluoroacetic acid (10mL), and dichloromethane (10mL). Stir at room temperature for 1h. After the reaction is completed by TLC monitoring, the reaction solution is concentrated to obtain an oily substance, add an appropriate amount of water, adjust the pH to neutral with a saturated NaHCO3 solution, extract with dichloromethane three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. The raw material i2 is obtained, 1.2g of yellow-white solid, and the yield is 93%. 1 H NMR (400MHz, DMSO-D6) δ7.69–7.66(m,2H),7.62–7.55(m,1H),7.54–7.49(m,2H),6.89–6. 85(m,2H),6.79–6.71(m,2H),2.94–2.90(m,4H),2.78–2.75(m,4H).LC-MS(ESI):m / z[M+H] + :317.99.

[0247] Preparation Example 16 Preparation of Intermediate n1

[0248]

[0249] Step 1: Preparation of j3 N-(4-methoxycyclohexyl)-2-nitroaniline

[0250] Using o-fluoronitrobenzene (204 μl, 1.9 mmol), 4-methoxycyclohexylamine (250 mg, 1.9 mmol), anhydrous potassium carbonate (525 mg, 3.8 mmol) as raw materials and 15 mL DMF as solvent, intermediate j3 was prepared by a similar method to intermediate j1, 475 mg of yellow oil, with a yield of 100%. LC-MS (ESI): m / z [M+H] + :251.13.

[0251] Step 2: Preparation of k5 N1-(4-methoxycyclohexyl)benzene-o-phenylenediamine

[0252] Intermediate j3 (475 mg, 1.9 mmol) was used as raw material and DCM as solvent. A similar preparation method was used as intermediate k1 to obtain intermediate k5, a gray oil 370 mg, with a yield of 90%. LC-MS (ESI): m / z [M+H] + :221.16.

[0253] Step 3: Preparation of a6 (1-(4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)methanol

[0254] Intermediate k5 (405 mg, 1.84 mmol) and glycolic acid (209 mg, 2.76 mmol) were used as raw materials and 4 mL of 20% HCl was used as solvent. The intermediate a6 was prepared by a method similar to that of intermediate a2. The intermediate a6 was a gray-black oil (479 mg) with a yield of 100%. 1 HNMR (400MHz, CDCl3) δ7.74–7.64(m,1H),7.54–7.46(m,1H),7.23(d,J=9.2Hz,2H),4.88(s,2H),4.54–4. 36(m,1H),3.42(s,3H),3.37–3.25(m,1H),2.36–2.22(m,4H),2.04(d,J=12.8Hz,2H),1.56–1.38(m,2H).

[0255] Step 4: Preparation of b7 2-Chloromethyl-1-(4-methoxycyclohexyl)-1H-benzo[d]imidazole

[0256] Intermediate a6 (475 mg, 1.82 mmol) was used as raw material and DCM as solvent. A preparation method similar to that of intermediate b3 was adopted to obtain intermediate b7, a gray solid (400 mg) with a yield of 72%. 1 H NMR (500MHz, DMSO-D6) δ8.09(s,1H),7.80(s,1H),7.48(d,J=5.0Hz,2H),5.36(s,3H),4.74–4.54(m,1H),3.48 (tt,J=11.0,4.0Hz,1H),2.40–2.25(m,2H),2.17(d,J=10.0Hz,2H),1.98(d,J=11.0Hz,2H),1.53–1.30(m,2H).

[0257] Step 5: Preparation of intermediate n1 N-(4-(4-(1-(4-methoxycyclohexyl))-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0258] Take a 50mL single-mouth bottle, add b7 (210mg, 0.75mmol), raw material i2 (239mg, 0.75mmol), anhydrous potassium carbonate (214mg, 1.5mmol), DMF (20mL), heat to 100℃, stir for 4h, monitor the reaction by TLC, add appropriate amount of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane = 2%), intermediate n1 is obtained as an off-white solid of 273mg, with a yield of 65%. 1H NMR (400MHz, CDCl3) δ8.02 (s, 2H), 7.77–7.74 (m, 1H), 7.70 (d, J = 1.2Hz, 1H), 7.68 (d, J=1.6Hz,1H),7.55–7.49(m,2H),7.45–7.39(m,2H),6.92(d,J=9.2Hz,2H),6.74(d,J= 9.2Hz,2H),6.32(s,1H),4.64–4.60(m,1H),3.90(s,2H),3.41(s,3H),3.37–3.29(m, 1H),3.09(s,4H),2.66(s,4H),2.39–2.28(m,5H),1.99(m,3H).LC-MS(ESI):m / z[M+H] + :560.26.

[0259] Preparation Example 17 Preparation of Intermediate n3

[0260]

[0261] Using b9 (108 mg, 0.39 mmol), i6 (137 mg, 0.39 mmol), anhydrous potassium carbonate (108 mg, 0.78 mmol) as raw materials and 20 mL of DMF as solvent, a similar preparation method to intermediate n1 was used to obtain intermediate n3, an off-white solid, 70 mg, with a yield of 30%. 1 H NMR (400MHz, DMSO-D6) δ7.72–7.55(m,4H),7.45(d,J=8.8Hz,1H),7.11(s,1H),6.88(d,J=8.8Hz,2H),6.79(d,J=8.8Hz,3H),4.51(s,1 H),3.81(s,5H),3.01(s,4H),2.50(s,4H),2.17(d,J=11.2Hz,2H),1.95–1.80(m,4H),1.67(s,1H),1.40(s,3H).LC-MS(ESI):m / z[M+H] + :297.74.

[0262] Preparation Example 18 Preparation of Intermediate n5

[0263]

[0264] Using b10 (100 mg, 0.36 mmol), i6 (127 mg, 0.36 mmol), anhydrous potassium carbonate (100 mg, 0.72 mmol) as raw materials and 20 mL DMF as solvent, a similar preparation method to intermediate n1 was used to obtain intermediate n5, an off-white solid, 40 mg, with a yield of 20%. 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.4Hz,2H),7.45(d,J=8.8Hz,1H),7.37(d,J=8.8Hz,2 H),7.22(d,J=2.4Hz,1H),6.98–6.85(m,4H),6.75(d,J=8.8Hz,2H),4.69–4.28(m,1H), 3.85(s,2H),3.84(s,3H),3.09(t,J=5.2Hz,4H),2.62(t,J=5.2Hz,4H),2.19(dd,J=12. 0,3.6Hz,2H),1.94(s,4H),1.82(s,1H),1.42(d,J=13.2Hz,3H).LC-MS(ESI):m / z[M+H] + :297.77.

[0265] Example

[0266] Example 1

[0267] N-(2-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0268]

[0269] Take raw material g4 (55mg, 0.17mmol), benzenesulfonyl chloride (22μl, 0.17mmol), triethylamine (47μl, 0.34mmol) as raw materials, dichloromethane (3mL) as solvent, stir at room temperature for 4h. After TLC monitoring, add appropriate amount of water to the system, extract with dichloromethane three times, wash the organic phase with saturated salt water, dry with anhydrous sodium sulfate, filter and concentrate. The product is obtained by silica gel column chromatography (methanol / dichloromethane = 4%), 33mg of white solid, and the yield is 41%. 1H NMR(400MHz,ACETONE-D6)δ8.58(s,1H),7.75–7.68(m,2H),7.63–7.55(m,2H),7.53–7.43(m,3H),7.28–7.14( m,2H),7.05–6.96(m,2H),6.85–6.77(m,2H),3.93(s,3H),3.87(s,2H),3.18–3.06(m,4H),2.66–2.63(m,4H).

[0270] Example 2

[0271] N-(3-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0272]

[0273] Using raw material g5 (68 mg, 0.21 mmol), benzenesulfonyl chloride (27 μl, 0.21 mmol), triethylamine (58 μl, 0.42 mmol) as raw materials and dichloromethane (4 mL) as solvent, a preparation method similar to Example 1 was adopted to obtain the product as a light yellow solid (78 mg) with a yield of 80%. 1 H NMR (400MHz, DMSO-D6) δ10.10(s,1H),7.78–7.71(m,2H),7.62–7.56(m,2H),7.56–7.46(m,3H),7.28–7.13(m,2H) ,7.01(t,J=8.0Hz,1H),6.66–6.54(m,2H),6.53–6.46(m,1H),3.85(s,3H),3.83(s,2H),3.01(s,3H),2.57(s,5H).

[0274] Example 3

[0275] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0276]

[0277] Using raw material g2 (45 mg, 0.12 mmol), benzenesulfonyl chloride (23 μl, 0.18 mmol), triethylamine (33 μl, 0.24 mmol) as raw materials and dichloromethane (10 mL) as solvent, a preparation method similar to Example 1 was adopted to obtain the product, 30 mg of white solid, with a yield of 50%. 1H NMR (400MHz, CDCl3) δ7.80(d,J=6.8Hz,1H),7.73–7.65(m,2H),7.56–7.49(m,1H),7.45–7.28(m,4H),6.92(d,J=8.8Hz,2H),6.75(d,J =8.8Hz,2H),6.32(s,1H),4.13(d,J=7.6Hz,2H),3.96(s,2H),3.22(s,4H),2.81(s,4H),2.37–2.28(m,1H),0.99(s,3H),0.97(s,3H).

[0278] Example 4

[0279] N-(4-(4-((1-cyclopentyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide (Preparation of GH-0223)

[0280]

[0281] Using raw material g9 (52 mg, 0.14 mmol), benzenesulfonyl chloride (88 μl, 0.7 mmol), triethylamine (40 μl, 0.28 mmol) as raw materials and dichloromethane (10 mL) as solvent, a preparation method similar to Example 1 was adopted to obtain the product as a white solid (47 mg) with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ7.81–7.75(m,1H),7.72–7.66(m,2H),7.54–7.43(m,2 H),7.40(dd,J=8.4,7.2Hz,2H),7.30–7.23(m,2H),6.92(d,J=8.8Hz,2H),6 .78(s,1H),6.73–6.71(m,2H),5.12(t,J=8.8Hz,1H),3.97(s,2H),3.15(s, 4H),2.70(s,4H),2.27–2.10(m,4H),2.06–2.02(m,2H),1.87–1.75(m,2H).

[0282] Example 5

[0283] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0284]

[0285] Take a 25mL single-mouth bottle, add raw material g3 (80mg, 0.2mmol), benzenesulfonyl chloride (38μl, 0.3mmol), triethylamine (56μl, 0.4mmol), dichloromethane (10mL), and stir under reflux for 6h. After TLC monitoring, concentrate the reaction solution, dissolve in methanol, add an appropriate amount of sodium tert-butoxide, reflux and stir for 2h, concentrate the reaction solution, add an appropriate amount of water, extract with dichloromethane three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. The product is obtained by silica gel column chromatography (methanol / dichloromethane = 2%), 67mg of white solid, and the yield is 63%. 1 H NMR (400MHz, CDCl3) δ7.78 (s, 1H), 7.71–7.69 (m, 1H), 7.69–7.67 (m, 1H), 7.60 (dd, J = 6. 0,3.2Hz,1H),7.55–7.49(m,1H),7.45–7.38(m,2H),7.29–7.25(m,2H),6.95–6.88(m,2H ),6.75(d,J=9.2Hz,2H),6.32(s,1H),4.55(s,1H),3.94(s,2H),3.14(s,4H),2.71(s,4H ),2.24(q,J=12.8Hz,2H),2.03–1.87(m,4H),1.82(d,J=12.4Hz,1H),1.50–1.38(m,3H).

[0286] Example 6

[0287] N-(4-(4-((6-Hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0288]

[0289] Take a 25mL two-necked bottle, add compound 54 (30mg, 0.06mmol), anhydrous dichloromethane (2mL), argon protection, ventilate three times, and stir in an ice bath for 5min. Slowly add 1M BBr3 (1mL) dropwise in an ice bath, and continue stirring in an ice bath for 4h. After the reaction is completed by TLC monitoring, methanol is slowly added dropwise to the reaction solution in an ice bath to quench the reaction. After concentrating the reaction solution, re-dissolve it with methanol, add 20mg of anhydrous piperazine, reflux and stir for 2h, and then concentrate the reaction solution. After silica gel column chromatography (methanol / dichloromethane = 3%), 18mg of white solid is obtained, with a yield of 64%. 1H NMR (400MHz, DMSO-D6) δ9.79(s,1H),9.23(s,1H),7.67(d,J=7.6Hz,2H),7.57(d,J=7.2Hz,1H),7.51(t,J=7.2Hz,2H),7.35–7.3 3(m,1H),6.88(d,J=8.4Hz,2H),6.76(d,J=9.2Hz,3H),6.66(dd,J=8.8,2.4Hz,1H),3.73–3.71(m,5H),3.01(s,4H),2.52(s,4H).

[0290] Example 7

[0291] N-(4-(4-((5-hydroxy-1-methyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0292]

[0293] Take a 25mL two-necked bottle, add compound 55 (30mg, 0.06mmol), anhydrous dichloromethane (2mL), argon protection, ventilate three times, and stir in an ice bath for 5min. Slowly add 1M BBr3 (1mL) dropwise in an ice bath, and continue stirring in an ice bath for 4h. After the reaction is completed by TLC monitoring, methanol is slowly added dropwise to the reaction solution in an ice bath to quench the reaction. After concentrating the reaction solution, re-dissolve it with methanol, add 20mg of anhydrous piperazine, reflux and stir for 2h, and then concentrate the reaction solution. After silica gel column chromatography (methanol / dichloromethane = 3%), 9mg of white solid is obtained, with a yield of 32%. 1 H NMR (400MHz, DMSO-D6) δ9.80 (s, 1H), 8.99 (s, 1H), 7.67 (d, J = 7.6Hz, 2H), 7.64–7.44 (m, 3H), 7.29 –7.26(m,1H),6.94–6.84(m,3H),6.80–6.70(m,3H),3.76–3.74(m,5H),3.02(s,4H),2.53(s,4H).

[0294] Example 8

[0295] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0296]

[0297] Using raw material g3 (60 mg, 0.15 mmol), p-chlorobenzenesulfonyl chloride (33 mg, 0.15 mmol), triethylamine (43 μl, 0.3 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 50 mg of a yellow-white solid with a yield of 58%. 1 H NMR(400MHz,DMSO-D6)δ9.88(s,1H),7.79–7.69(m,1H),7.68–7.58(m,4H),7.57–7.56(m,1H),7.24–7.09(m,2H),6.89–6.87(m,2H),6.8 2–6.73(m,2H),4.56(s,1H),3.87(s,2H),3.02(s,4H),2.55(s,4H),2.18(q,J=12.0Hz,2H),1.86(s,4H),1.68(s,1H),1.44–1.34(m,3H).

[0298] Example 9

[0299] 3-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0300]

[0301] Using raw material g3 (40 mg, 0.1 mmol), m-chlorobenzenesulfonyl chloride (22 mg, 0.1 mmol), triethylamine (28 μl, 0.2 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 40 mg of a yellow solid with a yield of 71%. 1 H NMR(400MHz, DMSO-D6)δ9.91(s,1H),7.76–7.64(m,3H),7.63–7.52(m,3H),7.19–7.12(m,2H),6.92–6.84(m,2H),6.83–6.75(m,2H),4. 57(t,J=12.4Hz,1H),3.84(s,2H),3.11–2.95(m,4H),2.53(s,4H),2.18(q,J=11.6Hz,2H),1.86(s,4H),1.69(s,1H),1.55–1.31(m,3H).

[0302] Example 10

[0303] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-methoxybenzenesulfonamide

[0304]

[0305] Using raw material g3 (140 mg, 0.36 mmol), p-methoxybenzenesulfonyl chloride (75 mg, 0.36 mmol), triethylamine (73 μl, 0.72 mmol) as raw materials and 15 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 176 mg of a white solid with a yield of 88%. 1 H NMR (400MHz, DMSO-D6) δ9.65 (s, 1H), 7.71 (d, J = 7.2Hz, 1H), 7.58 (dd, J = 11.6, 8.0 Hz,3H),7.15(pd,J=7.2,1.2Hz,2H),7.02(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H), 6.76(d,J=9.2Hz,2H),4.65–4.48(m,1H),3.82(s,2H),3.78(s,3H),2.99(s,4H), 2.51(s,4H),2.18(q,J=12.0Hz,2H),1.85(s,4H),1.69(s,1H),1.51–1.31(m,3H).

[0306] Embodiment 11

[0307] 2-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0308]

[0309] Using raw material g3 (80 mg, 0.21 mmol), o-chlorobenzenesulfonyl chloride (45 mg, 0.21 mmol), triethylamine (60 μl, 0.42 mmol) as raw materials and 10 mL DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 75 mg of a yellow-white oil with a yield of 64%. 1H NMR (400MHz, DMSO-D6) δ10.09 (s, 1H), 7.89 (dd, J = 8.0, 1.6Hz, 1H), 7.75–7.69 (m, 1H), 7. 65–7.54(m,3H),7.45(ddd,J=8.4,7.2,1.6Hz,1H),7.15(pd,J=7.2,1.2Hz,2H),6.97–6. 88(m,2H),6.79–6.72(m,2H),4.56(t,J=12.4Hz,1H),3.82(s,2H),2.98(t,J=4.8Hz,4H) ,2.50(s,4H),2.17(d,J=12.0Hz,2H),1.85(s,4H),1.70–1.63(m,1H),1.42–1.37(m,3H).

[0310] Example 12

[0311] N-(4-(4-(1-(4-hydroxycyclohexyl))-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0312]

[0313] Using raw material n1 (30 mg, 0.053 mmol) and 1M BBr3 (1 mL) as raw materials and 10 mL of anhydrous DCM as solvent, a preparation method similar to Example 6 was adopted to obtain 16 mg of a white solid with a yield of 55%. 1 H NMR (400MHz, MeOD) δ7.74–7.64(m,3H),7.64–7.59(m,1H),7.54(t,J=7.2Hz,1H),7. 45(t,J=7.6Hz,2H),7.31–7.16(m,2H),6.92(d,J=8.8Hz,2H),6.80(d,J=9.2Hz,2H) ,4.78–4.67(m,1H),3.91(s,2H),3.86–3.71(m,1H),3.09(s,4H),2.65(s,4H),2.43 (d,J=13.2Hz,2H),2.14(d,J=12.4Hz,2H),2.0–1.97(m,2H),1.52(d,J=12.4Hz,2H).

[0314] Embodiment 13

[0315] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)thiophene-2-sulfonamide

[0316]

[0317] Using raw material g3 (55 mg, 0.14 mmol), thiophene-2-sulfonyl chloride (20 μl, 0.14 mmol), triethylamine (40 μl, 0.28 mmol) as raw materials and 10 mL DCM as solvent, a preparation method similar to Example 5 was used to obtain 38 mg of a yellow solid with a yield of 51%. 1 H NMR(400MHz,MeOD)δ7.76–7.69(m,1H),7.67(dd,J=5.2,1.2Hz,1H),7.63–7.57(m,1H),7.38(dd,J =3.6,1.2Hz,1H),7.23(pd,J=7.2,1.2Hz,2H),7.02(dd,J=5.2,3.6Hz,1H),6.99–6.94(m,2H),6.87 –6.79(m,2H),4.69(ddd,J=12.4,8.8,3.6Hz,1H),3.87(s,2H),3.16–3.01(m,4H),2.62(t,J=4.8H z,4H),2.29(tt,J=12.0,6.8Hz,2H),2.06–1.89(m,4H),1.80(d,J=12.0Hz,1H),1.65–1.33(m,3H).

[0318] Embodiment 14

[0319] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)pyridine-3-sulfonamide

[0320]

[0321] Using raw material g3 (55 mg, 0.14 mmol), thiophene-2-sulfonyl chloride (20 μl, 0.14 mmol), triethylamine (40 μl, 0.28 mmol) as raw materials and 10 mL DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 33 mg of a yellow solid with a yield of 45%. 1H NMR(400MHz,MeOD)δ8.74(d,J=2.4Hz,1H),8.67(dd,J=5.2,1.6Hz,1H),8.03(dt,J=8.0,2.0Hz,1H), 7.79–7.67(m,1H),7.66–7.58(m,1H),7.51(dd,J=8.2,4.8Hz,1H),7.32–7.15(m,2H),6.93(d,J=8.8 Hz,2H),6.86–6.75(m,2H),4.74–4.57(m,1H),3.90(s,2H),3.10(t,J=4.8Hz,4H),2.63(t,J=4.8Hz, 4H), 2.29 (tt, J=12.0, 6.8Hz, 2H), 1.96 (d, J=11.2Hz, 4H), 1.80 (d, J=12.0Hz, 1H), 1.53–1.50 (m, 3H).

[0322] Embodiment 15

[0323] 4-Chloro-N-(4-(4-((1-cyclohexyl-6-hydroxy-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0324]

[0325] Take a 25mL two-necked bottle, add raw material n3 (80mg, 0.13mmol), anhydrous dichloromethane (2mL), argon protection, ventilate three times, and stir under ice bath for 5min. Slowly add 1M BBr3 (1mL) dropwise under ice bath, and continue stirring under ice bath for 4h. After the reaction is completed by TLC monitoring, methanol is slowly added dropwise to the reaction liquid under ice bath to quench the reaction. After concentrating the reaction liquid, dissolve it with methanol, add 30mg anhydrous piperazine, reflux and stir for 2h, and then concentrate the reaction liquid. After silica gel column chromatography (methanol / dichloromethane = 3%), 60mg of white solid is obtained, with a yield of 80%. 1 H NMR (400MHz, DMSO-D6) δ9.87(s,1H),9.13(s,1H),7.75–7.52(m,4H),7.33(d,J=8.8Hz,1H),6.99(s,1H),6.88(d,J=8.4Hz,2H),6.78(d,J=8.8Hz, 2H),6.66–6.59(m,1H),4.48(s,1H),3.74(s,2H),3.00(s,4H),2.48(s,4 H),2.08(s,2H),1.84(s,4H),1.70(d,J=12.0Hz,1H),1.54–1.26(m,3H).

[0326] Example 16

[0327] 4-Chloro-N-(4-(4-((1-cyclohexyl-5-hydroxy-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0328]

[0329] Using raw material n5 (46 mg, 0.07 mmol) and 1M BBr3 as raw materials and anhydrous DCM as solvent, a preparation method similar to Example 15 was adopted to obtain 33 mg of a white solid with a yield of 83%. 1 H NMR (400MHz, DMSO-D6) δ9.87 (s, 1H), 8.94 (s, 1H), 7.65 (d, J = 8.8Hz, 2H), 7.60 (d ,J=8.4Hz,2H),7.47(d,J=8.8Hz,1H),6.92–6.84(m,3H),6.78(d,J=8.8Hz,2H),6 .67(dd,J=8.8,2.4Hz,1H),4.52–4.46(m,1H),3.75(s,2H),3.12–2.93(m,4H),2 .50–2.46(m,4H),2.11(d,J=11.6Hz,2H),1.83(s,4H),1.67(s,1H),1.37(s,3H).

[0330] Embodiment 17

[0331] N-(2-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0332]

[0333] Using raw material g13 (40 mg, 0.1 mmol), benzenesulfonyl chloride (20 μl, 0.15 mmol), triethylamine (30 μl, 0.2 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 50 mg of a white solid with a yield of 94%. 1HNMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.80–7.77 (m, 3H), 7.65 (d, J = 8.0Hz, 1H), 7 .59(s,1H),7.46(t,J=7.2Hz,1H),7.38(t,J=7.6Hz,2H),7.25–7.20(m,2H),7.1 5–7.10(m,1H),7.03(s,2H),4.53(s,1H),3.88(s,2H),2.68–2.36(m,8H),2.25( d,J=12.4Hz,2H),2.08–1.91(m,4H),1.83(d,J=12.4Hz,1H),1.48–1.32(m,3H).

[0334] Embodiment 18

[0335] 4-Chloro-N-(2-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0336]

[0337] Using raw material g13 (50 mg, 0.13 mmol), p-chlorobenzenesulfonyl chloride (37 μl, 0.26 mmol), triethylamine (37 μl, 0.26 mmol) as raw materials and 8 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 62 mg of a white solid with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.77(s,1H),7.73(d,J=8.4Hz,2H),7.59(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),7.25–7.19(m,2H),7.16–6.99 (m,3H),4.54(t,J=12.4Hz,1H),3.90(s,2H),2.79–2.43(m,8H),2.31–2. 21(m,2H),2.05–1.91(m,4H),1.84(d,J=12.4Hz,1H),1.54–1.38(m,3H).

[0338] Embodiment 19

[0339] 3-Chloro-N-(2-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0340]

[0341] Using raw material g13 (50 mg, 0.13 mmol), m-chlorobenzenesulfonyl chloride (37 μl, 0.26 mmol), triethylamine (37 μl, 0.26 mmol) as raw materials and 8 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 67 mg of a white solid with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ8.00(s,1H),7.82–7.65(m,3H),7.59(d,J=8.0Hz,2H),7.45(d,J=7.6Hz,1H),7.34(t,J=8.0Hz,1H),7.24(d,J=6.0Hz,2H),7. 18–7.01(m,3H),4.54(s,1H),3.91(s,2H),2.73–2.47(m,8H),2.26(q,J=1 2.4Hz, 2H), 2.06–1.91 (m, 4H), 1.84 (d, J = 12.0Hz, 1H), 1.49–1.34 (m, 3H).

[0342] Embodiment 20

[0343] 2-Chloro-N-(2-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0344]

[0345] Using raw material g13 (50 mg, 0.13 mmol), m-chlorobenzenesulfonyl chloride (37 μl, 0.26 mmol), triethylamine (37 μl, 0.26 mmol) as raw materials and 8 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 70 mg of a white solid with a yield of 96%. 1 H NMR(400MHz, CDCl3)δ8.74(s,1H),8.23–8.11(m,1H),7.77(s,1H),7.65–7. 54(m,1H),7.48–7.33(m,4H),7.26–7.18(m,2H),7.11(d,J=7.6Hz,1H),7.06 –6.91(m,2H),4.58(t,J=12.4Hz,1H),3.92(s,2H),2.89–2.61(m,8H),2.37 –2.18(m,2H),2.09–1.93(m,4H),1.84(d,J=12.8Hz,1H),1.56–1.32(m,3H).

[0346] Embodiment 21

[0347] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-p-methoxybenzamide

[0348]

[0349] Take a 25mL single-mouth bottle, add raw material g3 (46mg, 0.12mmol), p-methoxybenzoic acid (27mg, 0.18mmol), HATU (69mg, 0.18mmol), DIPEA (31mg, 0.24mmol), 10mL DMF to dissolve, and stir at room temperature overnight. After the reaction is completed by TLC monitoring, the reaction solution is concentrated, an appropriate amount of water is added, and ethyl acetate is extracted three times. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and 23mg of a white solid is obtained by silica gel column chromatography (methanol / dichloromethane = 2%), with a yield of 37%. 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.81(s,1H),7.78–7.58(m,1H),7.62(s,1H),7.60(dd ,J=6.0,3.2Hz,1H),7.51(s,1H),7.49(s,1H),7.26–7.21(m,2H),6.97(s,1H),6.95(s,1 H),6.92(s,1H),6.90(s,1H),4.64–4.57(m,1H),3.91(s,2H),3.87(s,3H),3.14(s,4H), 2.70(s,4H),2.30–2.21(m,2H),1.97(s,4H),1.82(d,J=12.4Hz,1H),1.52–1.38(m,3H).

[0350] Embodiment 22

[0351] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-hydroxybenzenesulfonamide

[0352]

[0353] Using compound 10 (32 mg, 0.057 mmol) and 1M BBr3 as raw materials and anhydrous DCM as solvent, a preparation method similar to Example 15 was adopted to obtain 22 mg of a white solid with a yield of 70%. 1H NMR (400MHz, DMSO-D6) δ10.35(s,1H),9.55(s,1H),7.71(d,J=7.2Hz,1H),7.57(d,J= 7.2Hz,1H),7.48(d,J=8.8Hz,2H),7.19–7.11(m,2H),6.87(d,J=9.2Hz,2H),6.81(d, J=8.8Hz,2H),6.76(d,J=9.2Hz,2H),4.68–4.49(m,1H),3.83(s,2H),2.99(t,J=4.8H z,4H),2.58–2.41(m,4H),2.19–2.61(m,2H),1.86(s,4H),1.68(s,1H),1.39(s,3H).

[0354] Embodiment 23

[0355] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzamide

[0356]

[0357] Using raw material g3 (100 mg, 0.26 mmol), benzoic acid (50 mg, 0.41 mmol), HATU (147 mg, 0.386 mmol), and DIPEA (67 mg, 0.51 mmol) as raw materials and 10 mL of DMF as solvent, a preparation method similar to Example 21 was used to obtain 258 mg of a white solid with a yield of 46%. 1 H NMR(400MHz, CDCl3)δ7.95(s,1H),7.89–7.81(m,2H),7.77–7.69(m,1H),7.64–7.56(m,1H) ,7.54–7.48(m,3H),7.46–7.42(m,2H),7.25–7.19(m,2H),6.92–6.84(m,2H),4.59(tt,J=1 2.4,3.6Hz,1H),3.88(s,2H),3.13–3.10(m,4H),2.68–2.65(m,4H),2.24(tt,J=12.0,6.4H z,2H),1.96(s,4H),1.81(d,J=12.8Hz,1H),1.43(t,J=13.2Hz,2H),1.33(d,J=12.8Hz,1H).

[0358] Embodiment 24

[0359] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-methoxybenzenesulfonamide

[0360]

[0361] Using raw material g2 (60 mg, 0.16 mmol), p-methoxybenzenesulfonyl chloride (68 mg, 0.33 mmol), triethylamine (46 μl, 0.33 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 33 mg of a white solid with a yield of 38%. 1 H NMR (400MHz, CDCl3) δ7.76(d,J=7.2Hz,1H),7.61(d,J=8.4Hz,2H),7.36(s,1H),7.26(d,J=2.0Hz,2H),6.93(d,J=8.0Hz,2H),6.86(d,J=8.4Hz,2H) ,6.75(d,J=8.4Hz,2H),6.50(s,1H),4.15(d,J=7.6Hz,2H),3.92(s,2H),3 .82(s,3H),3.13(s,4H),2.71(s,4H),2.34(s,1H),0.97(d,J=6.4Hz,6H).

[0362] Embodiment 25

[0363] 4-Chloro-N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0364]

[0365] Using raw material g2 (80 mg, 0.22 mmol), p-chlorobenzenesulfonyl chloride (93 mg, 0.44 mmol), triethylamine (61 μl, 0.44 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was used to obtain 56 mg of a white solid with a yield of 47%. 1H NMR (400MHz, CDCl3) δ7.78–7.70(m,1H),7.61(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,3H),7.31–7.22(m,2H),6.93(d,J=9.2Hz,2H),6.75(d,J=8.8Hz,2H ),6.68(s,1H),4.14(d,J=7.6Hz,2H),3.89(s,2H),3.13(t,J=4.8Hz,4H), 2.69(t,J=5.2Hz,4H), 2.34(dt,J=13.6,6.8Hz,1H), 0.97(d,J=6.4Hz,6H).

[0366] Embodiment 26

[0367] 4-Bromo-N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0368]

[0369] Using raw material g2 (100 mg, 0.27 mmol), 4-bromobenzenesulfonyl chloride (106 mg, 0.41 mmol), triethylamine (77 μl, 0.55 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 96 mg of a white solid with a yield of 60%. 1 H NMR(400MHz,CHLOROFORM-D)δ7.77–7.69(m,1H),7.55–7.52(m,4H),7.37–7.34(m,1H),7.28–7.24(m,2H),6.98–6.90(m,2H),6 .85(s,1H),6.80–6.71(m,2H),4.15–4.12(m,2H),3.87(s,2H),3.12(s,4H),2.67(s,4H),2.45–2.24(m,1H),0.99–0.95(m,6H).

[0370] Embodiment 27

[0371] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-methylbenzenesulfonamide

[0372]

[0373] Using raw material g2 (100 mg, 0.27 mmol), p-toluenesulfonyl chloride (80 mg, 0.41 mmol), triethylamine (77 μl, 0.55 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 70 mg of a white solid with a yield of 50%. 1 H NMR (400MHz, CDCl3) δ7.75(d,J=7.6Hz,1H),7.57(d,J=7.6Hz,2H),7.36(d,J=7.6Hz,1H),7.28-7.26(m,2H),7.19(d,J=8.0Hz,2H),6.93(d,J=8.4Hz,2 H),6.74(d,J=8.8Hz,2H),6.61(s,1H),4.14(d,J=7.2Hz,2H),3.90(s,2H), 3.12(s,4H),2.70(s,4H),2.37(s,3H),2.34(s,1H),0.97(d,J=6.4Hz,6H).

[0374] Embodiment 28

[0375] 4-Fluoro-N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0376]

[0377] Using raw material g2 (100 mg, 0.27 mmol), p-fluorobenzenesulfonyl chloride (81 mg, 0.41 mmol), triethylamine (77 μl, 0.55 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 95 mg of a white solid with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.74–7.70(m,4H),7.39(d,J=8.0Hz,1H),7.33–7.24(m,2H),7.07(t,J=8.4Hz,2H),7.02–6.96(m,2H),6 .77(d,J=8.8Hz,2H),4.16(d,J=7.6Hz,2H),3.90(s,2H),3.12(s,4H),2.68(s,4H),2.42–2.31(m,1H),0.99(d,J=6.4Hz,6H).

[0378] Embodiment 29

[0379] 4-ethyl-N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0380]

[0381] Using raw material g2 (100 mg, 0.27 mmol), p-ethylbenzenesulfonyl chloride (70 μl, 0.41 mmol), triethylamine (80 μl, 0.55 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was used to obtain 84 mg of a white solid with a yield of 58%. 1 H NMR (100MHz, CDCl3) δ7.73(d,J=7.2Hz,1H),7.61(d,J=8.0Hz,2H),7.36(d,J=7.2 Hz,1H),7.31–7.24(m,2H),7.21(d,J=8.4Hz,2H),7.04(s,1H),6.96(d,J=8.4Hz,2 H),6.75(d,J=8.4Hz,2H),4.14(d,J=7.6Hz,2H),3.88(s,2H),3.11(s,4H),2.68( s, 6H), 2.35 (dt, J = 14.0, 7.2Hz, 1H), 1.22 (t, J = 7.6Hz, 3H), 0.97 (d, J = 6.4Hz, 6H).

[0382] Embodiment 30

[0383] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-trifluoromethylbenzenesulfonamide

[0384]

[0385] Using raw material g2 (100 mg, 0.27 mmol), 4-trifluoromethylbenzenesulfonyl chloride (100 mg, 0.41 mmol), triethylamine (80 μl, 0.55 mmol) as raw materials and 10 mL DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 93 mg of a white solid with a yield of 60%. 1H NMR (500MHz, CDCl3) δ7.81(d,J=8.0Hz,2H),7.73(d,J=7.5Hz,1H),7.67(d,J=8.0Hz,2H),7.36(d,J=7.5Hz,1H),7.27(q,J=7.0Hz,3H),6.94(d,J=8 .5Hz,2H),6.85(s,1H),6.76(d,J=8.5Hz,2H),4.13(d,J=7.5Hz,2H),3.88 (s,2H),3.13(s,4H),2.67(s,4H),2.42–2.27(m,1H),0.97(d,J=7Hz,6H).

[0386] Embodiment 31

[0387] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-isopropylbenzenesulfonamide

[0388]

[0389] Using raw material g2 (100 mg, 0.27 mmol), 4-isopropylbenzenesulfonyl chloride (90 mg, 0.41 mmol), triethylamine (77 μl, 0.55 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 93 mg of a white solid with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ7.78–7.70(m,1H),7.60(d,J=8.4Hz,2H),7.39–7.33(m ,1H),7.31–7.21(m,3H),6.94(d,J=8.8Hz,2H),6.76(d,J=8.8Hz,2H),6.35(s ,1H),4.14(d,J=7.6Hz,2H),3.88(s,2H),3.13(s,4H),2.93(p,J=6.8Hz,1H), 2.69(s,4H),2.38–2.30(m,1H),1.23(d,J=6.8Hz,6H),0.97(d,J=6.8Hz,6H).

[0390] Embodiment 32

[0391] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-(trifluoromethoxy)benzenesulfonamide

[0392]

[0393] Using raw material g2 (100 mg, 0.27 mmol), 4-isopropylbenzenesulfonyl chloride (70 μl, 0.41 mmol), triethylamine (77 μl, 0.55 mmol) as raw materials and 10 mL DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 65 mg of a white solid with a yield of 40%. 1 H NMR (500MHz, CDCl3) δ7.82–7.68(m,3H),7.45–7.33(m,1H),7.32–7.11(m,4H),6.93(d,J=8.0Hz,2H),6.82–6.74(m,2 H),6.68–6.62(m,1H),4.14(s,2H),3.87(s,2H),3.14(s,4H),2.68(s,4H),2.36–2.34(m,1H),0.97(d,J=6.5Hz,6H).

[0394] Embodiment 33

[0395] N-(4-(4-((1-isobutyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)methanesulfonamide

[0396]

[0397] Take a 25mL single-mouth bottle, add raw material g2 (100mg, 0.28mmol), anhydrous dichloromethane (10mL), triethylamine (77μl, 0.55mmol) under ice bath, stir for 3min, add methanesulfonyl chloride (32μl, 0.41mmol) under ice bath, stir for 8h. After TLC monitoring, add appropriate amount of water, extract with dichloromethane three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and obtain 23mg of yellow solid by silica gel column chromatography (methanol / dichloromethane=3%), with a yield of 19%. 1 H NMR (400MHz, DMSO-D6) δ9.24(s,1H),7.59(d,J=7.2Hz,1H),7.54(d,J=8.4Hz,1H),7.25–7.14(m,2H),7.08(d,J=8.8Hz,2H),6.90(d ,J=8.8Hz,2H),4.14(d,J=7.6Hz,2H),3.81(s,2H),3.07(s,4H),2.85(s,3H),2.61(s,4H),2.36–2.28(m,1H),0.89(d,J=6.8Hz,6H).

[0398] Embodiment 34

[0399] N-(4-(4-((1-(cyclohexylmethyl))-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0400]

[0401] Using raw material g10 (100 mg, 0.25 mmol), benzenesulfonyl chloride (50 μl, 0.38 mmol), triethylamine (70 μl, 0.5 mmol) as raw materials and 10 mL of DCM as solvent, a preparation method similar to Example 5 was adopted to obtain 20 mg of a white solid with a yield of 14%. 1 H NMR(400MHz, CDCl3)δ7.76–7.66(m,3H),7.50(td,J=7.6,1.2Hz,1H),7.44–7.33(m,3H),7.31–7.17(m,2H),6.98–6.92(m,3H),6.74(d ,J=8.8Hz,2H),4.14(d,J=7.6Hz,2H),3.86(s,2H),3.10(s,4H),2.66(s,4H),2.02–1.96(m,1H),1.72–1.63(m,5H),1.19–1.00(m,5H).

[0402] Embodiment 35

[0403] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzamide

[0404]

[0405] Using raw material g3 (119 mg, 0.3 mmol), p-chlorobenzoic acid (72 mg, 0.46 mmol), HATU (175 mg, 0.46 mmol), DIPEA (78 mg, 0.6 mmol) as raw materials and 10 mL of DMF as solvent, a preparation method similar to Example 21 was used to obtain 48 mg of a white solid with a yield of 30%. 1H NMR (400MHz, DMSO-D6) δ10.16(s,1H),7.98–7.93(m,3H),7.75–7.73(m,1H),7.68–7.54(m,4H),7.40–7.28(m,2H),7.00(d,J=8.4 Hz,2H),4.63(s,2H),4.48(s,1H),3.50–3.11(m,8H),2.22(d,J=12.4Hz,2H),1.95–1.88(m,4H),1.72(s,1H),1.61–1.35(m,3H).

[0406] Embodiment 36

[0407] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)methanesulfonamide

[0408]

[0409] Take a 25mL single-mouth bottle, add raw material g3 (150mg, 0.39mmol), anhydrous dichloromethane (10mL), triethylamine (108μl, 0.77mmol) under ice bath, stir for 3min, add methanesulfonyl chloride (45μl, 0.58mmol) under ice bath, stir for 8h. After TLC monitoring, add appropriate amount of water, extract with dichloromethane three times, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and obtain 170mg of yellow solid by silica gel column chromatography (methanol / dichloromethane=3%), with a yield of 94%. 1 H NMR(500MHz, CDCl3)δ7.80–7.70(m,1H),7.60–7.50(m,1H),7.25–7.21(m,2H), 7.16(d,J=9.0Hz,2H),6.87(d,J=9.0Hz,2H),6.64(s,1H),4.58(t,J=13.0Hz,1H ),3.89(s,2H),3.13(s,4H),2.92(s,3H),2.67(s,4H),2.30–2.15(m,2H),1.97( d,J=14.0Hz,4H),1.81(d,J=12.5Hz,1H),1.55–1.30(m,2H),1.30–1.25(m,1H).

[0410] Embodiment 37

[0411] 4-Chloro-N-(4-(4-(1-cyclohexyl-1H-benzo[d]imidazole-2-carbonyl))piperazin-1-yl)phenyl)benzenesulfonamide

[0412]

[0413] Using raw material g6 (123 mg, 0.3 mmol), p-chlorobenzenesulfonyl chloride (95 mg, 0.45 mmol), triethylamine (85 μl, 0.6 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was used to obtain 123 mg of a white solid with a yield of 71%. 1 H NMR (400MHz, CDCl3) δ7.80(d,J=6.8Hz,1H),7.62(d,J=8.4Hz,3H),7.37(d,J=8.4Hz,2H),7.34– 7.29(m,2H),7.07(s,1H),6.97(d,J=8.8Hz,2H),6.78(d,J=8.8Hz,2H),4.48(t,J=12.4Hz,1H), 3.95(t,J=5.2Hz,2H),3.79(t,J=5.2Hz,2H),3.23(t,J=5.2Hz,2H),3.15(t,J=5.2Hz,2H),2.32 –2.17(m,2H),2.06–1.87(m,4H),1.79(d,J=13.2Hz,1H),1.52–1.40(m,2H),1.39–1.28(m,1H).

[0414] Embodiment 38

[0415] N-(4-(4-(1-cyclohexyl-1H-benzo[d]imidazole-2-carbonyl))piperazin-1-yl)phenyl)benzenesulfonamide

[0416]

[0417] Using raw material g6 (100 mg, 0.25 mmol), benzenesulfonyl chloride (49 μl, 0.38 mmol), triethylamine (70 μl, 0.5 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was adopted to obtain 92 mg of a white solid with a yield of 67%. 1H NMR(400MHz, CDCl3)δ7.84–7.76(m,1H),7.71(d,J=6.8Hz,2H),7.66–7.59(m,1H),7.55–7.50(m, 1H),7.44–7.38(m,2H),7.35–7.27(m,2H),6.97(d,J=9.2Hz,2H),6.79(d,J=8.0Hz,2H),6.71(s,1 H),4.53–4.45(m,1H),3.97(t,J=5.2Hz,2H),3.81(t,J=5.2Hz,2H),3.25(t,J=5.2Hz,2H),3.16(s ,2H),2.24(qd,J=12.4,3.6Hz,2H),2.08–1.86(m,4H),1.79(d,J=12.8Hz,1H),1.49–1.40(m,3H).

[0418] Embodiment 39

[0419] N-(4-(4-(1-cyclohexyl-1H-benzo[d]imidazole-2-carbonyl))-1-yl)phenyl)-4-methoxybenzenesulfonamide

[0420]

[0421] Using raw material g6 (100 mg, 0.25 mmol), p-methoxybenzenesulfonyl chloride (79 mg, 0.38 mmol), triethylamine (70 μl, 0.5 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was adopted to obtain 90 mg of a white solid with a yield of 63%. 1 H NMR(400MHz, CDCl3)δ7.80(d,J=7.6Hz,1H),7.64(d,J=7.6Hz,3H),7.34–7.26(m,2H),7.08(s,1H) ,6.97(d,J=8.4Hz,2H),6.85(d,J=8.8Hz,2H),6.77(d,J=8.4Hz,2H),4.56–4.38(m,1H),4.00–3.89 (m,2H),3.81(s,3H),3.79(s,2H),3.25–3.19(m,2H),3.18–3.10(m,2H),2.28–2.18(m,2H),2.06– 1.98(m,2H),1.99–1.77(m,2H),1.78(d,J=13.2Hz,1H),1.53–1.40(m,2H),1.34(d,J=12.2Hz,1H).

[0422] Embodiment 40

[0423] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-4-methoxy-N-methylbenzenesulfonamide

[0424]

[0425] Take a 25mL single-mouth bottle, add compound 10 (30mg, 0.053mmol), anhydrous DMF (3mL) solvent, add NaH (2mg, 0.08mmol) under ice bath, stir for 1h under ice bath, then add iodomethane (11mg, 0.08mmol), stir overnight at room temperature. After the reaction is completed by TLC monitoring, add appropriate amount of water, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and obtain 12mg of white solid by silica gel column chromatography (ethyl acetate / petroleum ether=60%), with a yield of 40%. 1 HNMR (400MHz, CDCl3) δ7.77(s,1H),7.59(s,1H),7.49(d,J=8.4Hz,2H),7.26(s,3H),6.94–6.90(m,4H),6.79(d,J=8.8Hz,2H),4.57(s,1H), 3.91(s,2H),3.86(s,3H),3.17(s,4H),3.10(s,3H),2.70(s,4H),2.36 –2.14(m,2H),1.97(s,4H),1.82(d,J=12.4Hz,1H),1.53–1.33(m,3H).

[0426] Embodiment 41

[0427] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-N-methylbenzenesulfonamide

[0428]

[0429] Using compound 8 (75 mg, 0.133 mmol), iodomethane (28 mg, 0.2 mmol), NaH (7 mg, 0.27 mmol) as raw materials and anhydrous DMF (6 mL) as solvent, a preparation method similar to Example 40 was adopted to obtain 45 mg of a white solid with a yield of 59%. 1HNMR(400MHz, CDCl3)δ7.79–7.70(m,1H),7.60–7.58(m,1H),7.49(d,J=8.4Hz,2 H),7.42(d,J=8.8Hz,2H),7.25–7.22(m,2H),6.93(d,J=9.2Hz,2H),6.79(d,J=8. 8Hz,2H),4.69–4.48(m,1H),3.89(s,2H),3.16(s,4H),3.12(s,3H),2.67(s,4H), 2.30–2.20(m,2H),2.00–1.90(m,4H),1.82(d,J=12.0Hz,1H),1.50–1.37(m,3H).

[0430] Embodiment 42

[0431] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)-N-methylbenzenesulfonamide

[0432]

[0433] Using compound 5 (70 mg, 0.13 mmol), iodomethane (30 mg, 0.2 mmol), NaH (7 mg, 0.27 mmol) as raw materials and anhydrous DMF (6 mL) as solvent, a preparation method similar to Example 40 was adopted to obtain 40 mg of a white solid with a yield of 57%. 1 HNMR(400MHz, CDCl3)δ7.78–7.71(m,1H),7.62–7.51(m,4H),7.46–7.42(m,2H ),7.23(dd,J=6.4,3.2Hz,2H),6.93(d,J=9.2Hz,2H),6.78(d,J=9.2Hz,2H),4 .65–4.50(m,1H),3.89(s,2H),3.15(s,4H),3.12(s,3H),2.67(s,4H),2.28–2 .23(m,2H),1.98(d,J=12.8Hz,4H),1.81(d,J=12.0Hz,1H),1.50–1.20(m,3H).

[0434] Embodiment 43

[0435] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-2-methoxyphenyl)benzenesulfonamide

[0436]

[0437] Using raw material g14 (100 mg, 0.24 mmol), benzenesulfonyl chloride (46 μl, 0.36 mmol), triethylamine (67 μl, 0.48 mmol) and dichloromethane (10 mL) as raw materials, a preparation method similar to Example 5 was adopted to obtain 109 mg of a white solid with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.76 (s, 1H), 7.67 (d, J=8.0Hz, 2H), 7.59 (s, 1H), 7.47 (t, J= 7.6Hz,1H),7.41–7.33(m,3H),7.24(s,1H),6.60(s,1H),6.43(d,J=8.8Hz,1H),6. 24(s,1H),4.60–4.52(m,1H),3.90(s,2H),3.45(s,3H),3.09(s,4H),2.67(s,4H) ,2.30–2.20(m,2H),2.06–1.90(m,4H),1.82(d,J=12.0Hz,1H),1.47–1.30(m,3H).

[0438] Embodiment 44

[0439] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-2-hydroxyphenyl)benzenesulfonamide

[0440]

[0441] Using compound 43 (30 mg, 0.05 mmol) and 1M BBr3 as raw materials and anhydrous dichloromethane (1 mL) as solvent, a preparation method similar to Example 15 was adopted to obtain 12 mg of a white solid with a yield of 44%. 1 H NMR(400MHz, CDCl3)δ7.74(d,J=8.0Hz,2H),7.60–7.47(m,3H),7.39(t,J=7 .6Hz,2H),7.23(t,J=8.0Hz,2H),7.04(d,J=8.8Hz,1H),6.49(s,1H),6.26( d,J=8.8Hz,1H),4.55(s,1H),3.78(s,2H),3.02(s,4H),2.55(s,4H),2.21( q,J=12.4Hz,2H),2.02–1.89(m,4H),1.89–1.80(m,1H),1.50–1.40(m,3H).

[0442] Embodiment 45

[0443] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-2-methoxyphenyl)benzenesulfonamide

[0444]

[0445] Using raw material g14 (110 mg, 0.26 mmol), p-chlorobenzenesulfonyl chloride (83 mg, 0.39 mmol), triethylamine (72 μl, 0.52 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was used to obtain 111 mg of a white solid with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ7.77(dd,J=6.0,3.2Hz,1H),7.60(d,J=8.4Hz,3H),7.38(d,J=8.8Hz ,1H),7.34(d,J=8.8Hz,2H),7.25(s,1H),6.58(s,1H),6.44(dd,J=8.8,2.4Hz,1H),6.25( d,J=2.4Hz,1H),4.69–4.46(m,1H),3.92(d,J=4.0Hz,2H),3.49(s,3H),3.11(s,4H),2.68 (s,4H),2.30–2.20(m,2H),2.03–1.89(m,4H),1.82(d,J=12.4Hz,1H),1.51–1.32(m,3H).

[0446] Embodiment 46

[0447] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-2-hydroxyphenyl)benzenesulfonamide

[0448]

[0449] Using compound 45 (60 mg, 0.1 mmol) and 1M BBr3 as raw materials and anhydrous dichloromethane (2 mL) as solvent, a preparation method similar to Example 15 was adopted to obtain 12 mg of a white solid with a yield of 20%. 1H NMR (400MHz, CDCl3) δ7.64(d,J=8.4Hz,2H),7.57(d,J=8.0Hz,1H),7.49–7. 44(m,1H),7.32(d,J=8.0Hz,2H),7.26–7.20(m,3H),6.47(s,1H),6.30(d,J =8.8Hz,1H),4.55(s,1H),3.72(s,2H),3.03(s,4H),2.53(s,4H),2.21(d,J =12.8Hz,2H),1.99–1.86(m,4H),1.82(d,J=12.0Hz,1H),1.46–1.40(m,3H).

[0450] Embodiment 47

[0451] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-3-methoxyphenyl)benzenesulfonamide

[0452]

[0453] Using raw material g15 (100 mg, 0.24 mmol), benzenesulfonyl chloride (46 μl, 0.36 mmol), triethylamine (67 μl, 0.48 mmol) and dichloromethane (10 mL) as raw materials, a preparation method similar to Example 5 was adopted to obtain 108 mg of a white solid with a yield of 80%. 1 H NMR(400MHz, DMSO-D6)δ9.96(s,1H),7.81–7.64(m,3H),7.63–7.45(m,4H),7. 26–6.94(m,2H),6.68(d,J=8.4Hz,1H),6.64(d,J=2.4Hz,1H),6.54(dd,J=8.4, 2.4Hz,1H),4.56(t,J=12.4Hz,1H),3.82(s,2H),3.64(s,3H),2.82(s,4H),2.5 0(s,4H),2.18(d,J=11.6Hz,2H),1.86(s,4H),1.70(s,1H),1.50–1.32(m,3H).

[0454] Embodiment 48

[0455] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-3-methoxyphenyl)benzenesulfonamide

[0456]

[0457] Using raw material g15 (110 mg, 0.26 mmol), p-chlorobenzenesulfonyl chloride (83 mg, 0.39 mmol), triethylamine (72 μl, 0.52 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was used to obtain 107 mg of a white solid with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.70–7.50(m,3H),7.37(d,J=8.0Hz,2H),7.24(s,1H),6.81(s,1H),6.75–7.65(m,2H),6.49(d,J=8.4Hz,1H ),4.60(s,1H),3.93(s,2H),3.76(s,3H),3.00(s,4H),2.72(s,4H),2.2 8–2.20(m,2H),1.97(s,4H),1.82(d,J=12.0Hz,1H),1.50–1.30(m,3H).

[0458] Embodiment 49

[0459] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-3-hydroxyphenyl)benzenesulfonamide

[0460]

[0461] Using compound 48 (30 mg, 0.05 mmol) and 1M BBr3 as raw materials and anhydrous dichloromethane (2 mL) as solvent, a preparation method similar to Example 15 was used to obtain 4 mg of a white solid with a yield of 17%. HR-MS (ESI): m / z [M+H] + Calculate for C 30 H 35 O3N5ClS:580.2144; found:580.2172.

[0462] Embodiment 50

[0463] N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)-3-hydroxyphenyl)benzenesulfonamide

[0464]

[0465] Using compound 47 (30 mg, 0.05 mmol) and 1M BBr3 as raw materials and anhydrous dichloromethane (2 mL) as solvent, a preparation method similar to Example 15 was used to obtain 5 mg of a white solid with a yield of 17%. HR-MS (ESI): m / z [M+H] + Calculate for C 30 H 36 O3N5S:546.2533; found:546.2540.

[0466] Embodiment 51

[0467] 4-Chloro-N-(4-(4-((1-cyclohexyl-1H-benzo[d]imidazol-2-yl)))methyl)-2-oxopiperazin-1-yl)phenyl)benzenesulfonamide

[0468]

[0469] Using raw material g7 (50 mg, 0.124 mmol), p-chlorobenzenesulfonyl chloride (40 mg, 0.186 mmol), triethylamine (35 μl, 0.248 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was used to obtain 55 mg of a white solid with a yield of 77%. 1 H NMR (400MHz, DMSO-D6) δ7.80–7.70(m,4H),7.63(d,J=8.4Hz,2H),7.59(d,J=7.2Hz,1H),7.20–7.10(m,4H),7.08(d,J=8.4Hz,2H),4.56(s, 1H),3.94(s,2H),3.51(s,2H),3.25(s,2H),2.79(s,2H),2.20(d,J=12.4Hz,2H),1.92–1.80(m,4H),1.67–1.61(m,1H),1.52–1.30(m,3H).

[0470] Embodiment 52

[0471] 4-Chloro-N-(4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide

[0472]

[0473] Using raw material g16 (80 mg, 0.3 mmol), p-chlorobenzenesulfonyl chloride (64 mg, 0.3 mmol), triethylamine (84 μl, 0.6 mmol), and dichloromethane (10 mL) as raw materials, a preparation method similar to that of Example 5 was adopted to obtain 67 mg of a white solid with a yield of 51%.1 H NMR (400MHz, CDCl3) δ8.06–7.98(m,1H),7.76–7.68(m,2H),7.46–7.40(m,1H),7.36(d,J=6.8Hz,4H),7.3 1(d,J=8.0Hz,2H),6.98(d,J=8.0Hz,2H),4.01(d,J=7.6Hz,2H),2.15–2.04(m,1H),0.73(d,J=6.8Hz,6H).

[0474] Embodiment 53

[0475] 4-Chloro-N-(4-(1-cyclohexyl-1H-benzo[d]imidazol-2-yl)phenyl)benzenesulfonamide

[0476]

[0477] Using raw material g8 (100 mg, 0.34 mmol), p-chlorobenzenesulfonyl chloride (145 mg, 0.68 mmol), triethylamine (96 μl, 0.68 mmol), and dichloromethane (15 mL) as raw materials, a preparation method similar to that of Example 5 was used to obtain 72 mg of a white solid with a yield of 45%. 1 H NMR (400MHz, DMSO-D6) δ10.75(s,1H),7.84(d,J=8.4Hz,2H),7.82–7.76(m,1H),7.66(d,J=8.8Hz,2H),7.64–7.58(m,1H),7.52(d,J=8.4Hz,2H),7.2 8(d,J=8.8Hz,2H),7.20(tt,J=7.2,5.6Hz,2H),4.21–3.98(m,1H),2.38–2 .05(m,2H),1.92–1.72(m,4H),1.62(d,J=12.0Hz,1H),1.43–1.09(m,3H).

[0478] Embodiment 54

[0479] N-(4-(4-((6-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0480]

[0481] Take a 50mL single-mouth bottle, add raw material imidazole (250mg, 1.2mmol), raw material i2 (377mg, 1.2mmol), anhydrous potassium carbonate (332mg, 2.4mmol), DMF (20mL), heat to 100℃, and stir for 6h. After TLC monitoring, concentrate the reaction solution, add appropriate amount of water, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane = 2%), 260mg of white solid was obtained, with a yield of 44%. 1 H NMR(500MHz, CDCl3)δ7.69(d,J=7.0Hz,2H),7.63(dd,J=9.0,2.5Hz,1H),7.53–7.50(m,1H),7.43–7.39(m,2H),6.94–6 .90(m,3H),6.85–6.78(m,1H),6.74(dd,J=9.0,3.0Hz,2H),6.49(s,1H),3.89–3.85(m,8H),3.14(s,4H),2.71(s,4H).

[0482] Embodiment 55

[0483] N-(4-(4-((5-methoxy-N-1-methyl-1H-benzo[d]imidazol-2-yl)))methyl)piperazin-1-yl)phenyl)benzenesulfonamide

[0484]

[0485] Take a 50mL single-mouth bottle, add raw material b5 (30mg, 0.14mmol), raw material i2 (46mg, 0.14mmol), anhydrous potassium carbonate (138mg, 0.28mmol), DMF (8mL), heat to 100℃, and stir for 4h. After TLC monitoring, concentrate the reaction solution, add appropriate amount of water, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. After silica gel column chromatography (methanol / dichloromethane = 2%), 40mg of white solid was obtained, with a yield of 58%. 1 H NMR (400MHz, CDCl3) δ7.72–7.65(m,2H),7.55–7.48(m,1H),7.45–7.38(m,2H),7.24(dd,J=5.6,3.2Hz,2H),6.9 8–6.88(m,3H),6.79–6.70(m,2H),6.30(s,1H),3.87(s,2H),3.86(s,6H),3.14–3.11(m,4H),2.69–2.66(m,4H).

[0486] Biological activity test

[0487] 1. Test for inhibitory activity of Mycobacterium tuberculosis polyketide synthase 13

[0488] Compounds of different concentrations were placed in a 96-well plate for testing. The reaction system contained 0.64 μM Mycobacterium tuberculosis polyketide synthase 13, 0.1 M Tris-HCl, pH = 7 buffer, different concentrations of compounds or DMSO, and the total volume was 50 μL. Then 50 μL of 4-MUH (diluted with 0.1 M Tris-HCl, pH = 7 buffer and the final concentration was 30 μM) was added to the reaction mixture. The initial velocity data was obtained by monitoring the fluorescence increase every 10 minutes within 110 minutes. The variable slope dose response equation was fitted with a nonlinear regression curve using Prism software to obtain the IC of each compound. 50 .

[0489] Table 1. Inhibitory activity of some compounds of the present invention on Mycobacterium tuberculosis polyketide synthase 13

[0490]

[0491] It can be seen from the data in Table 1 that the compounds of the present invention have good Mycobacterium tuberculosis polyketide synthase 13 inhibitory activity.

[0492] 2. In vitro anti-tuberculosis activity test

[0493] The in vitro anti-tuberculosis activity was determined by Microplate Alamar Blue Assay (MABA) method. In a sterile 96-well plate, the test compound was dissolved in DMSO to prepare a 5 mg / mL initial solution. 199 μL 7H9 medium and 1 μL compound initial solution were added to the highest concentration well, mixed well, and then diluted 2-fold to the remaining wells. 37 R v The culture was cultured for 2 to 3 weeks to prepare a bacterial suspension, which was inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC and cultured at 37°C for 1 to 2 weeks until the turbidity reached McFarland 1 (equivalent to 10 7 CFU / mL), 100 μL of the bacterial solution was added to each well after dilution of 1:20, and the final concentration of the bacterial solution was 10 6CFU / mL. Two growth control wells without antibiotics were set up on each plate, and the 96-well plate was incubated at 37°C. After 7 days, 20 μL of 10×Alamar Blue and 50 μL of 5% Tween80 were added to the growth control wells and incubated at 37°C for 24 hours. If the color changed from blue to pink, the above amount of Alamar Blue and Tween80 mixture was added to the wells of each experimental drug, and incubated at 37°C for 24 hours. The color of each well was recorded, and the fluorescence value at 590 nm was measured using an enzyme reader to calculate the MIC. 90 .

[0494] Table 2. In vitro anti-Mycobacterium tuberculosis activity of some compounds of the present invention

[0495] Compound MIC (μg / mL) Compound 3 3.92 Compound 5 3.08 Compound 8 0.94 Compound 10 0.93 Compound 16 0.93 Compound 24 1.89 Compound 25 2.16 Compound 26 1.75 Compound 27 3.91 Compound 28 3.96 Compound 29 1.99 Compound 30 1.74 Compound 51 3.21

[0496] It can be seen from the data in Table 2 that the compounds of the present invention have good in vitro anti-Mycobacterium tuberculosis activity, especially compounds 8, 10 and 16 exhibit strong in vitro anti-Mycobacterium tuberculosis activity (MIC<1 μg / mL).

[0497] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydrogen, hydroxy, F, Cl, Br, cyano, C1-C3 alkyl or C1-C3 alkoxy; R2 is a substituted or unsubstituted C1-C7 alkyl group or a C3-C6 cycloalkyl group; R3 is hydrogen or C1-C3 alkyl; R4 is R5 is a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group; A is R6 is hydrogen, F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino; The substituted or unsubstituted substituents in R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkylamino; The substituted or unsubstituted substituents in R5 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy or 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 (I-1): in, R1, R2, R3, R4 and R6 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 (I-2): in, R1, R2, R3, R4 and R6 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 (I-3): in, R1, R2, R3, R4 and R6 are as described in claim 1.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (I-4): in, R1, R2, R3, R4 and R6 are as described in claim 1.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in, R1 is selected from hydrogen, hydroxy, F, Cl, Br, methoxy or methyl; R2 is methyl, ethyl, isopropyl, R3 is selected from hydrogen or methyl; R4 is selected from R6 is selected from hydrogen, F, Cl, Br, hydroxy, methoxy or methyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

8. A method for preparing a compound according to any one of claims 1 to 7, comprising the following steps: (1) The raw material a is condensed with an amino compound under alkaline conditions to obtain an intermediate b, b is reduced to obtain c, c is reacted with hydroxyacetic acid to obtain a benzimidazole compound d, the hydroxyl group in d is converted into chlorine to obtain e, and then the intermediate e is substituted with a corresponding piperazine compound to obtain an intermediate g, which is then reduced, acylated and substituted to obtain a product represented by formula (I-1); (2) Compound c reacts with methyl trichloroacetimidate to obtain benzimidazole compound j, and then intermediate j undergoes substitution reaction with the corresponding piperazine compound to obtain intermediate k, which is then subjected to reduction, acylation and substitution reactions to obtain the product shown in formula (I-2); (3) The intermediate e undergoes a substitution reaction with the corresponding piperazinone compound to obtain the intermediate s, which is then subjected to reduction, acylation and substitution reactions to obtain the product of formula (I-3); (4) Compound c reacts with an aldehyde compound to obtain a benzimidazole compound v, which is then subjected to reduction, acylation and substitution to obtain a product of formula (I-4); wherein R1, R2, R3, R4 and R6 are defined as in any one of claims 1 to 7.

9. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 9 in the preparation of an anti-Mycobacterium tuberculosis drug.

11. The use according to claim 10, characterized in that The anti-tuberculosis mycobacterium is achieved by inhibiting the polyketide synthase 13 of the mycobacterium tuberculosis.

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