An arylcarboxamide compound, a preparation method and use thereof

Abstract

The application relates to an aromatic formyl compound, a preparation method and application thereof, a structural formula of the aromatic formyl compound is shown as formula I, the aromatic formyl compound or a medicinal salt thereof provided by the application has good TMPRSS2 enzyme inhibiting activity, and provides a research basis for further development of antiviral drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. Specifically, this invention relates to an aryl formyl compound, its preparation method, and its uses. Background Technology

[0002] COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. Currently, treatment for the novel coronavirus primarily relies on vaccines. Although several vaccines are available, the SARS-CoV-2 virus is a single-stranded RNA virus, and its genome is prone to mutation as it spreads. The possibility of vaccine ineffectiveness due to viral mutations could become another unavoidable challenge in controlling the COVID-19 pandemic. Therefore, scientists and researchers worldwide are racing against time to develop effective drugs and vaccines to prevent SARS-CoV-2 infection, including repurposing existing drugs to target the virus and host proteins, particularly those that may prevent SARS-CoV-2 from entering human cells.

[0003] Currently, there are four small-molecule drugs for COVID-19 available globally: baricitinib (marketed in Japan), remdesivir (marketed in Japan, the US, and Europe), molnupiravir (marketed in the UK), and Paxlovid (US EUA / conditional approval in China). Baricitinib has shown efficacy in treating severe COVID-19; the US NIH's COVID-19 treatment guidelines recommend that severely ill patients try remdesivir, but not for mild or moderate cases. Although numerous clinical studies on antiviral treatments for COVID-19 have been conducted globally, current results are insufficient to provide evidence of the efficacy and safety of these drugs in treating COVID-19. The discovery of novel and safe treatments for COVID-19 is urgently needed.

[0004] Coronaviruses rely on the binding of their spike (S) protein to human cell receptors and the initiation of the S protein by host cell proteases. SARS-CoV-2 has been shown to use angiotensin-converting enzyme 2 (ACE2) as its entry receptor and transmembrane protease serine 2 (TMPRSS2) as the initiation factor for the S protein. Given the pathway of SARS-CoV-2's invasion of the human body, TMPRSS2 has an ideal target organ distribution, and drugs developed targeting TMPRSS2 possess a natural targeting advantage. Inhibiting TMPRSS2 activity can block or slow the process of SARS-CoV-2 entering host cells, thereby treating SARS-CoV-2 infection.

[0005] In view of this, the applicant has conducted relevant research and completed this invention. Summary of the Invention

[0006] One of the objectives of this invention is to provide an aryl formyl compound or a pharmaceutical salt thereof.

[0007] Another object of the present invention is to provide a method for synthesizing the said aryl compounds.

[0008] Another object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation in which the said aryl compounds or their pharmaceutical salts are used as active ingredients.

[0009] Another object of the present invention is to provide the use of the said aryl compounds or pharmaceutical salts thereof in the preparation of TMPRSS2 inhibitory drugs.

[0010] Another object of the present invention is to provide the use of the said aryl compounds or pharmaceutical salts thereof in the preparation of antiviral drugs.

[0011] The terminology used in the description of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The nomenclature used herein and the laboratory procedures described herein in organic chemistry, medicinal chemistry, and biology are well-known and commonly used in the art. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0012] As used in the description of embodiments of the invention and the appended claims, the singular forms of “a,” “an,” “the,” and “its” refer to the singular and plural of the article, unless the context clearly indicates otherwise. For example, a compound comprises one or more compounds.

[0013] As used in this article, “and / or” means any and all possible combinations of one or more of the related listed items.

[0014] As used in this article, the term "disease" refers to any change in the physical condition or organs that interrupts or interferes with their function and / or causes symptoms.

[0015] As used herein, the term "treatment" aims to alleviate or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of a compound or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, is received and one or more indications and symptoms show an observable and / or detectable reduction or improvement. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0016] As used herein, the term "subject" may refer to a patient or other animal that receives the compositions of the present invention to treat, prevent, reduce and / or alleviate the disease or condition described herein, and in particular to humans and mammals.

[0017] Technical Topic 1

[0018] This invention provides aryl compounds having the structure shown in Formula I, or pharmaceutical salts thereof:

[0019]

[0020] Where ring B represents R 1 Substituted or unsubstituted benzene ring, R 1 Substituted or unsubstituted five- or six-membered heteroaromatic rings;

[0021] R 1 It can be a monosubstituted or polysubstituted group, and can be independently represented by H, F, Cl, Br, C1-C5 alkyl, 1-3 halo-C1-C5 alkyl, C1-C5 alkoxy, 1-3 halo-C1-C5 alkoxy, NO2;

[0022] Ring A represents R 2 The substituted benzene ring, or ring A, represents the following bicyclic structure:

[0023]

[0024] R 2 It can be a single or multiple substituted group, independently represented by H, hydroxyl, amino, C1-C5 alkyl, 1-3 halogenated C1-C5 alkyl, C1-C5 alkoxy, 1-3 halogenated C1-C5 alkoxy, C2-C5 ester group, carbamoyl-substituted phenyl, cyano-substituted phenyl,

[0025] R 3 Represents C1-C5 alkyl, C3-C6 cycloalkyl, -C(O)NR x R y ;

[0026] R x R y Independently represented by H, C1-C5 alkyl;

[0027] R 4 Represents H, C1-C5 alkyl groups.

[0028] In some preferred embodiments of the present invention, the ring B represents R. 1 Substituted or unsubstituted benzene ring, R 1 Substituted or unsubstituted pyridine;

[0029] R1 It can be a monosubstituted or polysubstituted group, with independent representatives such as H, F, Cl, Br, methoxy, methyl, nitro, and trifluoromethyl;

[0030] The R 2 It can be a monosubstituted or polysubstituted group, independently represented by H, trifluoromethyl, amino, hydroxyl, carbamoyl-substituted phenyl, cyano-substituted phenyl,

[0031] R 3 Represents isopropyl, cyclopropyl, -C(O)NR x R y ;

[0032] R x R y Independent representatives: H, methyl;

[0033] R 4 Represents H, methyl, and ethyl.

[0034] In some preferred embodiments of the present invention, the C1-C5 alkyl group is selected from -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -(CH2)4CH3, -CH(CH3)(CH2)2CH3, -CH(CH2CH3)2, -CH2C(CH3)3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, -(CH2)2CH(CH3)2;

[0035] The 1-3 halogenated C1-C5 alkyl groups are selected from —CF3, —CH2CF3, —(CH2)2CF3, —(CH2)3CF3, and —(CH2)4CF3;

[0036] The C1-C5 alkoxy group is selected from -OCH3, -OCH2CH3, -OCH(CH3)2, -O(CH2)2CH3, -O(CH2)3CH3, -OCH2CH(CH3)2, -OC(CH3)3, -OCH(CH3)CH2CH3, -O(CH2)4CH3, - OCH(CH3)(CH2)2CH3, —OCH(CH2CH3)2, —OCH2C(CH3)3, —OCH2CH(CH3)CH2CH3, —OC(CH3)2CH2CH3, —OCH(CH3)CH(CH3)2, —O(CH2)2CH(CH3)2;

[0037] The 1-3 halogenated C1-C5 alkoxy groups are selected from —OCF3, —OCH2CF3, —O(CH2)2CF3, —O(CH2)3CF3, and —O(CH2)4CF3;

[0038] The five- or six-membered heteroaromatic ring is selected from pyridine, furan, pyrrole, thiophene, and thiazole;

[0039] The C2-C5 ester group is selected from: —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, —CH2C(O)OCH3, —CH2C(O)OC2H5, —CH2C(O)OC3H7, —(CH2)2C(O)OCH3, —(CH2)2C(O)OC2H5, —(CH2)3C(O)OCH3;

[0040] The cycloalkyl groups of C3-C6 are selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexane.

[0041] In some preferred embodiments of the present invention, ring A represents the following structure:

[0042]

[0043]

[0044] In some preferred embodiments of the present invention, the pharmaceutical salt is selected from acetate, trifluoroacetate, methanesulfonate, hydrochloride, phosphate or sulfate.

[0045] In some preferred embodiments of the present invention, the aryl compounds represented by Formula I or their pharmaceutical salts are selected from the following:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] As used herein, the term "alkyl" alone or in combination refers to a straight-chain or branched alkyl group. The term "Cm-n alkyl" (where m and n are each integers) refers to a straight-chain or branched alkyl group containing m to n carbon atoms. The term "C1-5 alkyl" alone or in combination in this invention refers to a straight-chain or branched alkyl group containing 1 to 5 carbon atoms. Indicative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and tert-pentyl.

[0052] As used herein, "C3-C6 cycloalkyl" refers to saturated cyclic aliphatic monocyclic systems having 3 to 6 carbon ring atoms, as described herein. This includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0053] "Halogen" and "halogen" refer to atoms selected from fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), and iodine (iodinated, -I).

[0054] As used herein, the term “C1-C5 alkoxy” alone or in combination refers to a straight-chain or branched alkoxy group containing 1 to 5 carbon atoms. Representative examples of C1-5 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, and pteropentoxy.

[0055] As used herein, the term "heteroaryl" alone or in combination refers to an aromatic ring containing one or more (e.g., 1 to 6, 1 to 5, 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyrazinyl.

[0056] The term ester group (also known as alkoxycarbonyl) refers to a group containing the formula -C(O)OR, where R is an alkyl group. The alkyl group preferably contains 1-5 carbon atoms.

[0057] As used herein, "pharmaceutical salt" refers to a salt that retains the desired biological activity of the target compound and exhibits minimal undesirable toxicological effects. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in a pure solution or a suitable inert solvent with a sufficient amount of acid in their neutral form. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid; and organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, bamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, etc. Trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheponic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, and salts formed from sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0058] Technical Theme Two

[0059] This invention also provides a method for synthesizing aryl compounds of Formula I or their pharmaceutical salts. Although the compounds of this invention can be obtained by any of the following routes, the conditions of the method, such as reactants, solvents, acids, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the descriptions below. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known to those skilled in the art, and such combinations can be readily performed by those skilled in the art.

[0060] Route 1:

[0061]

[0062] Substrate b was dissolved in pyridine, and then substrate a, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine were added. The mixture was stirred at room temperature, filtered, and the filter cake or filtrate was purified by column chromatography to obtain product c.

[0063] Route 2:

[0064]

[0065] S1: Dissolve substrate d in dichloromethane, add N,N'-di-BOC-S-methylisothiourea, mercuric chloride and triethylamine, react overnight, filter, and purify by column chromatography to obtain substrate e;

[0066] S2: Dissolve substrate e in dichloromethane, add trifluoroacetic acid, incubate overnight at room temperature, and then post-process to obtain product f.

[0067] Technical Theme 3

[0068] The present invention provides a pharmaceutical composition comprising an aryl formyl compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0069] As used herein, a "pharmaceutical composition" comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a methylformyl compound of formula I, and one or more pharmaceutically acceptable carriers, is prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, tinctures, ointments, lozenges, mixtures, suppositories, injections, inhalants, or sprays. Preferably, the pharmaceutical composition contains 0.1% to 99.5% by weight of the methylformyl compound of the present invention or its pharmaceutically acceptable salt as an active ingredient, more preferably 0.5% to 99.5% by weight of the active ingredient.

[0070] As used herein, “pharmaceutically acceptable carriers or excipients” include: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that some pharmaceutically acceptable excipients may be used for more than one function and for alternative functions, depending on the amount of said excipient present in the formulation and what other ingredients are present in the formulation. For example, when used orally, it can be formulated into oral preparations such as tablets, capsules, granules, and pills, containing fillers (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (e.g., gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose and polyvinylpyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, cetyl, boric acid, sodium benzoate, and leucine), stabilizers (methylparaben, propylparaben, etc.), and flavoring agents (e.g., commonly used sweeteners, acidulants, and flavorings, etc.). When used parenterally, the drug can be formulated as an injection, comprising a sterile powder for injection and a solvent for injection. The carrier or excipient used may contain sterile water, Ringer's solution, and isotonic sodium chloride solution. Suitable adjuvants such as antioxidants, buffers, and antibacterial agents may also be added depending on the properties of the drug. When used for rectal administration, the drug can be formulated as suppositories, etc. When used for pulmonary administration, the drug can be formulated as an inhaler or spray, etc. Many resources are available to those skilled in the art describing pharmaceutically acceptable excipients and which can be used to select suitable pharmaceutically acceptable excipients, such as the Remington Pharmacy Encyclopedia, the Chinese Pharmaceutical Yearbook, and Pharmaceutics.

[0071] This invention can be administered by any suitable method known in the art, such as oral, intravenous, intraperitoneal, intramuscular, local, transdermal, ocular, nasal, inhalation, subcutaneous, intramuscular, oral, sublingual, or rectal administration. The compound described above can be administered at any amount from 1 μg to 2000 mg / kg of the subject's body weight, for example, at doses of 1 μg to 1000 mg / kg body weight / day, 50 μg to 1000 mg / kg body weight / day, 100 μg to 1000 mg / kg body weight / day, 1 to 500 mg / kg body weight / day, 2 to 200 mg / kg body weight / day, or 5 to 100 mg / kg body weight / day. In some embodiments of this invention, the compound described above can be administered four times daily, three times daily, twice daily, once daily, once every two days, once weekly, or at other intervals, optionally repeating the dosing regimen as appropriate weekly or monthly. In this invention, the dosage of the compound can be adjusted according to factors such as the severity of the patient's or subject's condition, age, weight, gender, administration method, and course of treatment.

[0072] The compounds of the present invention can be used alone or in combination with one or more other active ingredients for the treatment, prevention, inhibition, or improvement of diseases or symptoms, wherein the combined use of the drugs is safer or more effective than the use of any one drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention in the manner and amount normally used for this purpose. When the compounds of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing the other drug and the compounds of the present invention in a unit dosage form are preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combination therapy may also include treatment with the compounds of the present invention and one or more other drugs administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used at lower doses than when used individually. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention also include those compositions containing one or more other active ingredients.

[0073] Technical Theme 4

[0074] The present invention also provides the use of aryl compounds of Formula I or their pharmaceutical salts in the preparation of drugs that inhibit transmembrane serine protease TMPRSS2.

[0075] Technology Theme 5

[0076] The present invention also provides the use of aryl compounds of Formula I or their pharmaceutical salts in antiviral drugs.

[0077] In some preferred embodiments, the virus includes coronaviruses or variants thereof.

[0078] Beneficial effects of the invention

[0079] The compound developed in this invention has been verified to have a significant inhibitory effect on the activity of the TMPRSS2 protease, and is expected to become a potential antiviral drug.

[0080] Instruction manual illustrations

[0081] Figure 1 This is a dose-response curve of compounds B-4, B-14, B-24, H-22, and H-45 of this application with carmosstatin mesylate. The x-axis of each measurement point from right to left is 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM.

[0082] Figure 2 This is a dose-response curve of compounds B-12, B-16, B-21, H-26, and H-46 of this application with carmosstatin mesylate. The x-axis of each measurement point from right to left is 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM.

[0083] Figure 3 This is a dose-response curve of compounds B-1, B-41, CO1, H-17, and H-43 of this application with carmosstatin mesylate. The x-axis of each measurement point from right to left is 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM. Detailed Implementation

[0084] The present invention is illustrated below with reference to specific embodiments. These embodiments are not intended to limit the scope of the invention, but rather to provide guidance to those skilled in the art for the preparation and use of the compounds, compositions, and methods of the present invention. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer should be followed. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0085] The chemical names of the compounds described in this application are generally derived from ChemDraw Ultra (Chambridge Soft) and are generated / or generally follow the principles of IUPAC nomenclature. The correspondence between the English abbreviations of the compounds and their chemical names is as follows:

[0086] Dichloromethane (DCM), methanol (MeOH), ethyl acetate (EA), petroleum ether (PE), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), N-chlorosuccinimide (NCS), polyphosphoric acid (PPA).

[0087] Some of the compounds in this embodiment were synthesized via the following route:

[0088] Route 1

[0089]

[0090] Substrate b was dissolved in pyridine, and then substrate a, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine were added. The mixture was stirred at room temperature, filtered, and the filter cake or filtrate was purified by column chromatography to obtain product c.

[0091] Route 2

[0092]

[0093] Substrate d was dissolved in dichloromethane and N,N'-di-BOC-S-methylisothiourea, mercuric chloride and triethylamine were added. The mixture was reacted overnight, filtered, and purified by column chromatography to obtain substrate e.

[0094] Substrate e was dissolved in dichloromethane, trifluoroacetic acid was added, and the mixture was left to stand overnight at room temperature. Post-treatment was then performed to obtain product f.

[0095] Example 1 1-Oxoisocyanate-7-yl-4-guanidinobenzoate (B-1)

[0096]

[0097] Add p-guanidinyl benzoate (0.59 g, 3.05 mmol) and pyridine (10 mL) to a 100 mL single-necked flask to dissolve the compound. Then add 1-oxo-7-hydroxyisocyanate (0.50 g, 3.05 mmol), DCC (0.75 g, 3.66 mmol), and DMAP (0.01 g, 0.01 mmol) sequentially. Stir at room temperature for 24 h, filter, wash with 5 mL of pyridine, and purify by filter cake column chromatography (DCM:MeOH = 10:1) to give compound B-1, 0.48 g white solid, yield 53.9%.

[0098] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.18(d,J=8.6Hz,2H),7.80(d,J=2.4Hz,1H),7.77(s, 3H),7.61–7.51(m,2H),7.45(d,J=8.5Hz,2H),4.56(t,J=6.0Hz,2H),3.11(t,J=6.0Hz,2H).

[0099] Example 2 1-Oxo-1,2,3,4-Tetrahydroisoquinoline-7-yl-4-guanidinobenzoate (B-2)

[0100]

[0101] Following the method of Example 1, the starting material was replaced with 3,4-dihydro-7-hydroxyisoquinoline-1(2H)-one (1.00 g, 6.13 mmol) to obtain compound B-2, 0.85 g white solid, yield 30.9%.

[0102] 1 H NMR (400MHz, MeOD-d4) δ8.36 (s, 1H), 8.06 (d, J = 8.0Hz, 2H), 7.99-7.97 (m, 1H), 7.43-7.39 (m, 3H), 4.56 (t, J = 4.0Hz, 2H) 3.09 (s, 2H).

[0103] Example 3 2-O-1,2,3,4-Tetrahydroquinoline-7-yl-4-guanidinobenzoate hydrochloride (B-3)

[0104]

[0105] Following the method of Example 1, the starting material was replaced with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (3.00 g, 18.00 mmol) to obtain compound B-3, 3.00 g white solid, yield 56.0%.

[0106] 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),10.22(s,1H),8.14(d,J=8.8Hz,2H),7.87(s,4H),7.43(d,J=8.4 Hz,2H),8.4(d,J=8.4Hz,1H),6.82-6.73(m,2H),2.90(t,J=7.3Hz,J=8.0Hz,2H)2.48(d,J=8.0Hz,2H).

[0107] Example 44-(3-oxomorpholino)phenyl 4-guanidinyl benzoate (B-4)

[0108]

[0109] H₂O (100 mL) was added to a 250 mL three-necked flask, followed by slow dropwise addition of concentrated sulfuric acid (12.75 g, 31.00 mmol). The mixture was cooled to 0-10 °C with cold hydrazine, and then 4-(4-aminophenyl)-3-morpholinone (5.00 g, 26.00 mmol) and an aqueous solution of NaNO₂ (2.14 g, 130.00 mmol) (20 mL) were added sequentially. The reaction was carried out at 110 °C for 3 h. The mixture was poured into 100 mL of ice water, extracted with EA (100 mL * 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 30:1) to give compound B-4-1, 2.77 g of pale red solid, yield 49.8%.

[0110] Following the method of Example 1, the starting material was replaced with B-4-1 (2.00 g, 10.40 mmol) to obtain compound B-4, 1.30 g white solid, with a yield of 39.3%.

[0111] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.6Hz,2H),7.88(s,4H),7.50(d,J=8.8Hz,2H),7.45(d ,J=8.6Hz,2H),7.33(d,J=8.8Hz,2H),4.23(s,2H),4.03–3.96(m,2H),3.82–3.73(m,2H).

[0112] Example 5 4-(2-Methoxy-2-oxyethyl)phenyl-4-guanidinylbenzoate (B-12)

[0113]

[0114] In a 100 mL single-necked flask, p-guanidinyl benzoate (0.59 g, 2.76 mmol) and pyridine (10 mL) were added and dissolved. Then, methyl 4-hydroxyphenylacetate (0.51 g, 3.06 mmol), DCC (0.76 g, 3.67 mmol), and DMAP (0.01 g, 0.01 mmol) were added sequentially. The mixture was stirred at room temperature for 24 h, filtered, washed with 5 mL of pyridine, and purified by column chromatography (DCM:MeOH = 10:1) of the filter cake. After concentration under reduced pressure, the solution was dissolved in 20 mL of methanol, and 2 mL of ethyl hydrogen chloride solution (4 mol / L) was added dropwise. The mixture was stirred at room temperature for 30 min, cooled to -10 °C for 30 min to crystallize, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound B-12, 0.45 g white solid, yield 40.3%.

[0115] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.16(d,J=8.4Hz,2H),7.87(s,4H),7.44(d,J =8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.23(d,J=8.8Hz,2H),3.74(s,2H),3.64(s,3H).

[0116] Example 6 1-Oxo-1,2,3,4-Tetrahydroisoquinoline-6-yl-4-guanidinobenzoate (B-13)

[0117]

[0118] Following the method of Example 1, the starting material was replaced with 3,4-dihydro-6-hydroxy-isoquinoline-1(2H)-one (1.00 g, 6.70 mmol) to obtain compound B-13, 1.80 g white solid, yield 54.0%.

[0119] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.17(d,J=8.8Hz,2H),8.00(s,1H),7.91(t,J=8Hz,J=22.4Hz, 4H),7.45(d,J=8.4Hz,2H),7.25(d,J=8.8Hz,2H),3.42-3.39(m,2H),2.95(t,J=6.4Hz,J=6.8Hz,2H).

[0120] Example 7 1-Oxoisocyanate-6-yl-4-guanidinylbenzoate (B-14)

[0121]

[0122] Following the method of Example 1, the starting material was replaced with 1-oxo-6-hydroxyisocyanate (1.00 g, 6.09 mmol) to obtain compound B-14, 0.80 g white solid, yield 44.9%.

[0123] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.17(d,J=8.4Hz,2H),8.03(d,J=8.4Hz,1H),7.85(s,4H),7 .46(d,J=8.4Hz,2H),7.53(d,J=1.2Hz,1H),7.45(d,J=8.4Hz,2H),7.39(t,J=5.2Hz,J=8.4Hz,2H).

[0124] Example 8 1-Oxoisoindoline-5-yl-4-guanidinylbenzoate (B-15)

[0125]

[0126] Add m-methoxybenzylamine (5.00 g, 36.50 mmol) to a 250 mL three-necked flask and dissolve in THF (30 mL). Add 30 mL of NaHCO3 aqueous solution (10.70 g, 3.50 mmol) dropwise at -10 °C. After stirring for 5 min, add 20 mL of ethyl chloroformate (4.75 g, 43.70 mmol) THF solution dropwise using a dropping funnel. React at -10 °C for 1 h, quench with 30 mL of water, extract with EA (50 mL * 3), wash with saturated brine (50 mL) on the organic phase, dry with anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE:EA = 10:1) to give compound B-15-1, 6.75 g of colorless oil, yield 88.6%.

[0127] PPA (21.00 g) preheated at 80 °C was added to a 150 mL single-necked flask, followed by B-15-1 (6.00 g, 28.00 mmol). The mixture was reacted at 100 °C for 2 h. While still hot, 100 mL of ice water was added, and the mixture was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 50:1) to give compound B-15-2, 0.60 g of gray solid, yield 13.0%.

[0128] Add B-15-2 (0.60 g, 3.60 mmol) to a 150 mL three-necked flask, dissolve in DCM (18 mL), replace with N2, add BBr3 (2.76 g, 11.00 mol) dropwise at -10 °C, react at room temperature for 2 h, quench with 50 mL of water dropwise at -10 °C, stir vigorously for 20 min, filter, and dry the filter cake under vacuum at 45 °C for 8 h to obtain compound B-15-3, 0.40 g brown solid, yield 74.5%.

[0129] Following the method of Example 5, the starting material was replaced with B-15-3 (0.20 g, 1.20 mmol) to obtain compound B-15, 0.20 g white solid, with a yield of 54.0%.

[0130] 1 H NMR (400MHz, DMSO-d6) δ10.53 (s, 1H), 8.66 (s, 1H), 8.18 (d, J = 8.8Hz, 2H), 7.89 (s, 4H), 7.76(d,J=8.4Hz,1H),7.53(d,J=1.2Hz,1H),7.45(d,J=8.4Hz,2H),7.40-7.37(m,2H).

[0131] Example 9 1-Oxo-1,3-dihydroisobenzofuran-5-yl-4-guanidinylbenzoate hydrochloride (B-16)

[0132]

[0133] Following the method of Example 5, the starting material was replaced with 5-hydroxyphthalide (1.00 eq., 3.33 mmol) to obtain compound B-16, 0.50 g white solid, yield 48.1%.

[0134] 1 H NMR (600MHz, DMSO) δ10.76 (s, 1H), 8.19 (d, J = 8.7Hz, 2H), 7.96 (d, J = 8.3Hz, 5H), 7.67 (d,J=1.2Hz,1H),7.53(dd,J=8.3,1.9Hz,1H),7.48(s,1H),7.47(s,1H),5.46(s,2H).

[0135] Example 10 1-Oxo-2,3-dihydro-1H-inden-5-yl-4-guanidinobenzoate hydrochloride (B-18)

[0136]

[0137] Following the method of Example 5, the starting material was replaced with 5-hydroxy-1-indanone (1.00 eq., 6.08 mmol) to give compound B-18, 1.25 g white solid, yield 73.9%.

[0138] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.21–8.15(m,2H),7.94(s,4H),7.74(d,J=8.3Hz,1H),7.53(d ,J=1.9Hz,1H),7.48–7.43(m,2H),7.35(dd,J=8.3,2.0Hz,1H),3.18–3.11(m,2H),2.72–2.65(m,2H).

[0139] Example 11 2-O-2H-chromene-6-yl-4-guanidinobenzoate hydrochloride (B-19)

[0140]

[0141] Following the method of Example 5, the starting material was replaced with 6-hydroxycoumarin (1.00 eq., 3.08 mmol) to obtain compound B-19, 0.57 g white solid, yield 56.5%.

[0142] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.23–8.14(m,2H),8.09(d,J=9.6Hz,1H),7.87(s,4H),7.72(d,J= 2.7Hz,1H),7.57(dd,J=9.0,2.6Hz,1H),7.53(d,J=9.0Hz,1H),7.50–7.39(m,2H),6.59(d,J=9.5Hz,1H).

[0143] Example 12 2,3-Dihydrobenzo[1,4-b]dioxin-6-yl-4-guanidinylbenzoate hydrochloride (B-20)

[0144]

[0145] Following the method of Example 5, the starting material was replaced with 6-hydroxy-1,4-benzodioxane (1.00 eq., 0.20 mmol) to give compound B-20, 0.45 g white solid, yield 72.7%.

[0146] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.12(d,J=8.4Hz,2H),7.87(s,4H),7.42(d,J=8.8Hz, 2H), 6.92 (d, J = 8.8Hz, 1H), 6.83 (d, J = 0.8Hz, 1H), 6.74-6.71 (m, 1H), 4.26 (t, J = 4.8Hz, 4H).

[0147] Example 13 2-O-2H-chromene-7-yl-4-guanidinobenzoate hydrochloride (B-21)

[0148]

[0149] Following the method of Example 5, the starting material was replaced with 7-hydroxycoumarin (1.00 eq., 0.62 mmol) to obtain compound B-21, 1.20 g white solid, in a yield of 60.0%.

[0150] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.23–8.15(m,2H),8.13(d,J=9.6Hz,1H),7.90(s,4H),7.85(d,J= 8.5Hz,1H),7.48(d,J=2.3Hz,1H),7.47–7.43(m,2H),7.33(dd,J=8.4,2.2Hz,1H),6.52(d,J=9.6Hz,1H).

[0151] Example 14 2-O-1,2,3,4-Tetrahydroquinoline-6-yl-4-guanidinobenzoate hydrochloride (B-22)

[0152]

[0153] To a 500 mL three-necked flask, p-hydroxyaniline (1.00 eq., 0.14 mol) was dissolved in ethyl acetate (150 mL). 3-chloropropionyl chloride (1.50 eq., 0.21 mol) in ethyl acetate (50 mL) was added dropwise at 0 °C, maintaining the temperature below 5 °C. After the addition was complete, the mixture was allowed to rise to room temperature for 2 h. Then, 200 mL of saturated sodium carbonate solution was added dropwise, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound B-22-1, 22.00 g of a light purple solid, with a yield of 80.4%.

[0154] B-22-1 (1.00 eq., 0.05 mol) was added to a 250 mL three-necked flask and dissolved in naphthalene (50 mL). Aluminum chloride (5.00 eq., 0.25 mol) was added, and the reaction was carried out under a nitrogen atmosphere by slowly increasing the temperature from room temperature to 150 °C for 8 h. The mixture was then poured into 100 mL of ice water and stirred vigorously. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound B-22-2, 7.00 g of gray solid, with a yield of 85.8%.

[0155] Following the method of Example 5, the starting material was replaced with B-22-2 (1.00 eq., 0.61 mmol) to obtain compound B-22, 1.40 g white solid, yield 70.0%.

[0156] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),10.19(s,1H),8.20–8.09(m,2H),7.87(s,4H),7.49–7.38(m,2H),7.11(d,J= 2.5Hz,1H),7.05(dd,J=8.5,2.6Hz,1H),6.92(d,J=8.5Hz,1H),2.90(t,J=7.5Hz,2H),2.47(dd,J=8.5,6.5Hz,2H).

[0157] Example 15 5-O-5,6,7,8-Tetrahydronaphth-2-yl-4-guanidinobenzoate hydrochloride (B-24)

[0158]

[0159] Following the method of Example 5, the starting material was replaced with 6-hydroxy-1-tetrahydronaphthone (1.00 eq., 0.60 mmol) to give compound B-24, 1.35 g white solid, yield 67.5%.

[0160] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.21–8.12(m,2H),7.97(d,J=8.5Hz,1H),7.91(s,4H),7.49–7.41(m,2H),7.32 (d,J=2.3Hz,1H),7.27(dd,J=8.5,2.3Hz,1H),2.99(t,J=6.0Hz,2H),2.63(dd,J=7.2,5.6Hz,2H),2.13–2.00(m,2H).

[0161] Example 16: Benzo[1,3-d]dioxolane-5-yl-4-guanidinobenzoate hydrochloride (B-25)

[0162]

[0163] Following the method of Example 5, the starting material was replaced with 3,4-methylenedioxyphenol (1.00 eq., 0.72 mmol) to give compound B-25, 1.70 g white solid, yield 77.7%.

[0164] 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.19–8.02(m,2H),7.87(s,4H),7.50 –7.31(m,2H),7.03–6.85(m,2H),6.72(dd,J=8.4,2.4Hz,1H),6.09(s,2H).

[0165] Example 17 1,3-Dioxoisoindoline-5-yl-4-guanidinylbenzoate hydrochloride (B-26)

[0166]

[0167] 4-Hydroxyphthalic acid (10.00 g, 54.90 mmol) was added to a 250 mL three-necked flask and dissolved in glacial acetic acid. Ammonium carbonate (10.55 g, 109.80 mmol) was added, and the mixture was refluxed for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to 15 mL. The pH was adjusted to 5 with 1 N NaOH solution, and the mixture was stirred vigorously for 10 min. The mixture was then filtered and dried under vacuum at 45 °C for 8 h to obtain compound B-26-1, 6.20 g of pale yellow solid, with a yield of 69.3%.

[0168] Following the method of Example 5, the starting material was replaced with B-26-1 (1.00 g, 6.13 mmol) to obtain compound B-26, 1.20 g white solid, with a yield of 60.3%.

[0169] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.47(s,1H),8.23–8.15(m,2H),7.95(d,J=8.1Hz ,1H),7.88(s,4H),7.82(d,J=2.0Hz,1H),7.74(dd,J=8.1,2.1Hz,1H),7.50–7.41(m,2H).

[0170] Example 18 2-Oxoindoline-5-yl-4-guanidinylbenzoate hydrochloride (B-29)

[0171]

[0172] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with 5-methoxyindol-2-one (3.00 g, 18.38 mmol) to obtain compound B-29-1, 2.30 g of brown solid, with a yield of 83.9%.

[0173] Following the method of Example 5, the starting material was replaced with B-29-1 (1.00 g, 6.70 mmol) to obtain compound B-29, 0.80 g white solid, with a yield of 38.5%.

[0174] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),10.44(s,1H),8.21–8.08(m,2H),7.84(s,4H),7.48–7.35 (m,2H),7.14(d,J=2.2Hz,1H),7.06(dd,J=8.3,2.4Hz,1H),6.87(d,J=8.3Hz,1H),3.54(s,2H).

[0175] Example 19 5,6,7,8-Tetrahydronaphth-2-yl-4-guanidinobenzoate hydrochloride (B-31)

[0176]

[0177] Following the method of Example 5, the starting material was replaced with 5,6,7,8-tetrahydronaphthalene-2-ol (1.00 g, 6.70 mmol) to obtain compound B-31, 1.50 g white solid, with a yield of 72.3%.

[0178] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.19–8.09(m,2H),7.82(s,4H),7.48–7.36(m,2H) ,7.13(d,J=8.0Hz,1H),7.00–6.90(m,2H),2.73(d,J=6.3Hz,4H),1.75(p,J=3.2Hz,4H).

[0179] Example 20 : Benzo[d]thiazolyl-5-yl-4-guanidinobenzoate hydrochloride (B-32)

[0180]

[0181] 10.00 g (81.20 mmol) of m-methoxyaniline was added to a 250 mL single-necked flask and dissolved in 50 mL of DCM. N-iodosuccinimide (81.20 mmol) and acetic acid (1.20 eq., 97.40 mmol) were added sequentially. The mixture was stirred at room temperature for 24 hours. Saturated NaHCO3 aqueous solution (50 mL) was added, and the mixture was extracted with DCM (50 mL x 3). The extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 20:1) to give compound B-32-1, 9.00 g of brown oil, yield 45.0%.

[0182] B-32-1 (5.00 g, 20.10 mmol), Na₂S (4.75 g, 60.30 mmol), CuI (0.19 g, 4.01 mmol), and NH₄OAc (7.24 g, 120.60 mmol) were added sequentially to a 100 mL single-necked flask and dissolved in DMSO (100 mL). The mixture was stirred at 140 °C for 10 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was extracted with 1000 mL of water using EA (500 mL x 3). The extract was washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound B-32-2, 0.60 g of colorless oil, yield 18.2%.

[0183] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with B-32-2 (0.60 g, 3.63 mmol) to obtain compound B-32-3, 0.45 g of pale yellow solid, with a yield of 82.6%.

[0184] Following the method of Example 5, the starting material was replaced with B-32-3 (0.45 g, 2.98 mmol) to obtain compound B-32, 0.45 g white solid, with a yield of 43.3%.

[0185] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.49(s,1H),8.26(d,J=8.7Hz,1H),8.23–8.12(m,2H),8.03(d,J=2.2Hz,1H),7.89(s,4H),7.51–7.36(m,3H).

[0186] Example 21 2,3-Dihydro-1H-inden-5-yl-4-guanidinylbenzoate hydrochloride (B-33)

[0187]

[0188] Following the method of Example 5, the starting material was replaced with 5-indanol (1.00 g, 7.45 mmol) to obtain compound B-33, 1.80 g white solid, in yield of 81.1%.

[0189] 1 H NMR (600MHz, DMSO-d6) δ10.66 (s, 1H), 10.53 (s, 1H), 8.14 (d, J = 12Hz, 2H), 7.92 (s,4H),7.43(d,J=6Hz,2H),7.28(d,J=6Hz,1H),7.1(s,1H),6.99-6.98(m,1H).

[0190] Example 22 2-Oxoindoline-6-yl-4-guanidinylbenzoate hydrochloride (B-34)

[0191]

[0192] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with 5-methoxyindol-2-one (1.00 g, 6.13 mmol) to obtain compound B-34-1, 0.75 g brown solid, with a yield of 82.1%.

[0193] Following the method of Example 5, the starting material was replaced with B-34-1 (0.50 g, 3.35 mmol) to obtain compound B-34, 0.40 g white solid, with a yield of 38.5%.

[0194] 1 H NMR (600MHz, DMSO-d6) δ10.56(s,1H),10.53(s,1H),8.15(d,J=12Hz,2H),7.86(s,4H),7.43(d ,J=6Hz,2H),7.26(d,J=6Hz,1H),6.80(t,J=6Hz,1H),6.79-6.74(d,J=30Hz,1H),3.51(s,2H).

[0195] Example 23 : Oxo-5,6,7,8-tetrahydronaphth-2-yl 4-guanidine-2-methoxybenzoate hydrochloride (B-38)

[0196]

[0197] 4-Amino-2-methoxybenzoic acid (3.00 g, 17.90 mmol) was added to a 100 mL single-necked flask and dissolved in methanol (30 mL). Thionyl chloride (1.40 g, 19.70 mmol) was then added at 0 °C. The mixture was refluxed overnight and concentrated under reduced pressure to give compound B-38-1, 3.10 g of pink solid, with a yield of 79.6%.

[0198] Add B-38-1 (2.00 g, 9.21 mmol) to a 100 mL single-necked flask, dissolve in ethanol (20 mL), add 50% aminonitrile aqueous solution (1.80 g, 23.04 mmol) at 20 °C, reflux overnight, concentrate under reduced pressure, then slurry with 3 mL methanol and 1 mL ethyl acetate, stir at room temperature for 0.5 h, filter, concentrate under reduced pressure to give compound B-38-2, 1.06 g white solid, yield 51.7%.

[0199] B-38-2 (2.00 g, 8.95 mmol) was added to a 100 mL single-necked flask, dissolved in 16 mL of water, and then 2 mL of concentrated hydrochloric acid was added. The mixture was reacted at 75 °C for 3 h, concentrated, and then stirred with 2 mL of methanol and 5 mL of ethyl acetate. The mixture was stirred at room temperature for 0.5 h, filtered, and concentrated under reduced pressure to give compound B-38-3, 1.80 g of white solid, with a yield of 82.2%.

[0200] Add p-B-38-3 (0.30 g, 1.22 mmol) and pyridine (10 mL) to a 100 mL single-necked flask and dissolve. Then add 6-hydroxy-1-tetrahydronaphthone (0.24 g, 1.47 mmol), DCC (0.30 g, 1.47 mmol), and DMAP (0.01 g, 0.02 mmol) sequentially. Stir at room temperature for 24 h, filter, wash with 1 mL of pyridine, and purify by column chromatography (DCM:MeOH = 10:1). Concentrate under reduced pressure to near dryness, dissolve in 5 mL of methanol, add 2 mL of ethyl hydrogen chloride solution (4 mol / L), stir at room temperature for 30 min, and cool to -10 °C for 30 min to crystallize.

[0201] The mixture was filtered, and the filter cake was dried under vacuum at 45°C for 8 hours to obtain compound B-38, 0.35 g of white solid, with a yield of 73.7%.

[0202] 1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.99(dd,J=12.0,8.4Hz,2H),7.89(s,4H),7.27(d,J=2.2Hz,1H),7.23(dd,J=8.5,2.3Hz,1H),7 .09(d,J=2.0Hz,1H),6.96(dd,J=8.4,1.9Hz,1H),3.92(s,3H),3.00(t,J=6.0Hz,2H),2.64(dd,J=7.2,5.7Hz,2H),2.16–2.04(m,2H).

[0203] Example 24 1-Oxo-1,2,3,4-Tetrahydroisoquinoline-6-yl-4-guanidino-2-methylbenzoate hydrochloride (B-39)

[0204]

[0205] Add m-methoxyphenethylamine (20.00 g, 13.20 mmol) to a 500 mL three-necked flask and dissolve in 150 mL of tetrahydrofuran.

[0206] Add 50 mL of NaHCO3 aqueous solution at -10℃, stir for 5 min, then add 50 mL of THF solution of ethyl chloroformate (17.20 g, 15.85 mmol) dropwise using a dropping funnel. React at -10℃ for 1 h, quench with 500 mL of water, extract with EA (300 mL * 3), wash the organic phase with saturated brine (300 mL), dry with anhydrous sodium sulfate, purify the filtrate by column chromatography (PE:EA = 10:1), and concentrate under reduced pressure to give compound B-39-1, 21.50 g of colorless oil, yield 73.0%.

[0207] PPA (66.00 g) preheated at 80 °C was added to a 250 mL single-necked flask, followed by B-39-1 (20.00 g, 8.96 mmol). The mixture was reacted at 100 °C for 2 h. While still hot, 200 mL of water was added, and the mixture was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 50:1) to give compound B-39-2, 5.50 g of gray solid, yield 34.7%.

[0208] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with B-39-2 (5.50 g, 31.00 mmol), yielding compound B-39-3, 4.80 g of yellow solid, with a yield of 95.0%.

[0209] 4-Amino-2-methylbenzoic acid (15.00 g, 7.80 mmol) was added to a 500 mL three-necked flask and dissolved in 120 mL of ethanol. Then, 30 mL of 25% hydrochloric acid-ethanol solution was added, and the mixture was stirred at 60 °C for 0.5 h. 30% aminonitrile aqueous solution (9.84 g, 233.00 mmol) was added dropwise, and the mixture was reacted at 75 °C for 5 h. The solution was concentrated under reduced pressure to 50 mL, stirred at -10 °C for 0.5 h, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound B-39-4, 8.50 g of white solid, with a yield of 47.5%.

[0210] B-39-4 (1.26 g, 5.52 mmol) was added to a 100 mL single-necked flask and dissolved in pyridine (10 mL). Then, B-39-3 (1.00 g, 6.13 mmol), DCC (1.52 g, 7.36 mmol), and DMAP (0.01 g, 0.06 mmol) were added sequentially. The synthesis and post-processing were performed according to Example 5 to obtain compound B-39, 1.45 g of white solid, with a yield of 70.1%.

[0211] 1 H NMR(600MHz,MeOD)δ8.24(d,J=8.8Hz,1H),8.03(d,J=8.4Hz,1H),7.31–7.26(m,2 H),7.25–7.20(m,2H),3.54(t,J=6.7Hz,2H),3.04(t,J=6.7Hz,2H),2.68(s,3H).

[0212] Example 25 5-O-5,6,7,8-Tetrahydronaphth-2-yl-4-guanidine-2-methylbenzoate hydrochloride (B-40)

[0213]

[0214] Following the synthesis method of B-39-4 in Example 24, the starting material was replaced with 4-amino-2-methylbenzoic acid (15.00 g, 7.80 mmol) to obtain compound B-40-1, 8.50 g white solid, with a yield of 47.5%.

[0215] Following the synthesis method of B-38 in Example 23, the starting material was replaced with B-40-1 (1.30 g, 5.55 mmol) to obtain compound B-40, 1.65 g white solid, with a yield of 71.6%.

[0216] 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.16(d,J=8.3Hz,1H),7.99(d,J=8.5Hz,1H),7.80(s,4H),7.33(d,J= 2.2Hz,1H),7.31–7.25(m,3H),3.01(t,J=6.1Hz,2H),2.65(t,J=6.4Hz,2H),2.62(s,3H),2.14–2.04(m,2H).

[0217] Example 26 4-(trifluoromethyl)phenyl-4-guanidine benzoate hydrochloride (B-41)

[0218]

[0219] Following the method of Example 5, but replacing the raw material with p-trifluoromethylphenol (1.00 g, 6.17 mmol), compound B-41 was obtained as 0.85 g of white solid, with a yield of 42.7%.

[0220] 1H NMR (600MHz, DMSO-d6) δ10.66(s,1H),8.22–8.15(m,2H),7.93(s,4H),7.88(d,J=8.5Hz,3H),7.56(d,J=8.3Hz,2H),7.49–7.43(m,2H).

[0221] Example 27 5-O-5,6,7,8-Tetrahydronaphth-2-yl-5-guanidinopyrrolidone trifluoroacetate (B-44)

[0222]

[0223] 5-Aminopyridine-2-carboxylic acid (2.00 g, 69.07 mmol) was added to a 250 mL three-necked flask and dissolved in SOCl2 (20 mL). Two drops of DMF were added, and the mixture was refluxed for 3 h. The mixture was concentrated under reduced pressure and then added dropwise to a DCM solution of 6-hydroxy-1-tetrahydronaphthone (2.35 g, 14.48 mmol) and triethylamine (5.13 g, 50.68 mmol) at -10 °C. The mixture was left to stand overnight at room temperature. The mixture was extracted with 100 mL of water, and the organic phase was concentrated under reduced pressure. The mixture was then slurried with 10 mL of DCM and 5 mL of n-hexane, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound B-44-1, 3.20 g of pale yellow solid, with a yield of 78.3%.

[0224] B-44-1 (1.00 g, 4.69 mmol) was dissolved in 20 mL of DCM in a 100 mL single-necked flask. Then, N,N'-di-BOC-S-methylisothiourea (2.04 g, 7.03 mmol), mercuric chloride (1.40 g, 5.16 mmol), and triethylamine (0.95 g, 9.38 mmol) were added at -10 °C, and the mixture was reacted overnight at room temperature. The mixture was filtered, and the filtrate was purified by column chromatography (PE:EA = 20:1) to give compound B-44-2, 1.80 g of white solid, yield 73.2%.

[0225] Add B-44-2 (1.80 g, 3.43 mmol) to a 100 mL single-necked flask, dissolve in DCM (10 mL), then add trifluoroacetic acid (5 mL), incubate overnight at room temperature, concentrate under reduced pressure, slurry with 5 mL EA, filter, and dry the filter cake under vacuum at 45 °C for 8 h to obtain compound B-44, 1.20 g white solid, yield 80.0%.

[0226] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.70(d,J=2.4Hz,1H),8.28(d,J=8.5Hz,1H),8.07(d,J=12.9Hz,4H),7.98(d,J=8.5Hz,1H),7.90(d d,J=8.5,2.5Hz,1H),7.32(d,J=2.3Hz,1H),7.28(dd,J=8.5,2.1Hz,1H),2.99(t,J=6.1Hz,2H),2.63(t,J=6.5Hz,2H),2.12–2.01(m,2H).

[0227] Example 28 5-O-5,6,7,8-Tetrahydronaphth-2-yl-6-guanidinenicotinate trifluoroacetate (B-47)

[0228]

[0229] Following the synthesis method of B-44-1 in Example 27, the starting material was replaced with 6-aminonicotinic acid (2.00 g, 69.07 mmol) to obtain compound B-47-1, 2.80 g white solid, with a yield of 68.5%.

[0230] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with B-47-1 (1.00 g, 4.69 mmol) to obtain compound B-47-2, 1.50 g white solid, with a yield of 61.0%.

[0231] Following the synthesis method of B-44 in Example 27, the starting material was replaced with B-47-2 (1.50 g, 2.86 mmol) to obtain compound B-47, 0.70 g white solid, yield 56.0%.

[0232] 1 H NMR (400MHz, DMSO-d6) δ11.81(d,J=14.6Hz,1H),9.03(d,J=2.2Hz,1H),8.67(s,3H),7.99(d,J=8.5Hz,1H),7.36(d,J=2.2Hz ,1H),7.32(dd,J=8.4,2.2Hz,1H),7.26(d,J=8.7Hz,1H),3.00(t,J=6.0Hz,2H),2.65(t,J=6.4Hz,2H),2.09(p,J=6.3Hz,2H).

[0233] Example 29 : Oxo-5,6,7,8-tetrahydronaphth-2-yl-2-fluoro-4-guanidine benzoate hydrochloride (B-49)

[0234]

[0235] 4-Amino-2-fluorobenzoic acid (2.00 g, 12.89 mmol) was added to a 100 mL three-necked flask and dissolved in 10 mL of ethanol. Concentrated hydrochloric acid (1.29 mL) was then added and stirred for 0.5 h. 50% aminonitrile aqueous solution (3.30 g, 38.67 mmol) was added dropwise. The reaction was carried out at 55 °C for 5 h, stirred at -10 °C for 0.5 h, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound B-49-1, 1.20 g of brown solid, with a yield of 39.9%.

[0236] Following the synthesis method of B-38 in Example 23, the starting material was replaced with B-49-1 (1.30 g, 5.55 mmol) to obtain compound B-49, 0.80 g white solid, with a yield of 38.2%.

[0237] 1 H NMR (400MHz, DMSO-d6) δ8.14(t,J=8.4Hz,1H),7.99(d,J=8.5Hz,1H),7.96(s,2H),7.91(s,2H),7.34(d, J=10.2Hz,2H),7.27(t,J=10.5Hz,2H),3.01(t,J=6.0Hz,2H),2.65(t,J=6.4Hz,2H),2.14–2.05(m,2H).

[0238] Example 30: Oxo-5,6,7,8-tetrahydronaphth-2-yl-3-chloro-4-guanidinium benzoate trifluoroacetate (B-50)

[0239]

[0240] 3-Chloro-4-aminobenzoic acid (2.00 g, 11.66 mmol) was added to a 250 mL single-necked flask and dissolved in DCM (40 mL). 6-hydroxy-1-tetrahydronaphthone (2.35 g, 11.66 mmol), DCC (2.89 g, 13.99 mmol), and DMAP (0.14 g, 1.17 mmol) were added sequentially. The mixture was reacted overnight at room temperature, filtered, and the filtrate was purified by column chromatography (DCM:MeOH = 100:1) to give compound B-50-1, 3.20 g of white solid, yield 87.0%.

[0241] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with B-50-1 (1.00 g, 4.69 mmol) to obtain compound B-50-2, 2.40 g white solid, yield 68.0%.

[0242] Following the synthesis method of B-44 in Example 27, the starting material was replaced with B-50-2 (1.00 g, 1.79 mmol) to obtain compound B-50, 0.60 g white solid, yield 71.0%.

[0243] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.29(d,J=2.0Hz,1H),8.16(dd,J=8.3,2.0Hz,1H),8.00(d,J=8.5Hz,1H),7.82 (s,4H),7.70(d,J=8.4Hz,1H),7.41–7.28(m,2H),3.01(t,J=6.0Hz,2H),2.65(t,J=6.4Hz,2H),2.09(p,J=6.2Hz,2H).

[0244] Example 31 5-O-5,6,7,8-Tetrahydronaphth-2-yl-4-guanidin-3-(trifluoromethyl)benzoate trifluoroacetate (B-51)

[0245]

[0246] Following the synthesis method of B-50-1 in Example 30, the starting material was replaced with 3-trifluoromethyl-4-aminobenzoic acid (2.00 g, 9.75 mmol) to obtain compound B-51-1, 1.80 g white solid, yield 52.9%.

[0247] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with B-51-1 (1.50 g, 4.29 mmol) to obtain compound B-51-2, 2.10 g white solid, with a yield of 82.8%.

[0248] Following the synthesis method of B-44 in Example 27, the starting material was replaced with B-51-2 (2.00 g, 3.38 mmol) to obtain compound B-51, 1.30 g white solid, with a yield of 76.5%.

[0249] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.46(d,J=8.4Hz,1H),8.42(d,J=2.0Hz,1H),8.01(d,J=8.5Hz,1H),7.79(d,J=8.3Hz,1H),7 .59(s,4H),7.38(d,J=2.2Hz,1H),7.34(dd,J=8.5,2.2Hz,1H),3.02(t,J=6.1Hz,2H),2.66(t,J=6.4Hz,2H),2.10(p,J=6.2Hz,2H).

[0250] Example 32 5-O-5,6,7,8-Tetrahydronaphth-2-yl-2-chloro-4-guanidinium benzoate trifluoroacetate (B-52)

[0251]

[0252] Following the synthesis method of B-44-1 in Example 27, the starting material was replaced with 6-amino-2-chloro-4-aminobenzoic acid (2.00 g, 11.66 mmol) to obtain compound B-52-1, 1.60 g white solid, yield 43.5%.

[0253] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with B-52-1 (1.00 g, 3.17 mmol), yielding compound B-52-2, 1.38 g white solid, with a yield of 78.0%.

[0254] Following the synthesis method of B-44 in Example 27, the starting material was replaced with B-52-2 (1.38 g, 2.47 mmol) to obtain compound B-52, 0.96 g white solid, with a yield of 82.4%.

[0255] 1H NMR (400MHz, DMSO-d6) δ10.27(d,J=22.5Hz,1H),7.99(dd,J=8.5,1.5Hz,1H),7.90–7.77(m,5H),7.35(d,J=1.7Hz,1H),7.21(dt,J=8. 5,1.9Hz,1H),7.16(d,J=2.4Hz,1H),7.11(dt,J=8.5,1.9Hz,1H),2.82(t,J=6.0Hz,2H),2.46(t,J=6.5Hz,2H),1.90(p,J=6.3Hz,2H).

[0256] Example 33 5-O-5,6,7,8-Tetrahydronaphth-2-yl-4-guanidin-2-nitrobenzoate trifluoroacetate (B-58)

[0257]

[0258] Following the synthesis method of B-44-1 in Example 27, the starting material was replaced with 4-amino-2-nitrobenzoic acid (2.00 g, 10.98 mmol) to obtain compound B-58-1, 1.44 g white solid, yield 40.0%.

[0259] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with B-58-1 (1.44 g, 4.29 mmol) to obtain compound B-58-2, 1.00 g white solid, yield 41.0%.

[0260] Following the synthesis method of B-44 in Example 27, the starting material was replaced with B-58-2 (1.00 g, 1.76 mmol) to obtain compound B-58, 0.55 g white solid, with a yield of 64.7%.

[0261] 1 H NMR (600MHz, DMSO) δ10.57(s,1H),8.15(d,J=8.3Hz,1H),8.04(s,4H),8.01(s,1H),7.99(s,1H),7.72(dd,J=8.3, 2.0Hz,1H),7.27(s,1H),7.25(dd,J=8.5,2.1Hz,1H),3.00(t,J=5.9Hz,2H),2.73–2.58(m,2H),2.17–2.00(m,2H).

[0262] Example 34 5-O-5,6,7,8-Tetrahydronaphth-2-yl-3-fluoro-4-guanidinium benzoate hydrochloride (B-59)

[0263]

[0264] Following the synthesis method of B-49-1 in Example 29, the starting material was replaced with 4-amino-3-fluorobenzoic acid (2.00 g, 12.89 mmol) to obtain compound B-59-1, 1.40 g brown solid, with a yield of 46.5%.

[0265] Following the synthesis method of B-38 in Example 23, the starting material was replaced with B-59-1 (1.30 g, 5.55 mmol) to obtain compound B-59, 1.10 g white solid, yield 52.5%.

[0266] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.11–8.02(m,2H),8.00(d,J=8.5Hz,1H),7.79(s,4H),7.64(t,J=8.1Hz,1H), 7.35(d,J=2.2Hz,1H),7.31(dd,J=8.5,2.3Hz,1H),3.01(t,J=6.0Hz,2H),2.65(t,J=6.4Hz,2H),2.15–2.04(m,2H).

[0267] Example 35 4-(2-((cyclopropylmethyl)amino)-2-oxoethyl)phenyl-4-guanidinylbenzoate (C01)

[0268]

[0269] In a 250 mL three-necked flask, p-hydroxyphenylacetic acid (3.49 g, 22.90 mmol) was added and dissolved in DMF (20 mL). EDCI (5.27 g, 27.48 mmol), HOBt (3.76 g, 27.48 mmol), and DIPEA (8.88 g, 68.7 mmol) were added sequentially at 0 °C. After stirring for 0.5 h, neopentylamine (2.00 g, 22.90 mmol) was added, and the mixture was stirred at room temperature for 12 h. 200 mL of water was added, and the mixture was extracted with EA (100 mL * 3). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 40:1) to give compound CO1-1, 2.60 g of white solid, yield 52.0%.

[0270] Following the method of Example 1, the starting material was replaced with CO1-1 (2.00 g, 9.0 mmol) to obtain compound CO1, 1.60 g white solid, with a yield of 51.6%.

[0271] 1H NMR (600MHz, DMSO-d6) δ8.19(t,J=5.6Hz,1H),8.14(d,J=8.4Hz,2H),7.83(s,4H),7.42(d,J=8.5Hz,2H),7.34(d,J=8.2Hz,2H),7. 18(d,J=8.4Hz,2H),3.44(s,2H),2.94(t,J=6.1Hz,2H),0.89(ddt,J=12.2,7.0,3.6Hz,1H),0.46–0.32(m,2H),0.19–0.09(m,2H).

[0272] Example 36 4-(2-(neopentylamino)-2-oxoethyl)phenyl-4-guanidinylbenzoate (CO2)

[0273]

[0274] Following the synthesis method of CO1-1 in Example 35, the starting material was replaced with cyclopropylmethylamine (2.00 g, 28.12 mmol) to obtain compound CO2-1, 2.30 g white solid, with a yield of 39.9%.

[0275] Following the method of Example 1, the starting material was replaced with CO2-1 (2.00 g, 9.70 mmol) to obtain compound CO2, 1.30 g white solid, with a yield of 36.6%.

[0276] 1 H NMR (600MHz, DMSO-d6) δ8.15-8.16(d,J=4Hz,2H),8.03-8.01(t,J=8Hz,1H),7.86(s,3H),7.44-7.42(t,J=8Hz ,2H),7.37-7.36(d,J=4Hz,2H),7.20-7.18(d,J=8Hz,2H),3.50(s,2H),2.9-2.89(d,J=4Hz,2H),0.94(s,9H).

[0277] Example 37 4-(2-(2-(dimethylamino)-2-oxoethyl)amino)-2-oxoethylphenyl 4-guanidine benzoate hydrochloride (CO3)

[0278]

[0279] CBZ-glycine (10.00 g, 4.80 mmol) was added to a 500 mL three-necked flask and dissolved in DCM (100 mL). EDCI (10.99 g, 5.70 mol), HOBt (7.75 g, 0.06 mol), DIPEA (21.60 g, 0.17 mol), and dimethylamine hydrochloride (4.67 g, 0.06 mol) were added sequentially at -10 °C. The mixture was reacted overnight at room temperature. 500 mL of water was added, and the mixture was extracted with EA (200 mL * 3). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was purified by column chromatography to give compound CO3-1, 6.80 g of colorless oil, with a yield of 60.2%.

[0280] Add 6.80 g (0.03 mol) of CO3-1 to a 250 mL three-necked flask, dissolve in methanol (30 mL), then add palladium on carbon (3.40 g), purge with hydrogen three times, react overnight at room temperature, filter, add 10 mL of ethyl hydrogen chloride solution (4 mol / L) to the filtrate, stir at room temperature for 0.5 h, concentrate under reduced pressure, and purify by column chromatography to give compound CO3-2, 2.80 g white solid, yield 70.2%.

[0281] Following the synthesis method of CO3-1 in Example 37, the starting materials were replaced with p-methoxyphenylacetic acid (3.66 g, 0.02 mol) and CO3-2 (2.80 g, 0.02 mol) to obtain compound CO3-3, 4.70 g white solid, with a yield of 94.0%.

[0282] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with CO3-3 (2.00 g, 8.00 mmol) to obtain compound CO3-4, 1.50 g white solid, with a yield of 79.4%.

[0283] Following the method of Example 5, the raw material was replaced with CO3-4 (0.20 g, 0.85 mmol) to obtain compound CO3, 0.30 g white solid, with a yield of 81.7%.

[0284] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.24(d,J=5.3Hz,1H),8.17(dd,J=8.5,1.6Hz,2H),7.93(s,4H),7.45(dd,J=8.5,1.5Hz,2H) ,7.43–7.37(m,2H),7.21(dd,J=8.4,1.5Hz,2H),3.96(d,J=5.3Hz,2H),3.57(s,2H),2.95(d,J=1.4Hz,3H),2.85(d,J=1.4Hz,3H).

[0285] Example 384'-Carbamoyl-[1,1'-Biphenyl]-4-yl-4-guanidinylbenzoate (C07)

[0286]

[0287] A cyanobiphenol solution (2.00 g, 10.20 mmol) was added to a 250 mL three-necked flask and dissolved in 40 mL of DMSO. A prepared 12% NaOH solution (1.22 g, 30.60 mmol) was added at 0-10 °C, followed by dropwise addition of 30% H₂O₂ solution (4.60 g, 40.80 mmol). The reaction was carried out at 0-10 °C for 2 h. Then, 70 mL of Na₂SO₃ aqueous solution (2.57 g, 20.40 mmol) was added to quench the reaction. Afterward, 200 mL of water was added and the mixture was stirred vigorously. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound C₀₇-1, 1.90 g of white solid, with a yield of 87.3%.

[0288] Following the method of Example 1, the starting material was replaced with CO7-1 (1.00 g, 4.69 mmol) to obtain compound CO7, 0.80 g white solid, with a yield of 50.6%.

[0289] 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.19(d,J=8.4Hz,2H),8.08(s,1H),8.02–7.93(m,5H),7.82(dd,J=17.3,8.3Hz,4H),7.43(dd,J=18.7,8.5Hz,5H).

[0290] Example 39 4'-Cyano-[1,1'-Biphenyl]-4-yl-4-guanidinylbenzoate hydrochloride (C06-1)

[0291]

[0292] Following the method of Example 5, the raw material was replaced with cyanobiphenol (2.00 g, 10.24 mmol) to obtain compound C06-1, 1.65 g white solid, with a yield of 45.6%.

[0293] 1 H NMR(600MHz,DMSO-d6)δ10.63(s,1H),8.20–8.15(m,2H),7.94(d,J=1.9Hz,1H),7.94–7.87(m ,7H),7.87–7.84(m,2H),7.45(d,J=2.0Hz,1H),7.43(d,J=2.2Hz,2H),7.42(d,J=2.1Hz,1H).

[0294] Example 40 8-O-5,6,7,8-Tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-1)

[0295]

[0296] Following the method of Example 5, the raw material was replaced with eplerenone (0.60 g, 3.08 mmol) to obtain compound H-1, 0.48 g white solid, with a yield of 48.1%.

[0297] 1 H NMR (400MHz, DMSO) δ10.46(s,1H),8.16(d,J=8.5Hz,2H),7.91(s,J=51.9Hz,4H),7.68(s,1H),7.48 (s,2H),7.43(d,J=8.5Hz,2H),2.98(t,J=5.9Hz,2H),2.64(t,J=6.4Hz,2H),2.08(p,J=6.2Hz,2H).

[0298] Example 41 5-O-5,6,7,8-Tetrahydronaphth-2-yl-2-bromo-4-guanidinium benzoate trifluoroacetate (H-3)

[0299]

[0300] Following the synthesis method of B-50-1 in Example 30, the starting material was replaced with 2-bromo-4-nitrobenzoic acid (4.00 g, 16.26 mmol) to obtain compound H-3-1, 1.90 g of yellow solid, with a yield of 66.7%.

[0301] H-3-1 (3.00 g, 7.70 mmol) was added sequentially to a 250 mL single-necked flask and dissolved in EtOH (60 mL). SnCl2·2H2O (6.95 g, 30.80 mmol) was then added. The mixture was stirred at 80 °C for 4 h, cooled to room temperature, and 100 mL of ice water was added. The pH was adjusted to 8 with 10% NaOH aqueous solution. The mixture was filtered, and the filtrate was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 5 mL of EA and 2 mL of PE were mixed and stirred at room temperature for 10 min. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound H-3-2, 1.74 g of yellow solid, with a yield of 62.8%.

[0302] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with H-3-2 (1.00 g, 2.78 mmol) to obtain compound H-3-3, 1.10 g white solid, with a yield of 73.2%.

[0303] Following the synthesis method of B-44 in Example 27, the starting material was replaced with H-3-3 (0.20 g, 0.33 mmol) to obtain compound H-3, 0.15 g white solid, with a yield of 88.0%.

[0304] 1 H NMR (400MHz, DMSO) δ10.32(s,1H),8.13(d,J=8.5Hz,1H),7.99(d,J=8.5Hz,1H),7.96(s,J=13.7Hz,4H),7.69(d,J=2.0Hz,1H),7.43(d d,J=8.5,2.0Hz,1H),7.32(d,J=4.3Hz,1H),7.29(dd,J=8.5,2.2Hz,1H),3.00(t,J=5.9Hz,2H),2.68–2.57(m,2H),2.15–2.01(m,2H).

[0305] Example 42 2-O-1,2,3,4-Tetrahydroquinoline-6-yl-2-fluoro-4-guanidinium benzoate hydrochloride (H-27)

[0306]

[0307] Following the synthetic route of B-39-4 in Example 24, the starting material was replaced with 4-amino-2-fluorobenzoic acid (2.00 g, 12.89 mmol) to obtain compound H-27-1, 1.39 g white solid, with a yield of 46.2%.

[0308] H-27-1 (0.29 g, 1.23 mmol) was added to a 100 mL single-necked flask and dissolved in pyridine (10 mL). Then, 6-hydroxy-3,4-dihydroquinoline-2(1H)-one (0.20 g, 1.23 mmol), DCC (0.38 g, 1.85 mmol), and DMAP (0.03 g, 0.25 mmol) were added sequentially. The reaction and post-treatment were performed as described in Example 5, yielding compound H-27, 0.25 g of yellow solid, with a yield of 53.2%.

[0309] 1H NMR (400MHz, DMSO) δ10.65(s,1H),10.19(s,1H),8.08(t,J=7.9Hz,1H),7.97(s,3H),7.30(dd,J=12.4,1.8Hz,1H),7.23(dd,J=8. 6,1.9Hz,1H),7.11(d,J=2.3Hz,1H),7.04(dd,J=8.5,2.5Hz,1H),6.91(d,J=8.5Hz,1H),2.90(t,J=7.5Hz,2H),2.49–2.40(m,2H).

[0310] Example 43 2-Oxoindol-5-yl-3-fluoro-4-guanidine benzoate hydrochloride (H-23)

[0311]

[0312] Following the synthetic route of B-39-4 in Example 24, the starting material was replaced with 4-amino-3-fluorobenzoic acid (1.50 g, 9.67 mmol) to obtain compound H-23-1, 0.87 g white solid, with a yield of 38.5%.

[0313] H-23-1 (0.20 g, 0.86 mmol) was added to a 100 mL single-necked flask and dissolved in pyridine (10 mL). Then, H-25-1 (0.14 g, 0.94 mmol), DCC (0.26 g, 1.28 mmol), and DMAP (0.02 g, 0.17 mmol) were added sequentially. The synthesis and post-processing were performed according to Example 5 to obtain compound H-23, 0.15 g of yellow solid, with a yield of 48.4%.

[0314] 1 H NMR(400MHz,DMSO)δ10.50(s,1H),10.28(s,1H),8.04–7.96(m,2H),7.84(s,4H),7.60(t,J =8.2Hz,1H),7.15(s,1H),7.07(dd,J=8.3,2.3Hz,1H),6.87(d,J=8.4Hz,1H),3.53(s,2H).

[0315] Example 44 3-Nitro-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidine benzoate hydrochloride (H-22)

[0316]

[0317] Concentrated sulfuric acid (6.67 g, 68.10 mmol) and concentrated nitric acid (4.29 g, 68.10 mmol) were added to a 250 mL single-necked flask. 6-Methoxy-1-naphthoone (4.00 g, 14.50 mmol) was added in portions at -10 °C. The mixture was stirred at room temperature for 3 h. 100 mL of ice water was added, and the mixture was extracted with EA (100 mL * 3). The extract was washed with saturated brine (100 mL) and purified by organic phase column chromatography (PE:EA = 20:1) to give compound H-22-1, 1.80 g of yellow solid, yield 38.3%.

[0318] H-22-1 (1.60 g, 7.20 mmol), AlCl3 (2.40 g, 18.00 mmol), and toluene (32 mL) were added sequentially to a 100 mL single-necked flask. The mixture was reacted at 105 °C for 3 h. 150 mL of ice water was added, and the mixture was extracted with EA (100 mL * 3). The mixture was washed with saturated brine (100 mL) and purified by organic phase column chromatography (DCM:MeOH = 100:1) to give compound H-22-2, 0.68 g of brown solid, with a yield of 45.6%.

[0319] Following the method of Example 5, the starting material was replaced with H-22-2 (0.31 g, 1.48 mmol) to obtain compound H-22, 0.25 g white solid, with a yield of 47.2%.

[0320] 1 H NMR (400MHz, DMSO) δ10.59 (s, 1H), 8.53 (s, 1H), 8.17 (d, J = 8.6Hz, 2H), 7.97 (s, 4H), 7.72 (s, 1H),7.47(d,J=8.6Hz,2H),3.09(t,J=5.8Hz,2H),2.71(t,J=6.4Hz,2H),2.21–2.03(m,,2H).

[0321] Example 45 1-Oxoisoindoline-5-yl-3-fluoro-4-guanidine benzoate hydrochloride (H-18)

[0322]

[0323] H-23-1 (0.18 g, 0.77 mmol) prepared in Example 43 and pyridine (10 mL) were added to a 100 mL single-necked flask. After dissolution, 5-hydroxyisoindol-1-one (0.13 g, 0.85 mmol), DCC (0.24 g, 1.16 mmol), and DMAP (0.02 g, 0.15 mmol) were added sequentially. The synthesis and post-treatment were performed as described in Example 5, yielding compound H-18, 0.12 g white solid, with a yield of 42.9%.

[0324] 1 H NMR (400MHz, DMSO) δ10.35(s,1H),8.67(s,1H),8.11–8.05(m,1H),8.05–8.01(m,1H),7.89(s,4H), 7.77(d,J=8.2Hz,1H),7.63(t,J=8.0Hz,1H),7.55(s,1H),7.41(dd,J=8.2,1.8Hz,1H),4.42(s,2H).

[0325] Example 46 1-Chloro-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-24)

[0326]

[0327] 6-hydroxy-1-tetrahydronaphthone (2.00 g, 12.33 mmol), NCS (2.50 g, 18.50 mmol), glacial acetic acid (0.80 g), and acetonitrile (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at room temperature for 6 h, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound H-24-1, 1.35 g of pink solid, with a yield of 55.8%.

[0328] Following the method of Example 5, the starting material was replaced with H-24-1 (0.50 g, 2.54 mmol) to obtain compound H-24, 0.50 g white solid, with a yield of 54.9%.

[0329] 1 H NMR (400MHz, DMSO) δ10.55(s,1H),8.20(d,J=10.7Hz,2H),7.99(d,J=6.9Hz,1H),7.91(s,4H),7.53( d,J=8.5Hz,1H),7.49(d,J=8.6Hz,2H),3.06(t,J=6.0Hz,2H),2.76–2.56(m,2H),2.25–2.04(m,2H).

[0330] Example 47 2-Oxoindoline-5-yl-2-fluoro-4-guanidine benzoate hydrochloride (H-25)

[0331]

[0332] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with 5-methoxyindol-2-one (2.35 g, 7.37 mmol) to obtain compound H-25-1, 1.85 g of gray solid, with a yield of 86.0%.

[0333] H-27-1 (0.31 g, 1.34 mmol) prepared in Example 42 and pyridine (10 mL) were added to a 100 mL single-necked flask. After dissolution, H-25-1 (0.20 g, 1.34 mmol), DCC (0.41 g, 2.01 mmol), and DMAP (0.03 g, 0.26 mmol) were added sequentially. The synthesis and post-processing were performed according to Example 5, yielding compound H-25, 0.21 g of yellow solid, with a yield of 42.9%.

[0334] 1 H NMR (400MHz, DMSO) δ10.49(s,1H),8.08(t,J=8.3Hz,1H),7.96(s,3H),7.29(dd,J=12.4,1.7Hz,1H),7. 22(dd,J=8.6,1.7Hz,1H),7.14(s,1H),7.05(dd,J=8.3,2.1Hz,1H),6.86(d,J=8.3Hz,1H),3.53(s,2H).

[0335] Example 48 2-O-1,2,3,4-Tetrahydroquinoline-6-yl-5-guanidinylpyridinecarboxylic acid trifluoroacetate (H-26)

[0336]

[0337] 5-Nitropyridine acid (0.50 g, 2.97 mmol), 6-hydroxy-3,4-dihydroquinoline-2(1H)-one (0.48 g, 2.97 mmol), HATU (1.47 g, 3.86 mmol), DIEA (0.77 g, 5.94 mmol), and DMF (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was reacted overnight at room temperature. 100 mL of water was added, and the mixture was stirred for 10 min. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound H-26-1, 0.77 g of yellow solid, with a yield of 82.8%.

[0338] H-26-1 (0.50 g, 1.60 mmol), 10% Pd / C (1.50 g), and methanol (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was then purged with hydrogen, stirred at room temperature for 3 h, filtered, and the filtrate was concentrated under reduced pressure to give compound H-26-2, 0.35 g of yellow solid, with a yield of 77.8%.

[0339] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with H-26-2 (0.35 g, 1.24 mmol) to obtain compound H-26-3, 0.19 g white solid, with a yield of 29.2%.

[0340] Following the synthesis method of B-44 in Example 27, the starting material was replaced with H-26-3 (0.19 g, 0.36 mmol) to obtain compound H-26, 0.11 g white solid, with a yield of 68.7%.

[0341] 1 H NMR (400MHz, DMSO) δ10.41(s,1H),10.19(s,1H),8.69(d,J=2.4Hz,1H),8.25(d,J=8.5Hz,1H),7.98(s,4H),7.89(dd,J=8.5,2 .5Hz,1H),7.13(d,J=2.2Hz,1H),7.06(dd,J=8.5,2.5Hz,1H),6.92(d,J=8.5Hz,1H),2.91(t,J=7.5Hz,2H),2.49–2.44(m,2H).

[0342] Example 49 1-Oxoisoindoline-5-yl-2-fluoro-4-guanidine benzoate hydrochloride (H-17)

[0343]

[0344] H-27-1 (0.31 g, 1.34 mmol) prepared in Example 42 and pyridine (10 mL) were added to a 100 mL single-necked flask. After dissolution, 5-hydroxyisoindol-1-one (0.20 g, 1.34 mmol), DCC (0.41 g, 2.01 mmol), and DMAP (0.03 g, 0.27 mmol) were added sequentially. The synthesis and post-treatment were performed as described in Example 5, yielding compound H-17, 0.23 g of yellow solid, with a yield of 46.9%.

[0345] 1 H NMR (400MHz, DMSO) δ10.92(s,1H),8.67(s,2H),8.13(t,J=8.4Hz,1H),8.06(s,3H),7.75(d,J=8.2Hz,2H),7.5 3(s,2H),7.38(dd,J=8.2,1.6Hz,2H),7.32(dd,J=12.4,1.7Hz,2H),7.25(dd,J=8.6,1.7Hz,2H),4.41(s,4H).

[0346] Example 50 1-Bromo-8-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-36)

[0347]

[0348] Eplerenone (1.00 g, 6.17 mmol), NBS (1.21 g, 6.79 mmol), glacial acetic acid (0.40 g), and acetonitrile (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was reacted overnight at room temperature, filtered, and purified by filter cake column chromatography (DCM:MeOH = 100:1) to give compound H-36-1, 0.32 g of pink solid, yield 21.3%.

[0349] Following the method of Example 5, the starting material was replaced with H-36-1 (0.20 g, 0.83 mmol) to obtain compound H-36, 0.12 g white solid, with a yield of 33.3%.

[0350] 1 H NMR (400MHz, DMSO) δ10.49(s,1H),8.19(d,J=8.6Hz,2H),7.87(s,4H),7.58(d,J=8.2Hz,1H),7.49(d, J=8.4Hz,1H),7.46(d,J=8.6Hz,2H),3.02(t,J=5.9Hz,2H),2.68(t,J=6.6Hz,2H),2.10–1.99(m,2H).

[0351] Example 51 1,3-Dibromo-8-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidine benzoate hydrochloride (H-37)

[0352]

[0353] Eplerenone (2.00 g, 12.33 mmol), NBS (4.83 g, 27.13 mmol), glacial acetic acid (0.80 g), and acetonitrile (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was reacted overnight at room temperature. 60 mL of water was added, and the mixture was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 10 mL of EA and 3 mL of PE were mixed and slurryed. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound H-37-1, 2.50 g of yellow solid, with a yield of 63.3%.

[0354] Following the method of Example 5, the starting materials were replaced with H-37-1 (0.50 g, 1.56 mmol), DCC (0.48 g, 2.43 mmol), and DMAP (0.04 g, 0.31 mmol) to obtain compound H-37, 0.43 g of yellow solid, with a yield of 59.7%.

[0355] 1H NMR (400MHz, DMSO) δ10.50 (s, 1H), 8.23 ​​(d, J = 8.6Hz, 2H), 7.91 (s, 1H), 7.89 (s, 4H), 7.48(d,J=8.6Hz,2H),3.02(t,J=5.5Hz,2H),2.74–2.64(m,2H),2.08–1.98(m,2H).

[0356] Example 52 1-Chloro-8-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-38)

[0357]

[0358] Eplerenone (1.00 g, 6.17 mmol), NCS (1.24 g, 9.26 mmol), glacial acetic acid (0.40 g), and acetonitrile (10 mL) were added to a 100 mL single-necked flask. The mixture was reacted overnight at 80 °C, filtered, and purified by filter cake column chromatography (DCM:MeOH = 100:1) to give compound H-38-1, 0.50 g of pink solid, yield 41.7%.

[0359] Following the method of Example 5, the starting material was replaced with H-38-1 (0.30 g, 1.53 mmol) to obtain compound H-38, 0.25 g white solid, with a yield of 51.0%.

[0360] 1 H NMR (400MHz, DMSO) δ10.54(s,1H),8.18(d,J=8.6Hz,2H),7.88(s,4H),7.62(d,J=8.3Hz,1 H),7.45(d,J=8.6Hz,3H),3.01(t,J=5.9Hz,2H),2.66(t,J=6.5Hz,2H),2.09–1.98(m,2H).

[0361] Example 53 3-Amino-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidine benzoate hydrochloride (H-40)

[0362]

[0363] Following the synthesis method of H-22-1 in Example 44, the starting material was replaced with 6-methoxy-1-naphthoone (6.00 g, 34.05 mmol) to obtain compound H-40-1, 3.00 g of yellow solid, with a yield of 39.6%.

[0364] Following the synthesis method of H-22-2 in Example 44, the starting material was replaced with H-40-1 (2.50 g, 11.10 mmol) to obtain compound H-40-2, 1.05 g brown solid, with a yield of 45.6%.

[0365] H-40-2 (1.00 g, 4.83 mmol), 10% Pd / C (1.50 g), and methanol (10 mL) were added sequentially to a 100 mL single-necked flask. Hydrogen gas was introduced, and the mixture was stirred at room temperature for 3 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give compound H-40-3, 0.50 g of yellow solid, with a yield of 58.1%.

[0366] H-40-3 (0.50 g, 2.82 mmol), di-tert-butyl dicarbonate (0.92 g, 4.23 mmol), triethylamine (0.86 g, 8.46 mmol), and methanol (10 mL) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 3 h, then 30 mL of water was added, and the pH was adjusted to 4 with 1 M HCl aqueous solution. The mixture was extracted with DCM (50 mL * 3), the organic phase was concentrated under reduced pressure, and purified by slurrying with 3 mL of methanol. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound H-40-4, 0.49 g of white solid, with a yield of 46.2%.

[0367] Following the method of Example 5, the starting material was replaced with H-40-4 (0.49 g, 1.30 mmol) to obtain compound H-40, 0.17 g white solid, with a yield of 31.9%.

[0368] 1 H NMR (400MHz, DMSO) δ10.32(s,1H),9.55(s,1H),8.20(s,1H),8.04(d,J=8.5Hz,2H),7.73(s,4H),7.36( d,J=8.5Hz,2H),6.86(s,1H),5.76(s,2H),2.85(t,J=5.7Hz,2H),2.55–2.51(m,2H),2.09–1.94(m,2H).

[0369] Example 54 2-Oxoindol-6-yl 2-fluoro-4-guanidine benzoate hydrochloride (H-42)

[0370]

[0371] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with 5-methoxyindol-2-one (1.00 g, 6.13 mmol) to obtain compound H-42-1, 0.64 g brown solid, with a yield of 70.3%.

[0372] H-27-1 (0.31 g, 1.34 mmol) was added to a 100 mL single-necked flask and dissolved in pyridine (10 mL). Then, H-42-1 (0.20 g, 1.34 mmol), DCC (0.41 g, 2.01 mmol), and DMAP (0.03 g, 0.26 mmol) were added sequentially. The synthesis and post-processing were performed according to Example 5 to obtain compound H-42, 0.20 g of yellow solid, with a yield of 40.8%.

[0373] 1 H NMR (400MHz, DMSO) δ10.66(s,1H),10.57(s,1H),8.11(t,J=8.4Hz,1H),7.99(s,4H),7.31(dd,J=12.4,1.8Hz,1H), 7.27(d,J=8.0Hz,1H),7.23(dd,J=8.6,1.8Hz,1H),6.80(dd,J=8.0,2.1Hz,1H),6.75(d,J=1.9Hz,1H),3.51(s,2H).

[0374] Example 55 1-Bromo-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-43)

[0375]

[0376] 6-Hydroxy-1-tetrahydronaphthone (2.00 g, 12.33 mmol), NBS (3.29 g, 18.5 mmol), glacial acetic acid (0.80 g), and acetonitrile (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at room temperature for 6 h, filtered, and purified by filter cake column chromatography (DCM:MeOH = 100:1) to give compound H-43-1, 0.80 g of pink solid, yield 26.9%.

[0377] Following the method of Example 5, the starting material was replaced with H-43-1 (0.50 g, 2.07 mmol) to obtain compound H-43, 0.25 g white solid, with a yield of 33.3%.

[0378] 1 H NMR (400MHz, DMSO) δ10.46(s,1H),8.20(d,J=8.6Hz,2H),8.01(d,J=8.5Hz,1H),7.86( s,4H),7.49–7.44(m,3H),3.03(t,J=6.0Hz,2H),2.68–2.62(m,2H),2.18–2.07(m,2H).

[0379] Example 563-Methyl-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidine benzoate hydrochloride (H-44)

[0380]

[0381] 2-Carboxyethyltriphenylphosphine bromide (5.40 g, 13.00 mmol), THF (13 mL), and DMSO (13 mL) were added to a 250 mL single-necked flask. 60% NaH (1.28 g, 53.28 mmol) was added in portions at -5 °C, and the mixture was stirred for 10 min. A mixed solution of 3-methoxy-4-methylbenzaldehyde (2.00 g, 13.32 mmol) in THF (1 mL) and DMSO (1 mL) was added dropwise. The mixture was reacted overnight at room temperature. 100 mL of ice water was added, and the mixture was stirred for 10 min. Extraction was performed using EA (100 mL x 3), followed by purification by organic phase column chromatography (PE:EA = 4:1) to give compound H-44-1, 1.00 g of yellow solid, yield 37.0%.

[0382] H-44-1 (1.00 g, 4.28 mmol), 10% Pd / C (2.00 g), and methanol (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was then purged with hydrogen, stirred at room temperature for 3 h, filtered, and the filtrate was concentrated under reduced pressure to give compound H-44-2, 0.90 g of white solid, with a yield of 89.1%.

[0383] H-44-2 (0.90 g, 4.32 mmol) and PPA (4.50 g) were added to a 100 mL single-necked flask and stirred at 90 °C for 3 h. 50 mL of ice water was added, and the mixture was extracted with EA (50 mL * 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound H-44-3, 0.70 g of yellow solid, with a yield of 85.4%.

[0384] Following the synthesis method of H-22-2 in Example 44, the starting material was replaced with H-44-3 (0.70 g, 3.68 mmol) to obtain compound H-44-4, 0.28 g brown solid, with a yield of 44.4%.

[0385] Following the method of Example 5, the starting material was replaced with H-44-4 (0.28 g, 1.59 mmol) to obtain compound H-44, 0.22 g white solid, with a yield of 37.3%.

[0386] 1H NMR (400MHz, DMSO) δ10.52(s,1H),8.19(d,J=8.6Hz,2H),7.90(s,4H),7.85(s,1H),7.45(d,J=8.6 Hz,2H),7.25(s,1H),2.94(t,J=5.7Hz,2H),2.61(t,J=6.3Hz,2H),2.17(s,3H),2.11–1.98(m,2H).

[0387] Example 57 3-Fluoro-5-oxo-5,6,7,8-tetrahydronaphth-2-yl-4-guanidinium benzoate hydrochloride (H-45)

[0388]

[0389] Following the synthesis method of H-44-1 in Example 56, the starting material was replaced with 4-fluoro-3-methoxybenzaldehyde (2.00 g, 13.00 mmol) to obtain compound H-45-1, 1.10 g white solid, yield 40.3%.

[0390] Following the synthesis method of H-44-2 in Example 56, the starting material was replaced with H-45-1 (0.90 g, 4.28 mmol) to obtain compound H-45-2, 0.88 g white solid, with a yield of 80.0%.

[0391] Following the synthesis method of H-44-3 in Example 56, the starting material was replaced with H-45-2 (0.88 g, 4.15 mmol) to obtain compound H-45-3, 0.73 g of yellow solid, with a yield of 91.2%.

[0392] Following the synthesis method of H-22-2 in Example 44, the starting material was replaced with H-45-3 (0.80 g, 4.12 mmol) to obtain compound H-45-4, 0.40 g brown solid, with a yield of 53.9%.

[0393] Following the method of Example 5, the starting material was replaced with H-45-4 (0.40 g, 2.22 mmol) to obtain compound H-45, 0.51 g white solid, with a yield of 67.1%.

[0394] 1H NMR (400MHz, DMSO) δ10.53(s,1H),8.18(d,J=8.6Hz,2H),7.89(s,4H),7.76(d,J=10.5Hz,1H),7.53(d ,J=7.2Hz,1H),7.46(d,J=8.6Hz,2H),2.96(t,J=5.6Hz,2H),2.64(t,J=6.4Hz,2H),2.12–2.00(m,2H).

[0395] Example 58: 4-Acrylamidophenyl-4-guanidinylbenzoate trifluoroacetate (H-46)

[0396]

[0397] In a 100 mL single-necked flask, tert-butyl (4-hydroxyphenyl)carbamate (3.00 g, 14.35 mmol), 4-nitrobenzoic acid (2.40 g, 14.35 mmol), EDCI (3.30 g, 17.22 mmol), DIEA (5.56 g, 43.05 mmol), HOBt (0.19 g, 1.44 mmol), and DMF (10 mL) were added sequentially. The mixture was reacted overnight at room temperature. Then, 100 mL of water was added, and the mixture was stirred for 10 min. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound H-46-1, 4.00 g of white solid, with a yield of 78.4%.

[0398] H-46-1 (4.00 g, 11.16 mmol) and EA (20 mL) were added to a 100 mL single-necked flask. After stirring, 10 mL of ethyl hydrochloride solution (4 mol / L) was added and the mixture was reacted overnight at room temperature. Then, 100 mL of water was added and the mixture was stirred for 10 min. The mixture was filtered and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound H-46-2, 3.00 g of gray solid, with a yield of 91.5%.

[0399] H-46-2 (3.00 g, 10.20 mmol), acrylic acid (0.74 g, 10.20 mmol), EDCI (2.35 g, 12.24 mmol), DIEA (3.96 g, 30.60 mmol), HOBt (0.14 g, 1.02 mmol), and DMF (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at room temperature for 3 h, then 100 mL of water was added, and the mixture was stirred for 10 min. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound H-46-3, 2.50 g of yellow solid, with a yield of 78.1%.

[0400] H-46-3 (2.50 g, 8.01 mmol), ethanol (100 mL), reduced iron powder (1.79 g, 32.02 mmol), ammonium chloride (1.72 g, 32.02 mmol), and water (33 mL) were added sequentially to a 250 mL single-necked flask. The mixture was reacted at 80 °C for 4 h. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. The filtrate was extracted with EA (50 mL * 3) and purified by organic phase column chromatography (DCM:MeOH = 10:1) to give compound H-46-4, 0.71 g of yellow solid, with a yield of 31.6%.

[0401] Following the synthesis method of B-44-2 in Example 27, the starting material was replaced with H-46-4 (0.71 g, 2.51 mmol) to obtain compound H-46-5, 0.55 g white solid, with a yield of 41.7%.

[0402] Following the synthesis method of B-44 in Example 27, the starting material was replaced with H-46-5 (0.55 g, 1.05 mmol) to obtain compound H-46, 0.32 g white solid, with a yield of 69.6%.

[0403] 1 H NMR (400MHz, DMSO) δ10.29(s,2H),8.16(d,J=8.6Hz,2H),7.85(s,4H),7.76(d,J=8.9Hz,2H),7.43(d,J=8.6Hz,2H) ,7.24(d,J=8.9Hz,2H),6.45(dd,J=17.0,10.1Hz,1H),6.28(dd,J=17.0,1.9Hz,1H),5.78(dd,J=10.1,1.9Hz,1H).

[0404] Example 59 2-Methyl-1-oxoisoindoline-5-yl-4-guanidinyl benzoate hydrochloride (H-47)

[0405]

[0406] 4-Methoxy-2-methylbenzoic acid (5.00 g, 30.09 mmol), SOCl2 (10.74 g, 90.27 mmol), and methanol (50 mL) were added to a 250 mL single-necked flask to dissolve the compound. The mixture was stirred at 80 °C for 3 h and concentrated under reduced pressure to give compound H-47-1, 5.03 g of yellow solid, with a yield of 90.8%.

[0407] H-47-1 (4.50 g, 24.97 mmol), NBS (6.67 g, 37.45 mmol), BPO (1.21 g, 4.99 mmol), and carbon tetrachloride (50 mL) were added to a 250 mL single-necked flask and dissolved. The mixture was stirred at 70 °C for 8 h, cooled to room temperature, and then 100 mL of ice water was added. The mixture was extracted with DCM (100 mL * 3), washed with saturated brine (100 mL) on the organic phase, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 50:1) to give compound H-47-2, 4.92 g of yellow solid, yield 76.0%.

[0408] H-47-2 (1.50 g, 5.79 mmol), methylamine hydrochloride (1.95 g, 28.95 mmol), potassium carbonate (4.00 g, 28.95 mmol), and methanol (30 mL) were added to a 100 mL single-necked flask and dissolved. The mixture was stirred at 70 °C for 5 h, filtered, and the filtrate was purified by column chromatography (DCM:MeOH = 30:1) to give compound H-47-3, 0.51 g of yellow solid, with a yield of 49.5%.

[0409] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with H-47-3 (0.40 g, 2.26 mmol) to obtain compound H-47-4, 0.25 g white solid, with a yield of 67.6%.

[0410] Following the method of Example 5, the starting material was replaced with H-47-4 (0.25 g, 1.53 mmol) to obtain compound H-47, 0.27 g white solid, with a yield of 49.1%.

[0411] 1 H NMR(600MHz,DMSO)δ10.49(s,1H),8.20–8.16(m,2H),7.86(s,4H),7.75(d,J=8.2Hz,1H),7.5 4(t,J=7.4Hz,1H),7.48–7.43(m,2H),7.38(dd,J=8.2,2.0Hz,1H),4.51(s,2H),3.09(s,3H).

[0412] Example 60 3,3-Difluoro-2-oxoindoline-5-yl-4-guanidinylbenzoate hydrochloride (H-48)

[0413]

[0414] 5-Bromoindole-2,3-dione (5.00 g, 22.12 mmol), acetonitrile (15 mL), and DCM (150 mL) were added to a 250 mL single-necked flask. Diethylaminosulfur trifluoride (8.9 g, 55.30 mmol) was added at -10 °C. The mixture was stirred at room temperature for 12 h. 100 mL of purified water was added, and the mixture was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM:MeOH = 100:1). The filtrate was concentrated under reduced pressure to give compound H-48-1, 4.75 g of yellow solid, with a yield of 86.4%.

[0415] Add H-48-1 (1.00 g, 4.03 mmol), bis(pinacolyl)diboron (3.07 g, 12.09 mmol), potassium acetate (1.19 g, 12.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.5 g, 0.81 mmol), and 1,4-dioxane (20 mL) to a 250 mL single-necked flask and dissolve. Stir at 100 °C for 12 h and cool to room temperature. After warming, sodium perborate tetrahydrate (1.55 g, 10.07 mmol) and purified water (20 mL) were added. The mixture was stirred at room temperature for 3 h, filtered, and the filtrate was extracted with EA (100 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM:MeOH = 100:1). The filtrate was concentrated under reduced pressure to give compound H-48-2, 0.65 g of yellow solid, with a yield of 86.7%.

[0416] Following the method of Example 5, the starting material was replaced with H-48-2 (0.30 g, 11.62 mmol) to obtain compound H-48, 0.23 g of yellow solid, with a yield of 37.1%.

[0417] 1 H NMR (400MHz, DMSO) δ11.39(s,1H),10.47(s,1H),8.16(d,J=8.7Hz,2H),7.86(s,4H),7.73(s,1H),7.48–7.41(m,3H),7.10(d,J=8.5Hz,1H).

[0418] Example 61 6-Chloro-2-oxoindoline-5-yl-4-guanidinylbenzoate hydrochloride (H-49)

[0419]

[0420] 5-Methoxyindoline-2-one (0.8 g, 4.90 mmol), NCS (0.98 g, 7.35 mmol), aluminum trichloride (0.65 g, 4.90 mmol), and acetonitrile (20 mL) were added to a 100 mL single-necked flask and dissolved. The mixture was stirred at room temperature for 12 h, filtered, and the filtrate was purified by column chromatography (DCM:MeOH = 50:1) to give compound H-49-1, 0.51 g of white solid, yield 52.6%.

[0421] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with H-49-1 (0.25 g, 1.26 mmol) to obtain compound H-49-2, 0.22 g white solid, with a yield of 95.6%.

[0422] Following the method of Example 5, the starting material was replaced with H-49-2 (0.22 g, 1.20 mmol) to obtain compound H-49, 0.26 g white solid, with a yield of 56.5%.

[0423] 1 H NMR (400MHz, DMSO) δ10.62(s,1H),10.47(s,1H),8.17(d,J=8.6Hz,2H),7.86(s,4H),7.45(d,J=8.7Hz,2H),7.33(s,1H),6.98(s,1H),3.56(s,2H).

[0424] Example 62 : Benzo[d]oxazol-5-yl-4-guanidinyl benzoate hydrochloride (H-50)

[0425]

[0426] 2-Amino-4-methoxyphenol (4.00 g, 28.74 mmol) and triethyl orthoformate (40 mL) were added to a 100 mL single-necked flask. The mixture was stirred at 100 °C for 12 h, filtered, cooled to room temperature, and then 200 mL of purified water was added. The mixture was extracted with EA (100 mL * 3), washed with saturated brine (100 mL) on the organic phase, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM:MeOH = 100:1) to give compound H-50-1, 3.6 g of red solid, yield 83.7%.

[0427] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with H-50-1 (1.00 g, 6.70 mmol) to obtain compound H-50-2, 0.58 g of gray solid, with a yield of 64.4%.

[0428] Following the method of Example 1, the starting material was replaced with H-50-2 (0.30 g, 2.22 mmol) to obtain compound H-50, 0.32 g white solid, with a yield of 48.5%.

[0429] 1 H NMR (400MHz, DMSO) δ8.84(s,1H),8.18(d,J=8.6Hz,2H),7.87(d,J=8.7Hz,1H),7.84( d,J=14.0Hz,1H),7.77(d,J=2.1Hz,4H),7.44(d,J=8.2Hz,2H),7.36(d,J=8.6Hz,1H).

[0430] Example 63 Benzo[d]oxazol-5-yl-4-guanidinyl benzoate hydrochloride (H-51)

[0431]

[0432] Following the method of Example 5, the starting material was replaced with H-50-2 (0.20 g, 1.48 mmol) to obtain compound H-51, 0.12 g white solid, with a yield of 25.0%.

[0433] 1 H NMR (400MHz, DMSO) δ10.72(d,J=52.7Hz,1H),10.63(s,1H),9.76(s,2H),8.14(d,J=8.6Hz,2H),7. 84(d,J=45.7Hz,4H),7.43(d,J=8.7Hz,2H),7.28(s,1H),7.10(d,J=5.9Hz,1H),7.09–6.96(m,1H).

[0434] Example 64 6-Fluoro-1-oxoisoindoline-5-yl-4-guanidinyl benzoate hydrochloride (H-52)

[0435]

[0436] Following the synthesis method of H-47-1 in Example 59, the starting material was replaced with 4-bromo-5-fluoro-2-methylbenzoic acid (5.00 g, 21.46 mmol) to obtain compound H-52-1, 5.10 g of yellow solid, with a yield of 96.2%.

[0437] Following the synthesis method of H-47-2 in Example 59, the starting material was replaced with H-52-1 (5.10 g, 20.64 mmol), yielding compound H-52-2, 5.70 g white solid, with a yield of 84.7%.

[0438] H-52-2 (4.00 g, 12.27 mmol) was dissolved in 40 mL of a 7 mol / L ammonia methanol solution in a 100 mL single-necked flask. The mixture was stirred at 70 °C for 3 h, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound H-52-3, 2.32 g of yellow solid, with a yield of 82.3%.

[0439] Following the synthesis method of H-48-2 in Example 60, the starting material was replaced with H-52-3 (1.00 g, 4.35 mmol) to obtain compound H-52-4, 0.18 g of yellow solid, with a yield of 24.7%.

[0440] Following the method of Example 5, the starting material was replaced with H-52-4 (0.18 g, 1.08 mmol) to obtain compound H-52, 0.15 g white solid, with a yield of 38.5%.

[0441] 1 H NMR (400MHz, DMSO) δ10.51 (s, 1H), 8.84 (s, 1H), 8.22 (d, J = 8.7Hz, 2H), 7.90 (s, 4H) ,7.74(d,J=5.9Hz,1H),7.71(d,J=8.9Hz,1H),7.49(d,J=8.7Hz,2H),4.43(s,2H).

[0442] Example 65 6-Nitro-1-oxoisoindoline-5-yl-4-guanidinylbenzoate hydrochloride (H-53)

[0443]

[0444] Following the synthesis method of H-47-1 in Example 59, the starting material was replaced with 4-methoxy-2-methylbenzoic acid (5.00 g, 30.09 mmol) to obtain compound H-53-1, 5.20 g brown solid, with a yield of 96.8%.

[0445] Concentrated sulfuric acid (3.53 g, 56.00 mmol) and concentrated nitric acid (8.23 g, 84.00 mmol) were added to a 250 mL single-necked flask. H-53-1 (5.00 g, 28.00 mmol) was added in portions at -10 °C. The mixture was stirred at room temperature for 3 h. Then, 150 mL of ice water was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was slurried with 10 mL of methanol. The mixture was then filtered again, and the filter cake was dried under vacuum at 45 °C for 8 h to give compound H-53-2, 3.20 g of white solid, with a yield of 50.7%.

[0446] Following the synthesis method of H-47-2 in Example 59, the starting material was replaced with H-53-2 (3.20 g, 14.21 mmol) to obtain compound H-53-3, 1.37 g white solid, with a yield of 31.7%.

[0447] H-53-3 (1.37 g, 4.51 mmol) was added to a 100 mL single-necked flask and dissolved in 20 mL of a 7 mol / L ammonia methanol solution. The mixture was stirred at 70 °C for 3 h and purified by column chromatography (DCM:MeOH = 100:1) to give compound H-53-4, 0.60 g of yellow solid, with a yield of 63.8%.

[0448] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with H-53-4 (0.60 g, 2.88 mmol) to obtain compound H-53-5, 0.47 g of yellow solid, with a yield of 83.9%.

[0449] Following the method of Example 5, the starting material was replaced with H-53-5 (0.40 g, 2.06 mmol) to obtain compound H-53, 0.33 g of yellow solid, with a yield of 40.7%.

[0450] 1 H NMR (600MHz, DMSO) δ10.51(s,1H),9.03(s,1H),8.36(s,1H),8.18(d,J=8.4Hz,2H),7.91(s,1H),7.90(s,4H),7.47(d,J=8.5Hz,2H),4.56(s,2H).

[0451] Example 66 2-Ethyl-1-oxoisoindoline-5-yl-4-guanidinyl benzoate hydrochloride (H-54)

[0452]

[0453] H-47-2 (1.35 g, 5.21 mmol), ethylamine (5.40 g), and methanol (20 mL) were added to a 100 mL single-necked flask and dissolved. The mixture was stirred at 70 °C for 5 h and purified by column chromatography (DCM:MeOH = 30:1) to give compound H-54-1, 0.71 g of yellow solid, with a yield of 71.2%.

[0454] Following the synthesis method of B-15-3 in Example 8, the starting material was replaced with H-54-1 (0.28 g, 1.50 mmol) to obtain compound H-54-2, 0.20 g white solid, with a yield of 74.1%.

[0455] Following the method of Example 5, the starting material was replaced with H-54-2 (0.20 g, 1.13 mmol) to obtain compound H-54, 0.25 g white solid, with a yield of 59.5%.

[0456] 1 H NMR (600MHz, DMSO) δ10.48(s,1H),8.22–8.15(m,2H),7.86(s,4H),7.75(d,J=8.2Hz,1H),7.55(d,J=1.5Hz,1 H),7.46–7.42(m,2H),7.38(dd,J=8.2,2.0Hz,1H),4.52(s,2H),3.56(q,J=7.2Hz,2H),1.19(t,J=7.2Hz,3H).

[0457] Biological Example 1 Tests on the inhibitory activity of compounds against TMPRSS2 enzyme

[0458] 1. Research Methods

[0459] This study employed a TMPRSS2-based fluorescence biochemical analysis method to determine the inhibitory activity of target compounds against TMPRSS2. The peptide substrate Boc-Gln-Ala-Arg-AMC contains the fluorescent chromophore 7-amino-4-methylcoumarin (AMC). Recombinant TMPRSS2 cleaves the substrate, releasing AMC, which then fluoresces. The fluorescence was monitored using a multi-mode microplate reader at an excitation wavelength of 340 nm and an emission wavelength of 440 nm. This method is characterized by high accuracy and suitability for high-throughput screening, enabling efficient enzyme activity screening.

[0460] The enzyme used in this study was recombinant human TMPRSS2 (106-492aa), which is composed of the full-length extracellular protein of TMPRSS2 and contains the active catalytic site. The enzyme cleaved the substrate Boc-Gln-Ala-Arg-AMC, which was purchased from Bachem, and the following procedures were performed.

[0461] 1.1 Thaw TMPRSS2 enzyme, Boc-Gln-Ala-Arg-AMC, and 1X Assay buffer (50mM Tris, pH 8; 150mM NaCl; 0.01% Tween 20) on ice. All of these reagents must be kept on ice throughout the experiment.

[0462] 1.2 Add 5 μL / well of the 4X analyte compound to the microplate and centrifuge the microplate at 1000 rpm for 1 minute.

[0463] Positive control wells (Pos.Ctrl): 5 μL / well compound dilution solvent

[0464] Blank control wells: 5 μL / well compound dilution solvent

[0465] 1.3 After the TMPRSS2 enzyme was completely thawed, 12 μL of the TMPRSS2 enzyme stock solution was added to 1327 μL of 1X AssayBuffer. At this point, the concentration of the enzyme dilution was 0.2 μM. 10 μL / well was then added to a white microplate. At this point, the concentration of TMPRSS2 in each well was 0.1 μM. 10 μL / well of 1X buffer was added to the blank control wells.

[0466] This step should be performed on ice. After adding the ingredients, centrifuge the microplate at 1000 rpm for 1 minute.

[0467] 1.4 Preparation of Boc-Gln-Ala-Arg-AMC working solution:

[0468] Boc-Gln-Ala-Arg-AMC working solution: Dilute Boc-Gln-Ala-Arg-AMC (10 mM) to 10 μM with 1X AssayBuffer;

[0469] This step should be performed on ice;

[0470] 1.5 Add 5 μL / well of Boc-Gln-Ala-Arg-AMC working solution to the microplate. At this point, the concentration of Boc-Gln-Ala-Arg-AMC is 2.5 μM. After adding the solution, centrifuge the microplate at 1000 rpm for 1 minute.

[0471] 1.6 After centrifugation, attach the membrane to the microplate, press the membrane firmly, and incubate at 25°C for 1 hour;

[0472] 1.7 After incubation, fluorescence intensity was measured on a plate reader, and the fluorescence values ​​were read (excitation at 340 nm and emission at 440 nm);

[0473] 1.8 Calculation of enzyme inhibition rate:

[0474]

[0475] 1.9 Half-maximal inhibitory concentration (IC50) 50The enzyme inhibition rates of carmostat mesylate and some compounds of this application were tested at concentrations of 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM using the aforementioned enzyme inhibition rate test method. Two sets of data were measured at each concentration, and the average of the two sets was taken. The concentration was plotted on the x-axis, and the TMPRSS2 enzyme activity inhibition rate on the y-axis. Data fitting was performed based on the x and y axis results to obtain a dose-response curve. The corresponding IC50 was calculated based on the dose-response curve. 50 .

[0476] 2. Experimental Results

[0477] First, a subset of target compounds were screened using a singletedose test (20 nM) to identify those with inhibitory potential. Then, the inhibitory compounds with the best inhibitory activity were subjected to gradient anti-enzyme activity assays to obtain dose-response curves and determine the corresponding IC50 values. 50 value.

[0478] 2.1 TMPRSS2 enzyme inhibition screening data:

[0479]

[0480]

[0481] 2.2 Dose-response curve of partial enzyme inhibitory activity test:

[0482] The enzyme inhibition rates of carmostat mesylate and some compounds of this application were tested at concentrations of 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM using the enzyme inhibition rate test method described in Example 1 of the biological study. Two sets of data were measured at each concentration, and the average of the two sets was taken. The concentration was plotted on the x-axis, and the average inhibition rate of the compound was plotted on the y-axis. Data fitting was performed based on the x and y axis results to obtain a dose-response curve of carmostat mesylate and some compounds of this application (see attached figure). Figure 1-3 ).

[0483] By comparing the dose-effect curves of carmostat mesylate and some compounds of this application:

[0484] From the table above and the instruction manual attached Figure 1-3 It can be seen that the inhibition rates of the compounds fit the curves well. Compounds B-4, B-13, B-14, B-18, B-24, B-49, H-22, H-44, H-45, and H-47 (IC) showed good inhibition rates. 50 <2.00 nM), significantly better than carmostat mesylate in inhibiting TMPRSS2; compounds B-12, B-21, H-26, etc. (2.00 nM ≤ IC50) 50Compounds with a concentration ≤4.00 nM showed good inhibitory effects on TMPRSS2; compounds B-41, CO1, H-17, etc. (≤4.00 nM) also showed good inhibitory effects. 50 (≤7.00 nM), its inhibitory effect on TMPRSS2 is comparable to that of carmostat mesylate.

[0485] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An aryl formyl compound or its pharmaceutical salt, characterized in that, Its structure is selected from the following: (1) Its structure is shown in Equation I: Where ring B represents R 1 Substituted or unsubstituted benzene ring; R 1 It can be a monosubstituted or polysubstituted group, and can be independently represented by H, F, Cl, Br, C1-C5 alkyl, 1-3 halo-C1-C5 alkyl, C1-C5 alkoxy, 1-3 halo-C1-C5 alkoxy, NO2; Ring A represents the following double-ring structure: R 4 Represents H, C1-C5 alkyl; (2) Its structure is selected from one of the following structures:

2. The aryl carboxyl compound or its pharmaceutical salt according to claim 1, characterized in that, The ring B represents R. 1 Substituted or unsubstituted benzene ring; R 1 It can be a monosubstituted or polysubstituted group, with independent representatives such as H, F, Cl, Br, methoxy, methyl, nitro, and trifluoromethyl; R 4 Represents H, methyl, and ethyl.

3. The aryl carboxyl compound or its pharmaceutical salt according to claim 1, characterized in that, The C1-C5 alkyl groups are selected from —CH3, —CH2CH3, —CH(CH3)2, —(CH2)2CH3, —(CH2)3CH3, —CH2CH(CH3)2, —C(CH3)3, —CH(CH3)CH2CH3, —(CH2)4CH3, —CH(CH3)(CH2)2CH3, —CH(CH2CH3)2, —CH2C(CH3)3, —CH2CH(CH3)CH2CH3, —C(CH3)2CH2CH3, —CH(CH3)CH(CH3)2, —(CH2)2CH(CH3)2; The 1-3 halogenated C1-C5 alkyl groups are selected from —CF3, —CH2CF3, —(CH2)2CF3, —(CH2)3CF3, and —(CH2)4CF3; The C1-C5 alkoxy group is selected from -OCH3, -OCH2CH3, -OCH(CH3)2, -O(CH2)2CH3, -O(CH2)3CH3, -OCH2CH(CH3)2, -OC(CH3)3, -OCH(CH3)CH2CH3, -O(CH2)4CH3, - OCH(CH3)(CH2)2CH3, —OCH(CH2CH3)2, —OCH2C(CH3)3, —OCH2CH(CH3)CH2CH3, —OC(CH3)2CH2CH3, —OCH(CH3)CH(CH3)2, —O(CH2)2CH(CH3)2; The 1-3 halogenated C1-C5 alkoxy groups are selected from —OCF3, —OCH2CF3, —O(CH2)2CF3, —O(CH2)3CF3, and —O(CH2)4CF3.

4. The aryl carboxyl compound or its pharmaceutical salt according to claim 1, characterized in that, Ring A represents the following structure:

5. The aryl carboxyl compound or its pharmaceutical salt according to claim 1, characterized in that, The medicinal salt is selected from acetate, trifluoroacetate, methanesulfonate, hydrochloride, phosphate, or sulfate.

6. The aryl carboxyl compound or its pharmaceutical salt according to claim 1, characterized in that, The aryl compounds or their pharmaceutical salts are selected from the following:

7. A method for preparing the compound as described in claim 1 or its pharmaceutical salt, characterized in that, Choose from any of the following routes: Route 1: Substrate b was dissolved in pyridine, and then substrate a, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine were added. The mixture was stirred at room temperature, filtered, and the filter cake or filtrate was purified by column chromatography to obtain product c. Route 2: S1: Dissolve substrate d in dichloromethane, add N,N'-di-BOC-S-methylisothiourea, mercuric chloride and triethylamine, react overnight, filter, and purify by column chromatography to obtain substrate e; S2: Dissolve substrate e in dichloromethane, add trifluoroacetic acid, incubate overnight at room temperature, and then post-process to obtain product f.

8. A pharmaceutical composition comprising an aryl carboxyl compound as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.

9. The use of the aryl carboxyl compound or its pharmaceutical salt according to any one of claims 1-6 in the preparation of a medicament for inhibiting the transmembrane serine protease TMPRSS2.

10. The use of the aryl carboxyl compounds or their pharmaceutical salts according to any one of claims 1-6 in the preparation of antiviral drugs, characterized in that, The virus mentioned includes the novel coronavirus or its variants.

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