Aryl formyl compound as well as preparation method and application thereof

Abstract

The invention relates to an aryl formyl compound as well as a preparation method and application thereof, the structural formula of the aryl formyl compound is as shown in formula I. The aryl formyl compound or pharmaceutical salt thereof provided by the invention has good TMPRSS2 enzyme inhibitory activity, and provides a research basis for further development of antiviral drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to an aromatic formyl compound and a preparation method and application thereof. Background Art

[0002] Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Currently, the treatment of the new coronavirus mainly relies on vaccines. Although there are several vaccines on the market, the new coronavirus is a single-stranded RNA virus, and its genome is prone to mutation as the virus spreads. The problem of vaccine protection failure due to viral mutation may become another difficult problem that must be faced in the prevention and control of the new coronavirus epidemic. Therefore, scientists and researchers around the world are racing against time to develop effective drugs and vaccines to prevent SARS-CoV-2 infection, including repurposing existing drugs to target viral and host proteins, especially drugs that may prevent SARS-CoV-2 from entering human cells.

[0003] Currently, there are four small molecule drugs for COVID-19 that have been marketed worldwide, including Baricitinib (marketed in Japan), Remdesivir (marketed in Japan, the United States, and Europe), Molnupiravir (marketed in the United Kingdom), and Paxlovid (US EUA / conditional approval in China). Baricitinib has a therapeutic effect on severe COVID-19; the US NIH "COVID-19 Treatment Guidelines" recommends that severe patients can try Remdesivir, but it is not recommended for mild and moderate patients. Although many clinical studies on COVID-19 antiviral treatment have been conducted around the world, the current research results are not sufficient to constitute evidence of the effectiveness and safety of these drugs in treating COVID-19. The discovery of new and safe new coronavirus treatment drugs is imminent.

[0004] Coronaviruses rely on the binding of the viral spike (S) protein to human cell receptors and the activation of the S protein by host cell proteases. It has been confirmed that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as an entry receptor and transmembrane protease serine 2 (TMPRSS2) as an activation factor for the S protein. Targeting the way the new coronavirus invades the human body, TMPRSS2 has an ideal target organ distribution as a drug treatment target, and drugs developed with TMPRSS2 as a target have a natural targeting advantage. Inhibiting TMPRSS2 activity can block or slow the process of the new coronavirus entering the host cell, thereby treating new coronavirus infection.

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

[0006] One of the purposes of the present invention is to provide an aromatic formyl compound or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a method for synthesizing the aromatic formyl compound.

[0008] Another object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation containing the aromatic formyl compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Another object of the present invention is to provide the use of the aromatic formyl compound or its pharmaceutically acceptable salt in the preparation of TMPRSS2 inhibitory drugs.

[0010] Another object of the present invention is to provide the use of the aromatic formyl compound or its pharmaceutically acceptable salt in the preparation of antiviral drugs.

[0011] The terms used in the description of the present invention herein are only for describing specific embodiments and are not intended to limit the present invention. The nomenclature used herein and the laboratory operations in the organic chemistry, medicinal chemistry, and biology described herein are well known and commonly used in the art. Unless otherwise mentioned, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this art belongs.

[0012] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", "the", and "its" refer to both the singular and the plural, unless the context clearly dictates otherwise. For example, a compound includes one or more than one compound.

[0013] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items.

[0014] As used herein, the term "disease" refers to any change in the state of the body or some organ that interrupts or interferes with the performance of its functions and / or causes symptoms.

[0015] As used herein, the term "treatment" is intended to alleviate or eliminate the disease state or condition being targeted. If the subject receives a therapeutic amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to the methods described herein, and one or more signs and symptoms of the subject show an observable and / or detectable decrease or improvement, the subject is successfully "treated". It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also not achieving complete treatment, but achieving some biological or medically relevant results.

[0016] As used herein, the term "subject" may refer to a patient or other animal receiving the composition of the present invention to treat, prevent, alleviate and / or alleviate the disease or condition described in the present invention, and in the present invention, particularly refers to humans and mammals.

[0017] Technical Theme 1

[0018] The present invention provides an aromatic formyl compound or a pharmaceutically acceptable salt thereof having a structure as shown in Formula I:

[0019]

[0020] Among them, ring B represents R 1 Substituted or unsubstituted benzene ring, R 1 a substituted or unsubstituted five-membered or six-membered heteroaromatic ring;

[0021] R 1 is a mono- or poly-substituted group, independently representing H, F, Cl, Br, C1-C5 alkyl, 1-3 halogenated C1-C5 alkyl, C1-C5 alkoxy, 1-3 halogenated C1-C5 alkoxy, or NO2;

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

[0023]

[0024] R 2 is a mono- or poly-substituted group, independently representing H, hydroxyl, amino, C1-C5 alkyl, 1-3 halogenated C1-C5 alkyl, C1-C5 alkoxy, 1-3 halogenated C1-C5 alkoxy, C2-C5 ester, 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 represents H, C1-C5 alkyl;

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

[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 is a mono- or poly-substituted group, independently representing H, F, Cl, Br, methoxy, methyl, nitro, trifluoromethyl;

[0030] The R 2 is a mono- or poly-substituted group, independently representing 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 It 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 group is selected from —CF3, —CH2CF3, —(CH2)2CF3, —(CH2)3CF3, —(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 group is selected from -OCF3, -OCH2CF3, -O(CH2)2CF3, -O(CH2)3CF3, -O(CH2)4CF3;

[0038] The five-membered 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 C3-C6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexane.

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

[0042]

[0043]

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

[0045] In some preferred embodiments of the present invention, the aromatic formyl compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] As used herein, the term "alkyl" used alone or in combination refers to a straight or branched alkyl group. The term "Cm-n alkyl" (m and n are each integers) refers to a straight or branched alkyl group containing m to n carbon atoms. The term "C1-5 alkyl" used alone or in combination in the present invention refers to a straight or branched alkyl group containing 1 to 5 carbon atoms. Representative 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 a saturated cyclic aliphatic monocyclic ring system having 3 to 6 carbon ring atoms as described herein, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0053] "Halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) and iodine (iodo, -I).

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

[0055] As used herein, the term "heteroaryl", alone or in combination, refers to a 5- to 6-membered monocyclic aromatic ring containing 1 or more (e.g., 1 to 6, or 1 to 5, or 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, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

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

[0057] As used herein, "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. 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, etc.; 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-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic 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, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, etc., including salts formed by sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

[0058] Technical Theme 2

[0059] The present invention also provides a method for synthesizing an aromatic formyl compound or a pharmaceutically acceptable salt thereof as shown in Formula I. Although the compounds of the present invention can be prepared by any of the following routes, the conditions of the method, such as reactants, solvents, acids, bases, the amount of the compounds used, reaction temperature, reaction time, etc., are not limited to the following description. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known to those skilled in the art, and those skilled in the art can easily perform the above combination.

[0060] Route 1:

[0061]

[0062] Dissolve substrate b in pyridine, add substrate a, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, stir at room temperature, filter with suction, and purify the filter cake or filtrate 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, and leave at room temperature overnight, followed by post-treatment to obtain product f.

[0067] Technical Theme 3

[0068] The present invention provides a pharmaceutical composition, which comprises an aromatic formyl compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0069] As used herein, "pharmaceutical composition" contains a therapeutically effective amount of the aryl formyl compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, wine preparations, decoctions, lozenges, mixtures, suppositories, injections, inhalants or sprays. The pharmaceutical composition preferably contains 0.1% to 99.5% by weight of the aryl formyl compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and more preferably contains 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, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example, when used for oral administration, oral preparations such as tablets, capsules, granules and pills can be prepared, 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, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; 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, polyvinyl pyrrolidone and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants and spices, etc.). When used for parenteral administration, an injection can be prepared, including sterile powder for injection and solvent for injection, and the carrier or excipient used includes sterile water, Ringer's solution and isotonic sodium chloride solution, and suitable additives such as antioxidants, buffers and antibacterial agents can also be added according to the properties of the drug. When used for rectal administration, the drug can be prepared into suppositories, etc. When used for pulmonary administration, the drug can be prepared into inhalants or sprays, etc. There are many resources available to those skilled in the art, which describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books such as "Remington's Pharmaceutical Encyclopedia", "Chinese Pharmaceutical Annals", and "Pharmaceutics".

[0071] The present invention can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ocularly, nasally, by inhalation, subcutaneously, intramuscularly, buccally, sublingually, and rectal administration, and the compound as described above can be administered in any amount of 1 μg to 2000 mg / kg of the subject's body weight, for example, 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, and 5 to 100 mg / kg body weight / day. In some embodiments of the present invention, the compound as described above can be administered 4 times a day, 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time a week, or other intervals, and the dosage regimen as described above can be repeated weekly or monthly as appropriate. In the present 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 conditions, 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 commonly used for this purpose. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing the other drugs and the compounds of the present invention in a unit dosage form is preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combined therapy can also include treatment with the compounds of the present invention and one or more other drugs in different overlapping schedules. It can also be expected that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients can be used in lower doses than when each is used alone. 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 the aromatic formyl compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting the transmembrane serine protease TMPRSS2.

[0075] Technical Theme 5

[0076] The present invention also provides the use of the aromatic formyl compound shown in formula I or its pharmaceutically acceptable salt in antiviral drugs.

[0077] In some preferred embodiments, the virus comprises a coronavirus or a variant thereof.

[0078] Advantageous Effects of the Invention

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

[0080] Instruction Manual

[0081] Figure 1 This is a dose-effect curve diagram of the compounds B-4, B-14, B-24, H-22, H-45 of the present application and camostat mesylate, wherein the horizontal coordinates of the measuring points are 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0.0064 nM from right to left.

[0082] Figure 2 This is a dose-effect curve diagram of the compounds B-12, B-16, B-21, H-26, H-46 of the present application and camostat mesylate, wherein the horizontal coordinates of the measuring points are 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, 0.0064 nM from right to left.

[0083] Figure 3 This is a dose-effect curve diagram of the compounds B-1, B-41, C01, H-17, H-43 of the present application and camostat mesylate, wherein the horizontal coordinates of the measuring points are 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM from right to left. DETAILED DESCRIPTION

[0084] The present invention is described below in conjunction with specific examples. These examples are not intended to limit the scope of the present invention, but provide guidance for those skilled in the art to prepare and use the compounds, compositions and methods of the present invention. If no specific conditions are specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially.

[0085] The chemical names of the compounds described in this application are usually generated from ChemDraw Ultra (ChambridgeSoft) and / or usually follow the principles of IUPAC nomenclature. The English abbreviations of the compounds and the chemical names are 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 example were synthesized by the following route:

[0088] Route 1

[0089]

[0090] Dissolve substrate b in pyridine, add substrate a, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, stir at room temperature, filter with suction, and purify the filter cake or filtrate by column chromatography to obtain product c;

[0091] Route 2

[0092]

[0093] 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;

[0094] The substrate e was dissolved in dichloromethane, trifluoroacetic acid was added, and the mixture was allowed to stand at room temperature overnight. The product f was obtained after post-treatment.

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

[0096]

[0097] In a 100 mL single-necked bottle, p-guanidinobenzoic acid hydrochloride (0.59 g, 3.05 mmol) was added, and pyridine (10 mL) was dissolved, followed by the addition of 1-oxo-7-hydroxyisochroman (0.50 g, 3.05 mmol), DCC (0.75 g, 3.66 mmol), and DMAP (0.01 g, 0.01 mmol). 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) to obtain compound B-1, 0.48 g of a white solid, with a yield of 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-tetrahydroisoquinolin-7-yl 4-guanidinobenzoate (B-2)

[0100]

[0101] According to the method of Example 1, the raw material was replaced with 3,4-dihydro-7-hydroxyisoquinolin-1(2H)-one (1.00 g, 6.13 mmol) to obtain compound B-2, 0.85 g of white solid, with a yield of 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-Oxo-1,2,3,4-tetrahydroquinolin-7-yl 4-guanidinobenzoate hydrochloride (B-3)

[0104]

[0105] According to the method of Example 1, the raw 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 of white solid, with a yield of 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 4:4-(3-oxomorpholino)phenyl 4-guanidinobenzoate (B-4)

[0108]

[0109] Add H2O (100 mL) to a 250 mL three-necked flask, slowly drop concentrated sulfuric acid (12.75 g, 31.00 mmol), cool to 0-10 ° C with cold hydrazine, add 4-(4-aminophenyl)-3-morpholinone (5.00 g, 26.00 mmol), NaNO2 (2.14 g, 130.00 mmol) in water (20 mL), react at 110 ° C for 3 h. Pour into 100 mL of ice water, extract with EA (100 mL*3), wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM: MeOH = 30: 1) to obtain compound B-4-1, 2.77 g of light red solid, yield 49.8%.

[0110] According to the method of Example 1, the raw material was replaced with B-4-1 (2.00 g, 10.40 mmol) to obtain compound B-4, 1.30 g of 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-oxoethyl)phenyl 4-guanidinobenzoate (B-12)

[0113]

[0114] In a 100 mL single-mouth bottle, p-guanidinobenzoic acid hydrochloride (0.59 g, 2.76 mmol) was added, pyridine (10 mL) was dissolved, and then 4-hydroxyphenylacetic acid methyl ester (0.51 g, 3.06 mmol), DCC (0.76 g, 3.67 mmol), DMAP (0.01 g, 0.01 mmol) were added in sequence. The mixture was stirred at room temperature for 24 h, filtered, washed with 5 mL of pyridine, and the filter cake was purified by column chromatography (DCM: MeOH = 10: 1). After reduced pressure concentration, 20 mL of methanol was dissolved, 2 mL of hydrogen chloride ethyl acetate solution (4 mol / L) was added dropwise, stirred at room temperature for 30 min, cooled to -10 ° C for crystallization for 30 min, filtered, and the filter cake was dried in vacuo at 45 ° C for 8 h to obtain compound B-12, 0.45 g of 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-tetrahydroisoquinolin-6-yl 4-guanidinobenzoate (B-13)

[0117]

[0118] According to the method of Example 1, the raw material was replaced with 3,4-dihydro-6-hydroxy-isoquinolin-1(2H)-one (1.00 g, 6.70 mmol) to obtain compound B-13, 1.80 g of white solid, with a yield of 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-Oxoisochroman-6-yl 4-guanidinobenzoate (B-14)

[0121]

[0122] According to the method of Example 1, the raw material was replaced with 1-oxo-6-hydroxyisochroman (1.00 g, 6.09 mmol) to obtain compound B-14, 0.80 g of white solid, with a yield of 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-Oxoisoindolin-5-yl 4-guanidinobenzoate (B-15)

[0125]

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

[0127] PPA (21.00 g) preheated at 80°C was added to a 150 mL single-mouth bottle, and B-15-1 (6.00 g, 28.00 mmol) was added. The mixture was reacted at 100°C for 2 h. 100 mL of ice water was added while hot, 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. The mixture was purified by column chromatography (DCM:MeOH=50:1) to obtain compound B-15-2, 0.60 g of a gray solid, with a yield of 13.0%.

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

[0129] According to the method of Example 5, the raw material was replaced with B-15-3 (0.20 g, 1.20 mmol) to obtain compound B-15, 0.20 g of 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-guanidinobenzoate hydrochloride (B-16)

[0132]

[0133] According to the method of Example 5, the raw material was replaced with 5-hydroxyphthalide (1.00 eq., 3.33 mmol) to obtain compound B-16, 0.50 g of white solid, with a yield of 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] According to the method of Example 5, the raw material was replaced with 5-hydroxy-1-indanone (1.00 eq., 6.08 mmol) to obtain compound B-18, 1.25 g of white solid, with a yield of 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] Embodiment 11 :2-Oxo-2H-chromen-6-yl 4-guanidinobenzoate hydrochloride (B-19)

[0140]

[0141] According to the method of Example 5, the raw material was replaced with 6-hydroxycoumarin (1.00 eq., 3.08 mmol) to obtain compound B-19, 0.57 g of white solid, with a yield of 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-guanidinobenzoate hydrochloride (B-20)

[0144]

[0145] According to the method of Example 5, the raw material was replaced with 6-hydroxy-1,4-benzodioxane (1.00 eq., 0.20 mmol) to obtain compound B-20, 0.45 g of white solid, with a yield of 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-Oxo-2H-chromen-7-yl 4-guanidinobenzoate hydrochloride (B-21)

[0148]

[0149] According to the method of Example 5, the raw material was replaced with 7-hydroxycoumarin (1.00eq., 0.62mmol) to obtain compound B-21, 1.20g of white solid, with 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] Embodiment 14 :2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-guanidinobenzoate hydrochloride (B-22)

[0152]

[0153] Add p-hydroxyaniline (1.00 eq., 0.14 mol) to a 500 mL three-necked flask and dissolve it in ethyl acetate (150 mL). Add 3-chloropropionyl chloride (1.50 eq., 0.21 mol) in ethyl acetate (50 mL) dropwise at 0 ° C. The temperature was controlled below 5 ° C. After the addition, the temperature was raised to room temperature and reacted for 2 h. Add 200 mL of saturated sodium carbonate solution dropwise, and extract with EA (200 mL * 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 obtain compound B-22-1, 22.00 g of 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, decalin (50 mL) was dissolved, and aluminum chloride (5.00 eq., 0.25 mol) was added. The temperature was slowly raised from room temperature under a nitrogen atmosphere and reacted at 150 ° C for 8 h. Pour into 100 mL of ice water and stir vigorously. Filter with suction, and dry the filter cake in 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] According to the method of Example 5, the raw material was replaced with B-22-2 (1.00 eq., 0.61 mmol) to obtain compound B-22, 1.40 g of white solid, with a yield of 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] Embodiment 15 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-guanidinobenzoate hydrochloride (B-24)

[0158]

[0159] According to the method of Example 5, the raw material was replaced with 6-hydroxy-1-tetralone (1.00 eq., 0.60 mmol) to obtain compound B-24, 1.35 g of white solid, with a yield of 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]dioxolan-5-yl 4-guanidinobenzoate hydrochloride (B-25)

[0162]

[0163] According to the method of Example 5, the raw material was replaced with 3,4-methylenedioxyphenol (1.00 eq., 0.72 mmol) to obtain compound B-25, 1.70 g of white solid, with a yield of 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] Embodiment 17 :1,3-Dioxoisoindolin-5-yl 4-guanidinobenzoate hydrochloride (B-26)

[0166]

[0167] In a 250mL three-necked flask, add 4-hydroxyphthalic acid (10.00g, 54.90mmol), dissolve it in glacial acetic acid, add ammonium carbonate (10.55g, 109.80mmol), reflux for 4 hours, cool to room temperature, concentrate under reduced pressure to 15mL, adjust the pH value to 5 with 1N NaOH solution, stir vigorously for 10min, filter and dry in vacuum at 45℃ for 8h to obtain compound B-26-1, 6.20g of light yellow solid, yield 69.3%.

[0168] According to the method of Example 5, the raw material was replaced with B-26-1 (1.00 g, 6.13 mmol) to obtain compound B-26, 1.20 g of 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] Embodiment 18 :2-Oxoindolin-5-yl 4-guanidinobenzoate hydrochloride (B-29)

[0171]

[0172] According to the synthesis method of B-15-3 in Example 8, the raw material was replaced with 5-methoxyindole-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] According to the method of Example 5, the raw material was replaced with B-29-1 (1.00 g, 6.70 mmol) to obtain compound B-29, 0.80 g of 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] Embodiment 19 :5,6,7,8-Tetrahydronaphthalen-2-yl 4-guanidinobenzoate hydrochloride (B-31)

[0176]

[0177] According to the method of Example 5, the raw 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 of 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] Embodiment 20 :Benzo[d]thiazol-5-yl 4-guanidinobenzoate hydrochloride (B-32)

[0180]

[0181] In a 250 mL single-necked bottle, m-methoxyaniline (10.00 g, 81.20 mmol) was added, and DCM (50 mL) was used to dissolve it. N-iodosuccinimide (81.20 mmol) and acetic acid (1.20 eq., 97.40 mmol) were added in sequence. 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*3). The mixture was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA=20:1) to obtain compound B-32-1, 9.00 g of brown oil, with a yield of 45.0%.

[0182] In a 100 mL single-mouth bottle, 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 in sequence, dissolved in DMSO (100 mL), and stirred at 140 ° C for 10 hours under a nitrogen atmosphere. Filtered, the filtrate was added with 1000 mL of water, extracted with EA (500 mL*3), the organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound B-32-2, 0.60 g of colorless oil, with a yield of 18.2%.

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

[0184] According to the method of Example 5, the raw material was replaced with B-32-3 (0.45 g, 2.98 mmol) to obtain compound B-32, 0.45 g of 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] Embodiment 21 :2,3-Dihydro-1H-inden-5-yl 4-guanidinobenzoate hydrochloride (B-33)

[0187]

[0188] According to the method of Example 5, the raw material was replaced with 5-indanol (1.00 g, 7.45 mmol) to obtain compound B-33, 1.80 g of white solid, with a 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] Embodiment 22 :2-Oxoindolin-6-yl 4-guanidinobenzoate hydrochloride (B-34)

[0191]

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

[0193] According to the method of Example 5, the raw material was replaced with B-34-1 (0.50 g, 3.35 mmol) to obtain compound B-34, 0.40 g of 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] Embodiment 23 :Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-guanidine-2-methoxybenzoate hydrochloride (B-38)

[0196]

[0197] In a 100mL single-necked bottle, add 4-amino-2-methoxybenzoic acid (3.00g, 17.90mmol), dissolve in methanol (30mL), add thionyl chloride (1.40g, 19.70mmol) at 0℃, reflux overnight, and concentrate under reduced pressure to obtain compound B-38-1, 3.10g pink solid, with a yield of 79.6%.

[0198] B-38-1 (2.00 g, 9.21 mmol) was added to a 100 mL single-mouth bottle and dissolved in ethanol (20 mL). A 50% aminonitrile aqueous solution (1.80 g, 23.04 mmol) was added at 20 °C. The reaction was refluxed overnight. After concentrating under reduced pressure, 3 mL of methanol and 1 mL of ethyl acetate were slurried. The mixture was stirred at room temperature for 0.5 h. The mixture was filtered and concentrated under reduced pressure to obtain compound B-38-2, 1.06 g of a white solid, with a yield of 51.7%.

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

[0200] In a 100mL single-mouth bottle, add B-38-3 (0.30g, 1.22mmol), dissolve in pyridine (10mL), then add 6-hydroxy-1-tetralone (0.24g, 1.47mmol), DCC (0.30g, 1.47mmol), DMAP (0.01g, 0.02mmol), stir at room temperature for 24h, filter, wash with 1mL pyridine, purify the filter cake by column chromatography (DCM: MeOH = 10: 1), concentrate under reduced pressure to near dryness, dissolve in 5mL methanol, add 2mL hydrogen chloride ethyl acetate solution (4mol / L) dropwise, stir at room temperature for 30min, cool to -10℃ for crystallization for 30min,

[0201] After suction filtration, the filter cake was dried under vacuum at 45°C for 8 h 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] Embodiment 24 :1-Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl 4-guanidino-2-methylbenzoate hydrochloride (B-39)

[0204]

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

[0206] NaHCO3 aqueous solution (50 mL) was added dropwise at -10°C. After stirring for 5 min, a THF solution (50 mL) of ethyl chloroformate (17.20 g, 15.85 mmol) was added dropwise through a dropping funnel. The mixture was reacted at -10°C for 1 h. 500 mL of water was added dropwise to quench the mixture. The mixture was extracted with EA (300 mL*3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the filtrate was purified by column chromatography (PE:EA=10:1). The compound B-39-1 was concentrated under reduced pressure to obtain 21.50 g of a colorless oil with a yield of 73.0%.

[0207] PPA (66.00 g) preheated at 80°C was added to a 250 mL single-mouth bottle, and B-39-1 (20.00 g, 8.96 mmol) was added. The reaction was carried out at 100°C for 2 h. 200 mL of water was added while hot, and EA (100 mL*3) was used for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was purified by column chromatography (DCM:MeOH=50:1) to obtain compound B-39-2, 5.50 g of gray solid, with a yield of 34.7%.

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

[0209] In a 500mL three-necked flask, add 4-amino-2-methylbenzoic acid (15.00g, 7.80mmol), dissolve in ethanol (120mL), add 25% ethanol hydrochloric acid (30mL), stir at 60°C for 0.5h, add 30% aminonitrile aqueous solution (9.84g, 233.00mmol) dropwise, react at 75°C for 5h, concentrate under reduced pressure to 50mL, stir at -10°C for 0.5h, filter, and dry the filter cake in vacuum at 45°C for 8h to obtain compound B-39-4, 8.50g of white solid, yield 47.5%.

[0210] In a 100mL single-necked bottle, add B-39-4 (1.26g, 5.52mmol), dissolve pyridine (10mL), and then add B-39-3 (1.00g, 6.13mmol), DCC (1.52g, 7.36mmol), and DMAP (0.01g, 0.06mmol). Refer to Example 5 for synthesis and post-treatment to obtain compound B-39, 1.45g 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] Embodiment 25 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-guanidine-2-methylbenzoate hydrochloride (B-40)

[0213]

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

[0215] According to the synthesis method of B-38 in Example 23, the raw material was replaced with B-40-1 (1.30 g, 5.55 mmol) to obtain compound B-40, 1.65 g of 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] Embodiment 26 :4-(Trifluoromethyl)phenyl 4-guanidine benzoate hydrochloride (B-41)

[0218]

[0219] According to the method of Example 5, the raw material was replaced with trifluoromethylphenol (1.00 g, 6.17 mmol) to obtain compound B-41, 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] Embodiment 27 :5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 5-guanidine picolinate 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 2 drops of DMF were added after dissolving SOCl2 (20 mL). The reaction was refluxed for 3 h, concentrated under reduced pressure, and added dropwise to a DCM solution of 6-hydroxy-1-tetralone (2.35 g, 14.48 mmol) and triethylamine (5.13 g, 50.68 mmol) at -10 °C at room temperature overnight. The organic phase was extracted with (100 mL) water, concentrated under reduced pressure, slurried with 10 mL DCM and 5 mL n-hexane, filtered, and the filter cake was dried under vacuum at 45 °C for 8 h to obtain compound B-44-1, 3.20 g of light yellow solid, with a yield of 78.3%.

[0224] Add B-44-1 (1.00 g, 4.69 mmol) to a 100 mL single-mouth bottle, dissolve in DCM (20 mL), add 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) at -10 ° C, react at room temperature overnight. Filter by suction, and purify the filtrate by column chromatography (PE: EA = 20: 1) to obtain compound B-44-2, 1.80 g of white solid, yield 73.2%.

[0225] B-44-2 (1.80 g, 3.43 mmol) was added to a 100 mL single-necked bottle, and trifluoroacetic acid (5 mL) was added after dissolving in DCM (10 mL). The mixture was allowed to stand at room temperature overnight, and concentrated under reduced pressure. The mixture was slurried with 5 mL EA, and filtered. The filter cake was dried under vacuum at 45 °C for 8 h to obtain compound B-44, 1.20 g of a white solid, with a yield of 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] Embodiment 28 :5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 6-guanidine nicotinate trifluoroacetate (B-47)

[0228]

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

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

[0231] According to the synthesis method of B-44 in Example 27, the raw material was replaced with B-47-2 (1.50 g, 2.86 mmol) to obtain compound B-47, 0.70 g of white solid, with a yield of 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] Embodiment 29 :Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 2-fluoro-4-guanidine benzoate hydrochloride (B-49)

[0234]

[0235] In a 100mL three-necked flask, add 4-amino-2-fluorobenzoic acid (2.00g, 12.89mmol), dissolve in ethanol (10mL), add concentrated hydrochloric acid (1.29mL), stir for 0.5h, then add dropwise 50% aminonitrile aqueous solution (3.30g, 38.67mmol), react at 55℃ for 5h, stir at -10℃ for 0.5h, filter, and dry the filter cake in vacuum at 45℃ for 8h to obtain compound B-49-1, 1.20g brown solid, yield 39.9%.

[0236] According to the synthesis method of B-38 in Example 23, the raw material was replaced with B-49-1 (1.30 g, 5.55 mmol) to obtain compound B-49, 0.80 g of 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] Embodiment 30:Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 3-chloro-4-guanidine benzoate trifluoroacetate (B-50)

[0239]

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

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

[0242] According to the synthesis method of B-44 in Example 27, the raw material was replaced with B-50-2 (1.00 g, 1.79 mmol) to obtain compound B-50, 0.60 g of white solid, with a yield of 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] Embodiment 31 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-guanidine-3-(trifluoromethyl)benzoate trifluoroacetate (B-51)

[0245]

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

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

[0248] According to the synthesis method of B-44 in Example 27, the raw material was replaced with B-51-2 (2.00 g, 3.38 mmol) to obtain compound B-51, 1.30 g of 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] Embodiment 32 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 2-chloro-4-guanidine benzoate trifluoroacetate (B-52)

[0251]

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

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

[0254] According to the synthesis method of B-44 in Example 27, the raw material was replaced with B-52-2 (1.38 g, 2.47 mmol) to obtain compound B-52, 0.96 g of 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] Embodiment 33 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine-2-nitrobenzoate trifluoroacetate (B-58)

[0257]

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

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

[0260] According to the synthesis method of B-44 in Example 27, the raw material was replaced with B-58-2 (1.00 g, 1.76 mmol) to obtain compound B-58, 0.55 g of 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] Embodiment 34 :5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl 3-fluoro-4-guanidine benzoate hydrochloride (B-59)

[0263]

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

[0265] According to the synthesis method of B-38 in Example 23, the raw material was replaced with B-59-1 (1.30 g, 5.55 mmol) to obtain compound B-59, 1.10 g of white solid, with a yield of 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] Embodiment 35 :4-(2-((cyclopropylmethyl)amino)-2-oxoethyl)phenyl 4-guanidinobenzoate (C01)

[0268]

[0269] In a 250 mL three-necked flask, p-hydroxyphenylacetic acid (3.49 g, 22.90 mmol) was added, and DMF (20 mL) was dissolved. EDCI (5.27 g, 27.48 mmol), HOBt (3.76 g, 27.48 mmol), and DIPEA (8.88 g, 68.7 mmol) were added in sequence at 0°C. After stirring for 0.5 h, neopentylamine (2.00 g, 22.90 mmol) was added. The mixture was stirred at room temperature for 12 h, 200 mL of water was added, and EA (100 mL*3) was used for extraction. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was purified by column chromatography (DCM:MeOH=40:1) to obtain compound C01-1, 2.60 g of white solid, with a yield of 52.0%.

[0270] According to the method of Example 1, the raw material was replaced with C01-1 (2.00 g, 9.0 mmol) to obtain compound C01, 1.60 g of 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] Embodiment 36 :4-(2-(neopentylamino)-2-oxoethyl)phenyl 4-guanidinobenzoate (C02)

[0273]

[0274] According to the synthesis method of C01-1 in Example 35, the raw material was replaced with cyclopropylmethylamine (2.00 g, 28.12 mmol) to obtain compound C02-1, 2.30 g of white solid, with a yield of 39.9%.

[0275] According to the method of Example 1, the raw material was replaced with C02-1 (2.00 g, 9.70 mmol) to obtain compound C02, 1.30 g of 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] Embodiment 37 :4-(2-(2-(dimethylamino)-2-oxoethyl)amino)-2-oxoethylphenyl 4-guanidine benzoate hydrochloride (C03)

[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 in sequence at -10 °C. The mixture was reacted at room temperature overnight. 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 obtain compound C03-1, 6.80 g of colorless oil, with a yield of 60.2%.

[0280] C03-1 (6.80 g, 0.03 mol) was added to a 250 mL three-necked flask. After dissolving in methanol (30 mL), palladium carbon (3.40 g) was added. The mixture was replaced with hydrogen three times. The reaction was allowed to react at room temperature overnight. The mixture was filtered with suction. 10 mL of ethyl acetate solution (4 mol / L) of hydrogen chloride was added to the filtrate. The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. The compound C03-2 was purified by column chromatography, 2.80 g of a white solid, and the yield was 70.2%.

[0281] According to the synthesis method of C03-1 in Example 37, the raw materials were replaced with p-methoxyphenylacetic acid (3.66 g, 0.02 mol) and C03-2 (2.80 g, 0.02 mol) to obtain compound C03-3, 4.70 g of white solid, with a yield of 94.0%.

[0282] According to the synthesis method of B-15-3 in Example 8, the raw material was replaced with C03-3 (2.00 g, 8.00 mmol) to obtain compound C03-4, 1.50 g of white solid, with a yield of 79.4%.

[0283] According to the method of Example 5, the raw material was replaced with C03-4 (0.20 g, 0.85 mmol) to obtain compound C03, 0.30 g of 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] Embodiment 38:4'-Carbamoyl-[1,1'-biphenyl]-4-yl 4-guanidinobenzoate (C07)

[0286]

[0287] Add cyanobiphenol (2.00 g, 10.20 mmol) and DMSO (40 mL) to a 250 mL three-necked flask to dissolve it. Add the prepared 12% NaOH solution (1.22 g, 30.60 mmol) at 0-10°C, add 30% H2O2 solution (4.60 g, 40.80 mmol) dropwise, react at 0-10°C for 2 h, add 70 mL of Na2SO3 aqueous solution (2.57 g, 20.40 mmol), add 200 mL of water after quenching, stir vigorously, filter, and dry the filter cake in vacuo at 45°C for 8 h to obtain compound C07-1, 1.90 g of white solid, with a yield of 87.3%.

[0288] According to the method of Example 1, the raw material was replaced with C07-1 (1.00 g, 4.69 mmol) to obtain compound C07, 0.80 g of 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] Embodiment 39 :4'-Cyano-[1,1'-biphenyl]-4-yl 4-guanidinobenzoate hydrochloride (C06-1)

[0291]

[0292] According to 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 of 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] Embodiment 40 :8-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-1)

[0295]

[0296] According to 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 of 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] Embodiment 41 :5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-2-bromo-4-guanidine benzoate trifluoroacetate (H-3)

[0299]

[0300] According to the synthesis method of B-50-1 in Example 30, the raw 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] In a 250mL single-necked bottle, H-3-1 (3.00g, 7.70mmol) and EtOH (60mL) were added in sequence, after dissolving, SnCl2·2H2O (6.95g, 30.80mmol) were added, and the mixture was stirred at 80°C for 4h, cooled to room temperature, 100mL of ice water was added, and the pH was adjusted to 8 with 10% NaOH aqueous solution, filtered, and the filtrate was extracted with EA (100mL*3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, slurried with 5mL EA and 2mL PE, stirred at room temperature for 10min, filtered, and the filter cake was dried under vacuum at 45°C for 8h to obtain compound H-3-2, 1.74g of yellow solid, with a yield of 62.8%.

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

[0303] According to the synthesis method of B-44 in Example 27, the raw material was replaced with H-3-3 (0.20 g, 0.33 mmol) to obtain compound H-3, 0.15 g of 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] Embodiment 42 :2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl-2-fluoro-4-guanidine benzoate hydrochloride (H-27)

[0306]

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

[0308] In a 100mL single-necked bottle, add H-27-1 (0.29g, 1.23mmol), dissolve pyridine (10mL), and then add 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.20g, 1.23mmol), DCC (0.38g, 1.85mmol), DMAP (0.03g, 0.25mmol) in sequence. The reaction mixture was treated with reference to Example 5 to obtain compound H-27, 0.25g 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] Embodiment 43 :2-oxoindole-5-yl 3-fluoro-4-guanidine benzoate hydrochloride (H-23)

[0311]

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

[0313] In a 100mL single-necked bottle, add H-23-1 (0.20g, 0.86mmol), dissolve pyridine (10mL), and then add H-25-1 (0.14g, 0.94mmol), DCC (0.26g, 1.28mmol), and DMAP (0.02g, 0.17mmol). Refer to Example 5 for synthesis and post-treatment to obtain compound H-23, 0.15g 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] Embodiment 44 :3-Nitro-5-oxo-5,6,7,8-tetrahydronaphthalen-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-mouth bottle, and 6-methoxy-1-tetralone (4.00 g, 14.50 mmol) was added in batches at -10 °C. The mixture was stirred at room temperature for 3 h, and 100 mL of ice water was added. The mixture was extracted with EA (100 mL*3), washed with saturated brine (100 mL), and purified by organic phase column chromatography (PE:EA=20:1) to obtain compound H-22-1, 1.80 g of yellow solid, with a yield of 38.3%.

[0318] In a 100 mL single-necked bottle, H-22-1 (1.60 g, 7.20 mmol), AlCl3 (2.40 g, 18.00 mmol), and toluene (32 mL) were added in sequence, and the reaction was carried out at 105 ° C for 3 h. 150 mL of ice water was added, and EA (100 mL*3) was used for extraction. The product was washed with saturated brine (100 mL) and purified by organic phase column chromatography (DCM: MeOH = 100: 1) to obtain compound H-22-2, 0.68 g of brown solid, with a yield of 45.6%.

[0319] According to the method of Example 5, the raw material was replaced with H-22-2 (0.31 g, 1.48 mmol) to obtain compound H-22, 0.25 g of 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] Embodiment 45 :1-Oxoisoindolin-5-yl 3-fluoro-4-guanidine benzoate hydrochloride (H-18)

[0322]

[0323] In a 100 mL single-mouth bottle, add H-23-1 (0.18 g, 0.77 mmol) prepared in Example 43 and pyridine (10 mL). After dissolution, add 5-hydroxyisoindole-1-one (0.13 g, 0.85 mmol), DCC (0.24 g, 1.16 mmol), and DMAP (0.02 g, 0.15 mmol) in sequence. Refer to Example 5 for synthesis and post-treatment to obtain compound H-18, 0.12 g of 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] Embodiment 46 :1-Chloro-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-24)

[0326]

[0327] In a 100 mL single-necked bottle, add 6-hydroxy-1-tetralone (2.00 g, 12.33 mmol), NCS (2.50 g, 18.50 mmol), glacial acetic acid (0.80 g), acetonitrile (20 mL) in sequence, stir at room temperature for 6 h, filter, and dry the filter cake in vacuo 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] According to the method of Example 5, the raw material was replaced with H-24-1 (0.50 g, 2.54 mmol) to obtain compound H-24, 0.50 g of 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] Embodiment 47 :2-Oxoindolin-5-yl-2-fluoro-4-guanidine benzoate hydrochloride (H-25)

[0331]

[0332] According to the synthesis method of B-15-3 in Example 8, the raw material was replaced with 5-methoxyindole-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] In a 100 mL single-necked bottle, add H-27-1 (0.31 g, 1.34 mmol) prepared in Example 42 and pyridine (10 mL). After dissolution, add H-25-1 (0.20 g, 1.34 mmol), DCC (0.41 g, 2.01 mmol), and DMAP (0.03 g, 0.26 mmol) in sequence. Refer to Example 5 for synthesis and post-treatment to obtain 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] Embodiment 48 :2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl-5-guanidinepicolinic acid trifluoroacetate (H-26)

[0336]

[0337] In a 100 mL single-necked bottle, 5-nitropyric acid (0.50 g, 2.97 mmol), 6-hydroxy-3,4-dihydroquinolin-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 in sequence. The mixture was reacted at room temperature overnight. 100 mL of water was added, stirred for 10 min, and filtered. The filter cake was dried in vacuo at 45 ° C for 8 h to obtain compound H-26-1, 0.77 g of a yellow solid, with a yield of 82.8%.

[0338] In a 100mL single-necked bottle, add H-26-1 (0.50g, 1.60mmol), 10% Pd / C (1.50g), and methanol (10mL) in sequence, replace with hydrogen, stir at room temperature for 3h, filter, and concentrate the filtrate under reduced pressure to obtain compound H-26-2, 0.35g of yellow solid, with a yield of 77.8%.

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

[0340] According to the synthesis method of B-44 in Example 27, the raw material was replaced with H-26-3 (0.19 g, 0.36 mmol) to obtain compound H-26, 0.11 g of 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] Embodiment 49 :1-Oxoisoindolin-5-yl-2-fluoro-4-guanidine benzoate hydrochloride (H-17)

[0343]

[0344] In a 100 mL single-mouth bottle, add H-27-1 (0.31 g, 1.34 mmol) prepared in Example 42 and pyridine (10 mL). After dissolution, add 5-hydroxyisoindole-1-one (0.20 g, 1.34 mmol), DCC (0.41 g, 2.01 mmol), and DMAP (0.03 g, 0.27 mmol) in sequence. Refer to Example 5 for synthesis and post-treatment to obtain 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] Embodiment 50 :1-Bromo-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-36)

[0347]

[0348] In a 100 mL single-necked bottle, add eplerenone (1.00 g, 6.17 mmol), NBS (1.21 g, 6.79 mmol), glacial acetic acid (0.40 g), and acetonitrile (10 mL) in sequence, react at room temperature overnight, filter, and purify the filter cake by column chromatography (DCM: MeOH = 100: 1) to obtain compound H-36-1, 0.32 g of pink solid, with a yield of 21.3%.

[0349] According to the method of Example 5, the raw material was replaced with H-36-1 (0.20 g, 0.83 mmol) to obtain compound H-36, 0.12 g of 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] Embodiment 51 :1,3-Dibromo-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-37)

[0352]

[0353] In a 100 mL single-necked bottle, 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 in sequence, and the reaction was allowed to react at room temperature overnight. 60 mL of water was added, and EA (100 mL*3) was used for extraction. 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 used for slurrying, and the mixture was filtered off with suction. The filter cake was dried under vacuum at 45 ° C for 8 h to obtain compound H-37-1, 2.50 g of a yellow solid, with a yield of 63.3%.

[0354] According to the method of Example 5, the raw 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] Embodiment 52 :1-Chloro-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine 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 bottle, and the mixture was reacted at 80 °C overnight. The mixture was filtered and purified by column chromatography (DCM: MeOH = 100: 1) to obtain compound H-38-1, 0.50 g of a pink solid, with a yield of 41.7%.

[0359] According to the method of Example 5, the raw material was replaced with H-38-1 (0.30 g, 1.53 mmol) to obtain compound H-38, 0.25 g of 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] Embodiment 53 :3-amino-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-40)

[0362]

[0363] According to the synthesis method of H-22-1 in Example 44, the raw material was replaced with 6-methoxy-1-tetralone (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] According to the synthesis method of H-22-2 in Example 44, the raw material was replaced with H-40-1 (2.50 g, 11.10 mmol) to obtain compound H-40-2, 1.05 g of brown solid, with a yield of 45.6%.

[0365] In a 100mL single-necked bottle, add H-40-2 (1.00g, 4.83mmol), 10% Pd / C (1.50g), and methanol (10mL) in sequence, introduce hydrogen, stir at room temperature for 3h, filter, and concentrate the filtrate under reduced pressure to obtain compound H-40-3, 0.50g of a 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 bottle and stirred at room temperature for 3 h. 30 mL of water was added, and 1 M HCl aqueous solution was used to adjust the pH to 4. DCM (50 mL*3) was used for extraction. The organic phase was concentrated under reduced pressure, and 3 mL of methanol was used for pulping and purification. 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, and the yield was 46.2%.

[0367] According to the method of Example 5, the raw material was replaced with H-40-4 (0.49 g, 1.30 mmol) to obtain compound H-40, 0.17 g of 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] Embodiment 54 :2-oxoindole-6-yl 2-fluoro-4-guanidine benzoate hydrochloride (H-42)

[0370]

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

[0372] In a 100mL single-necked bottle, add H-27-1 (0.31g, 1.34mmol), dissolve pyridine (10mL), and then add H-42-1 (0.20g, 1.34mmol), DCC (0.41g, 2.01mmol), and DMAP (0.03g, 0.26mmol). Refer to Example 5 for synthesis and post-treatment to obtain compound H-42, 0.20g 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] Embodiment 55 :1-Bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-43)

[0375]

[0376] In a 100 mL single-necked bottle, 6-hydroxy-1-tetralone (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 in sequence, stirred at room temperature for 6 h, filtered, and purified by filter cake column chromatography (DCM: MeOH = 100: 1) to obtain compound H-43-1, 0.80 g of pink solid, with a yield of 26.9%.

[0377] According to the method of Example 5, the raw material was replaced with H-43-1 (0.50 g, 2.07 mmol) to obtain compound H-43, 0.25 g of 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] Embodiment 56:3-methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-44)

[0380]

[0381] 2-Carboxyethyltriphenylphosphonium bromide (5.40 g, 13.00 mmol), THF (13 mL) and DMSO (13 mL) were added to a 250 mL single-necked bottle, 60% NaH (1.28 g, 53.28 mmol) was added in batches at -5 °C, stirred for 10 min, 3-methoxy-4-methylbenzaldehyde (2.00 g, 13.32 mmol) in THF (1 mL) and DMSO (1 mL) was added dropwise, reacted at room temperature overnight, 100 mL of ice water was added, stirred for 10 min, extracted with EA (100 mL*3), and purified by organic phase column chromatography (PE:EA=4:1) to obtain compound H-44-1, 1.00 g of yellow solid, yield 37.0%.

[0382] In a 100 mL single-necked bottle, add H-44-1 (1.00 g, 4.28 mmol), 10% Pd / C (2.00 g), and methanol (10 mL) in sequence, replace with hydrogen, stir at room temperature for 3 h, filter, and concentrate the filtrate under reduced pressure to obtain compound H-44-2, 0.90 g of a white solid, with a yield of 89.1%.

[0383] Add H-44-2 (0.90 g, 4.32 mmol) and PPA (4.50 g) to a 100 mL single-necked bottle, stir at 90 °C for 3 h, add 50 mL of ice water, extract with EA (50 mL*3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain compound H-44-3, 0.70 g of a yellow solid, with a yield of 85.4%.

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

[0385] According to the method of Example 5, the raw material was replaced with H-44-4 (0.28 g, 1.59 mmol) to obtain compound H-44, 0.22 g of 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] Embodiment 57 :3-Fluoro-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-guanidine benzoate hydrochloride (H-45)

[0388]

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

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

[0391] According to the synthesis method of H-44-3 in Example 56, the raw 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] According to the synthesis method of H-22-2 in Example 44, the raw material was replaced with H-45-3 (0.80 g, 4.12 mmol) to obtain compound H-45-4, 0.40 g of brown solid, with a yield of 53.9%.

[0393] According to the method of Example 5, the raw material was replaced with H-45-4 (0.40 g, 2.22 mmol) to obtain compound H-45, 0.51 g of 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-guanidinobenzoate trifluoroacetate (H-46)

[0396]

[0397] In a 100 mL single-necked bottle, 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 in sequence. The mixture was reacted at room temperature overnight. 100 mL of water was added, stirred for 10 min, and filtered. The filter cake was dried in vacuo at 45 ° C for 8 h to obtain compound H-46-1, 4.00 g of white solid, with a yield of 78.4%.

[0398] In a 100mL single-necked bottle, add H-46-1 (4.00g, 11.16mmol) and EA (20mL), add 10mL of hydrogen chloride ethyl acetate solution (4mol / l) with stirring, react at room temperature overnight, add 100mL of water, stir for 10min, filter, and dry the filter cake in vacuo at 45°C for 8h to obtain compound H-46-2, 3.00g of gray solid, yield 91.5%.

[0399] In a 100 mL single-necked bottle, 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 in sequence, stirred at room temperature for 3 h, 100 mL of water was added, stirred for 10 min, filtered, and the filter cake was dried in vacuo at 45 ° C for 8 h to obtain compound H-46-3, 2.50 g of a yellow solid, with a yield of 78.1%.

[0400] In a 250 mL single-necked bottle, 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 in sequence, reacted at 80 ° C for 4 h, filtered while hot, and the filtrate was concentrated under reduced pressure. EA (50 mL * 3) was extracted and purified by organic phase column chromatography (DCM: MeOH = 10: 1) to obtain compound H-46-4, 0.71 g of yellow solid, with a yield of 31.6%.

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

[0402] According to the synthesis method of B-44 in Example 27, the raw material was replaced with H-46-5 (0.55 g, 1.05 mmol) to obtain compound H-46, 0.32 g of 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] Embodiment 59 :2-Methyl-1-oxoisoindolin-5-yl-4-guanidinobenzoate hydrochloride (H-47)

[0405]

[0406] Add 4-methoxy-2-methylbenzoic acid (5.00 g, 30.09 mmol), SOCl2 (10.74 g, 90.27 mmol) and methanol (50 mL) into a 250 mL single-necked bottle, stir at 80 ° C for 3 h, and concentrate under reduced pressure to obtain compound H-47-1, 5.03 g of yellow solid, with a yield of 90.8%.

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

[0408] In a 100 mL single-necked bottle, add 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) to dissolve, stir at 70 ° C for 5 h, filter, and purify the filtrate by column chromatography (DCM: MeOH = 30: 1) to obtain compound H-47-3, 0.51 g of yellow solid, yield 49.5%.

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

[0410] According to the method of Example 5, the raw material was replaced with H-47-4 (0.25 g, 1.53 mmol) to obtain compound H-47, 0.27 g of 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] Embodiment 60 :3,3-Difluoro-2-oxoindolyl-5-yl-4-guanidinobenzoate 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-mouth bottle. Diethylaminosulfur trifluoride (8.9 g, 55.30 mmol) was added at -10 °C, and the mixture was stirred at room temperature for 12 h. 100 mL of purified water was added, and EA (100 mL*3) was used for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (DCM: MeOH = 100: 1). The compound H-48-1 was concentrated under reduced pressure to obtain 4.75 g of a yellow solid with a yield of 86.4%.

[0415] In a 250 mL single-necked bottle, H-48-1 (1.00 g, 4.03 mmol), bis(pinacol)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), 1,4-dioxane (20 mL) were added and dissolved, stirred at 100 °C for 12 h, and cooled to room temperature. After warming, sodium perborate tetrahydrate (1.55 g, 10.07 mmol) and purified water (20 mL) were added, 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 the filtrate was purified by column chromatography (DCM: MeOH = 100: 1). It was concentrated under reduced pressure to obtain compound H-48-2, 0.65 g of a yellow solid, with a yield of 86.7%.

[0416] According to the method of Example 5, the raw 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] Embodiment 61 :6-Chloro-2-oxoindolin-5-yl-4-guanidinobenzoate hydrochloride (H-49)

[0419]

[0420] In a 100 mL single-necked bottle, 5-methoxyindolin-2-one (0.8 g, 4.90 mmol), NCS (0.98 g, 7.35 mmol), aluminum chloride (0.65 g, 4.90 mmol), and acetonitrile (20 mL) were added 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 obtain compound H-49-1, 0.51 g of white solid, with a yield of 52.6%.

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

[0422] According to the method of Example 5, the raw material was replaced with H-49-2 (0.22 g, 1.20 mmol) to obtain compound H-49, 0.26 g of 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] Embodiment 62 :Benzo[d]oxazol-5-yl-4-guanidinobenzoate hydrochloride (H-50)

[0425]

[0426] In a 100 mL single-mouth bottle, add 2-amino-4-methoxyphenol (4.00 g, 28.74 mmol) and triethyl orthoformate (40 mL), stir at 100 ° C for 12 h, filter, cool to room temperature, add 200 mL of purified water, extract with EA (100 mL*3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and purify the filtrate by column chromatography (DCM: MeOH = 100: 1) to obtain compound H-50-1, 3.6 g of red solid, yield 83.7%.

[0427] According to the synthesis method of B-15-3 in Example 8, the raw 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] According to the method of Example 1, the raw material was replaced with H-50-2 (0.30 g, 2.22 mmol) to obtain compound H-50, 0.32 g of 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] Embodiment 63 :Benzo[d]oxazol-5-yl-4-guanidinobenzoate hydrochloride (H-51)

[0431]

[0432] According to the method of Example 5, the raw material was replaced with H-50-2 (0.20 g, 1.48 mmol) to obtain compound H-51, 0.12 g of 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] Embodiment 64 :6-Fluoro-1-oxoisoindolin-5-yl-4-guanidinobenzoate hydrochloride (H-52)

[0435]

[0436] According to the synthesis method of H-47-1 in Example 59, the raw 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] According to the synthesis method of H-47-2 in Example 59, the raw material was replaced with H-52-1 (5.10 g, 20.64 mmol) to obtain compound H-52-2, 5.70 g of white solid, with a yield of 84.7%.

[0438] In a 100mL single-necked bottle, add H-52-2 (4.00g, 12.27mmol) and dissolve it in 7mol / L ammonia methanol solution (40mL). Stir at 70℃ for 3h, filter, and dry the filter cake in vacuo at 45℃ for 8h to obtain compound H-52-3, 2.32g of yellow solid, with a yield of 82.3%.

[0439] According to the synthesis method of H-48-2 in Example 60, the raw 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] According to the method of Example 5, the raw material was replaced with H-52-4 (0.18 g, 1.08 mmol) to obtain compound H-52, 0.15 g of 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] Embodiment 65 :6-Nitro-1-oxoisoindolin-5-yl-4-guanidinobenzoate hydrochloride (H-53)

[0443]

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

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

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

[0447] In a 100 mL single-necked bottle, add H-53-3 (1.37 g, 4.51 mmol) and dissolve it in 7 mol / L ammonia methanol solution (20 mL). Stir at 70 °C for 3 h and purify by column chromatography (DCM:MeOH=100:1) to obtain compound H-53-4, 0.60 g of a yellow solid, with a yield of 63.8%.

[0448] According to the synthesis method of B-15-3 in Example 8, the raw 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] According to the method of Example 5, the raw 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] Embodiment 66 :2-Ethyl-1-oxoisoindolin-5-yl-4-guanidinobenzoate hydrochloride (H-54)

[0452]

[0453] In a 100 mL single-necked bottle, add H-47-2 (1.35 g, 5.21 mmol), ethylamine (5.40 g), and methanol (20 mL) to dissolve, stir at 70 ° C for 5 h, and purify by column chromatography (DCM: MeOH = 30: 1) to obtain compound H-54-1, 0.71 g of yellow solid, yield 71.2%.

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

[0455] According to the method of Example 5, the raw material was replaced with H-54-2 (0.20 g, 1.13 mmol) to obtain compound H-54, 0.25 g of 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 , Compounds' inhibitory activity against TMPRSS2 enzyme

[0458] 1. Research Methods

[0459] This study used a method based on TMPRSS2 fluorescence biochemical analysis to determine the enzyme inhibitory activity of the target on TMPRSS2. The peptide substrate Boc-Gln-Ala-Arg-AMC contains the fluorescent chromophore 7-amino-4-methylcoumarin (AMC). Recombinant TMPRSS2 releases AMC after cleaving the substrate, and AMC produces fluorescence. The fluorescence is monitored by a multifunctional microplate reader at an excitation wavelength of 340nm and an emission wavelength of 440nm. This method is characterized by high accuracy and is suitable for high-throughput screening, and can efficiently complete enzyme activity screening.

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

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

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

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

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

[0465] 1.3 After the TMPRSS2 enzyme is completely thawed, take 12 μL of TMPRSS2 enzyme stock solution and add it to 1327 μL 1X Assay Buffer. At this time, the concentration of the enzyme dilution is 0.2 μM. Take 10 μL / well and add it to the white microplate. At this time, the concentration of TMPRSS2 enzyme in each well is 0.1 μM; add 10 μL / well 1X buffer to the blank control well;

[0466] Please perform this step on ice. After adding, centrifuge the microplate at 1000 rpm for 1 minute.

[0467] 1.4 Prepare 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] Please perform this step on ice;

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

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

[0472] 1.7 After the incubation, perform fluorescence intensity detection on a plate reader and read the fluorescence value (Excitation at 340nm and emission at 440nm);

[0473] 1.8 Calculation of enzyme inhibition rate:

[0474]

[0475] 1.9 Half inhibitory concentration (IC 50): The enzyme inhibition rates of camostat mesylate and some compounds of the present application at concentrations of 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM were tested by the aforementioned enzyme inhibition test method. Two groups of inhibition rates were measured in parallel for each concentration, and the average value of the two groups of data was taken. The concentration was used as the horizontal axis and the TMPRSS2 enzyme activity inhibition rate was used as the vertical axis. Data fitting was performed according to the horizontal and vertical coordinates to obtain a dose-effect curve, and the corresponding IC was calculated according to the dose-effect curve. 50 .

[0476] 2. Experimental results

[0477] First, some targets were subjected to Singledose screening test (20nM) to screen out targets with inhibitory potential, and then gradient antienzyme activity test was performed on targets with good inhibitory effect to obtain the dose-effect curve and the corresponding IC 50 value.

[0478] 2.1TMPRSS2 enzyme inhibition screening data:

[0479]

[0480]

[0481] 2.2 Partial enzyme inhibition activity test dose-effect curve:

[0482] The enzyme inhibition rates of camostat mesylate and some compounds of the present application at concentrations of 100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM, 0.032 nM, and 0.0064 nM were tested by the test method of enzyme inhibition rate in Biological Example 1. Two groups of inhibition rates were measured in parallel for each concentration, and the average value of the two groups of data was taken. The concentration was used as the horizontal axis and the average value of the compound inhibition rate was used as the vertical axis. Data fitting was performed according to the horizontal and vertical coordinate results to obtain a dose-effect curve of camostat mesylate and some compounds of the present application (see Appendix). Figure 1-3 ).

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

[0484] From the table above and the instructions attached Figure 1-3 It can be seen that the inhibition rate of the compounds is well fitted with the curve. Compounds B-4, B-13, B-14, B-18, B-24, B-49, H-22, H-44, H-45, H-47 (IC 50 <2.00nM), the inhibitory effect on TMPRSS2 was significantly better than that of camostat mesylate; compounds B-12, B-21, H-26, etc. (2.00nM≤IC 50≤4.00nM), with good inhibitory effect on TMPRSS2; compounds B-41, C01, H-17, etc. (4.00nM≤IC 50 ≤7.00nM), and its inhibitory effect on TMPRSS2 was comparable to that of camostat mesylate.

[0485] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An aromatic formyl compound or a pharmaceutically acceptable salt thereof having a structure as shown in Formula I: in, Ring B represents R 1 Substituted or unsubstituted benzene ring, R 1 a substituted or unsubstituted five-membered or six-membered heteroaromatic ring; R 1 is a mono- or poly-substituted group, independently representing H, F, Cl, Br, C1-C5 alkyl, 1-3 halogenated C1-C5 alkyl, C1-C5 alkoxy, 1-3 halogenated C1-C5 alkoxy, or NO2; Ring A represents R 2 The substituted benzene ring or ring A represents the following bicyclic structure: R 2 is a mono- or poly-substituted group, independently representing H, hydroxyl, amino, C1-C5 alkyl, 1-3 halogenated C1-C5 alkyl, C1-C5 alkoxy, 1-3 halogenated C1-C5 alkoxy, C2-C5 ester, carbamoyl-substituted phenyl, cyano-substituted phenyl, R 3 represents C1-C5 alkyl, C3-C6 cycloalkyl, -C(O)NR x R y ; R x , R y Independently represents H, C1-C5 alkyl; R 4 Represents H, C1-C5 alkyl.

2. The aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The ring B represents R 1 Substituted or unsubstituted benzene ring, R 1 Substituted or unsubstituted pyridine; R 1 is a mono- or poly-substituted group, independently representing H, F, Cl, Br, methoxy, methyl, nitro, trifluoromethyl; The R 2 is a mono- or poly-substituted group, independently representing H, trifluoromethyl, amino, hydroxyl, carbamoyl-substituted phenyl, cyano-substituted phenyl, R 3 Represents isopropyl, cyclopropyl, -C(O)NR x R y ; R x , R y Independent representatives H, methyl; R 4 It represents H, methyl, and ethyl.

3. The aromatic formyl compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, characterized in that: 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; The 1-3 halogenated C1-C5 alkyl group is selected from —CF3, —CH2CF3, —(CH2)2CF3, —(CH2)3CF3, —(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 group is selected from -OCF3, -OCH2CF3, -O(CH2)2CF3, -O(CH2)3CF3, -O(CH2)4CF3; The five-membered or six-membered heteroaromatic ring is selected from pyridine, furan, pyrrole, thiophene, and thiazole; 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; The C3-C6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexane.

4. The aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The ring A represents the following structure:

5. The aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is selected from acetate, trifluoroacetate, methanesulfonate, hydrochloride, phosphate or sulfate.

6. The aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The aromatic formyl compound represented by formula I or its pharmaceutically acceptable salt is selected from the following:

7. A method for preparing the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that: Choose from any of the following routes: Route 1: Dissolve substrate b in pyridine, add substrate a, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, stir at room temperature, filter with suction, and purify the filter cake or filtrate 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, and leave at room temperature overnight. Post-treatment gives product f.

8. A pharmaceutical composition comprising the aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and optionally, one or more pharmaceutically acceptable carriers or excipients.

9. Use of the aromatic formyl compound of the structure represented by formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting the transmembrane serine protease TMPRSS2.

10. Use of the aromatic formyl compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of antiviral drugs, characterized in that: The virus includes the new coronavirus or its variants.

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