Diphenylmethane derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a diphenylmethane derivative as well as a preparation method and application thereof. The diphenylmethane derivative is a compound as shown in a formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: # imgabs0 #, wherein X is CH2; y is selected from-NH <->,-CO <->,-NHCONH <->, # imgabs1 # imgabs2 #. The diphenylmethane derivative disclosed by the invention is stable in property, easy to preserve, easy to prepare and good in realizability. The compound has prominent in-vivo and in-vitro drug effects and good safety when being used for preparing anti-cardiac protection drugs (heart failure and cardiac hypertrophy).

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to diphenylmethane derivatives and preparation methods and applications thereof. Background Art

[0002] Heart failure (HF) is regarded as the end stage of various cardiovascular diseases, which is characterized by poor prognosis and high mortality. HF mainly occurs in elderly patients over 60 years old, and sometimes in younger patients who survive acute myocardial infarction (MI). HF can be induced by many reasons, including coronary artery disease (CAD), hypertension, diabetes, family history of heart disease, obesity, chronic lung disease or the use of cardiotoxins. Among them, ischemic heart disease caused by impaired myocardial perfusion is considered to be the most common cause of heart failure. Despite progress in the treatment of heart failure with the combination of several drugs (including RASi, β-blockers, MRAs and SGLT2 inhibitors), there is still no single drug that can reduce the mortality of heart failure.

[0003] Sodium hydrogen exchanger 1 (NHE1) is encoded by the SLC9A1 gene and is a membrane transporter belonging to the mammalian Na+ / H+ exchanger (NHE) gene family. It is reported that the NHE family contains at least 9 isoforms, whose function is to exchange extracellular Na+ for intracellular H+. NHE1 is the only isoform present in cardiomyocytes and can regulate the homeostasis of sodium and calcium ions. Animal experimental results show that NHE1 gene knockout has a cardioprotective effect during ischemia and reperfusion. Knocking out NHE1 can find better recovery of left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVDP) and coronary flow. This makes NHE1 considered a promising target for cardioprotection.

[0004] The current clinical treatment of heart failure is effective, but generally not satisfactory. How to develop more anti-heart failure drugs and improve the cure rate of patients is still a scientific problem that needs to be solved urgently. Summary of the invention

[0005] The purpose of the present invention is to provide a diphenylmethane derivative, a preparation method thereof and application thereof in treating heart failure.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] A diphenylmethane derivative, which is a compound represented by formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Among them, X is CH 2 ;

[0010] Y is selected from: -NH-, -CO-, -NHCONH-

[0011] When the said Y is it may be substituted by 1 - 3 Rs 7 ; R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl;

[0012] R 1 is selected from: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, -C(=NH)NH 2 , acylguanidyl, substituted acylguanidyl, guanidyl, substituted guanidyl, iminoamide group, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, CO-(C 1 -C 6 alkyl), substituted CO-(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, C5 - C14 heteroaromatic ring, substituted C5 - C14 heteroaromatic ring, aryl, substituted aryl; the substituent is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;

[0013] R 2 is selected from: hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl;

[0014] R 3 is selected from: hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl;

[0015] R 4 is OR 5 ;

[0016] R 5 is selected from C 1 -C 6 alkyl, substituted C 1 -C 6Alkyl, C5-C14 aryl heterocycle, substituted C5-C14 aryl heterocycle; wherein, the C5-C14 aryl heterocycle contains 1-3 heteroatoms, and the heteroatoms are N, O or S atoms; wherein, the substituted C5-C14 aryl heterocycle is substituted by 1-3 identical or different R 6 substituted;

[0017] R 6 is selected from hydrogen, halogen, C 1 -C 6 alkyl.

[0018] In one preferred embodiment, the aryl is selected from: phenyl, naphthyl, anthryl, phenanthryl, pyrenyl.

[0019] The substituted aryl is a substituent of phenyl, naphthyl, anthryl, phenanthryl, pyrenyl.

[0020] In one preferred embodiment, CO-(C 1 -C 6 alkyl) is selected from: -CO-CH 3 、-CO-CH 2 CH 3 、-CO-CH 2 CH 2 CH 3 、-CO-CH 2 (CH 3 ) 2 、-CO-CH 2 CH 2 CH 2 CH 3 .

[0021] In one preferred embodiment, R 1 is -NHC(=NH)NH 2 .

[0022] In one preferred embodiment, when R 1 or R 5 is a C5-C14 aryl heterocycle or a substituted C5-C14 aryl heterocycle, the C5-C14 aryl heterocycle is selected from: pyridine, pyrazine, pyrimidine, pyrazine, pyridazine, pyran, piperidine, piperazine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, dioxane, hexahydropyrazine, morpholine, dithiane; the substituted C5-C14 aryl heterocycle is a substituent of the C5-C14 aryl heterocycle.

[0023] In one preferred embodiment, when R 1 is C 1 -C 6 alkoxy, C 1 -C 6 alkoxy is selected from: -O-CH3 、 -O-CH 2 CH 3 、 -O-CH 2 CH 2 CH 3 、 -O-CH 2 (CH 3 ) 2 、 -O-CH 2 CH 2 CH 2 CH 3 。

[0024] In one preferred embodiment, when R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl is selected from: -CH 3 、 -CH 2 CH 3 、 -CH 2 CH 2 CH 3 、 -CH 2 (CH 3 ) 2 、 -CH 2 CH 2 CH 2 CH 3 。

[0025] In one preferred embodiment, R 2 is selected from C 1 -C 4 alkyl;

[0026] In one preferred embodiment, R 3 is selected from C 1 -C 4 alkyl;

[0027] In one preferred embodiment, R 6 is selected from C 1 -C 4 alkyl.

[0028] In one preferred embodiment, when Y is -NHCONH- and R 1 is a substituted phenyl, the substituent is not methoxy.

[0029] In one preferred embodiment, Y is R 1 is not piperazine.

[0030] In one preferred embodiment, R4 For

[0031] Based on the same inventive concept, the present invention also claims to protect another diphenylmethane derivative, which is a compound represented by formula I, its optical isomer or its pharmaceutically acceptable salt:

[0032]

[0033] Wherein, X is CO;

[0034] Y is selected from: -NH-, -CO-, -NHCONH-,

[0035] When said Y is it may be substituted by 0 - 3 R 7 ; R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl;

[0036] R 1 is selected from: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, -CONHC(=NH)NH 2 -, -C(=NH)NH 2 -, acylguanidyl, substituted acylguanidyl, guanidyl, substituted guanidyl, imide amide group, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, C5 - C14 heteroaryl, substituted C5 - C14 heteroaryl, aryl, substituted aryl; the substituent is selected from halogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkoxy, C 1 -C 6 alkoxy;

[0037] R 2 is selected from: hydrogen, halogen, C 1 -C 6 alkyl;

[0038] R 3 is selected from: hydrogen, halogen, C 1 -C 6 alkyl;

[0039] R 4 is OR 5 ;

[0040] R 5 selected from C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C5-C14 aryl heterocycle, substituted C5-C14 aryl heterocycle; wherein, the C5-C14 aryl heterocycle contains 1-3 heteroatoms, and the heteroatoms are N, O or S atoms; wherein, the substituted C5-C14 aryl heterocycle is substituted by 1-3 identical or different R 6 substituents;

[0041] R 6 selected from hydrogen, halogen, C 1 -C 6 alkyl.

[0042] In one preferred embodiment, the aryl is selected from: phenyl, naphthyl, anthryl, phenanthryl, pyrenyl.

[0043] The substituted aryl is a substituent of phenyl, naphthyl, anthryl, phenanthryl, pyrenyl.

[0044] In one preferred embodiment, when R 1 is a substituted aryl, the substituents are selected from halogen, C 1 -C 4 alkyl, halo C 1 -C 4 alkoxy, C 1 -C 4 alkoxy.

[0045] In one preferred embodiment, when R 1 is a substituted aryl, the substituents are selected from monohalomethoxymethane, dihalomethoxymethane, trihalomethoxymethane, monohaloethoxymethane, dihaloethoxymethane, trihaloethoxymethane, monohalopropoxymethane, dihalopropoxymethane, trihalopropoxymethane; the halogen elements are selected from: fluorine, chlorine, bromine, iodine.

[0046] In one preferred embodiment, R 1 is -NHC(=NH)NH 2 ,

[0047] In one preferred embodiment, when R 1 or R 5 is a C5-C14 aryl heterocycle or a substituted C5-C14 aryl heterocycle, the C5-C14 aryl heterocycle is selected from: pyridine, pyrazine, pyrimidine, pyrazine, pyridazine, pyran, piperidine, piperazine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, dioxane, hexahydropyrazine, morpholine, dithiane; the substituted C5-C14 aryl heterocycle is a substituent of the C5-C14 aryl heterocycle.

[0048] In one preferred embodiment, R 1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is selected from: -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH 2 (CH 3 ) 2 , -O-CH 2 CH 2 CH 2 CH 3 .

[0049] In one preferred embodiment, R 1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is selected from: -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 .

[0050] In one preferred embodiment, R 2 is selected from C 1 -C 4 alkyl;

[0051] In one preferred embodiment, R 3 is selected from C 1 -C 4 alkyl;

[0052] In one preferred embodiment, R 6 is selected from C 1 -C 4 alkyl.

[0053] In one preferred embodiment, R 4 is

[0054] In one preferred embodiment, Y is -NHCONH-, R 4 is When R 1 is not cyclohexyl or

[0055]

[0056] In one preferred embodiment, the diphenylmethane derivative is the following compound, its optical isomer or its pharmaceutically acceptable salt:

[0057] (R)-4-chloro-N-(diaminomethylene)-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}benzamide;

[0058] (R)-5-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-1,2,4-oxadiazol-3-amine;

[0059] (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carbonitrile;

[0060] (R)-[4-chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone;

[0061] (R)-{2-chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone;

[0062] (R)-[4'-amino-4-chloro-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone;

[0063] (R)-[4-chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone;

[0064] (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-ol;

[0065] (R)-5-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-2-(piperidin-1-yl)pyridine;

[0066] (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-amine;

[0067] (R)-1-{4'-Chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine;

[0068] (S)-1-{4'-Chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine;

[0069] (R)-1-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}piperazine;

[0070] (R)-N-Carbamoyl-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carboxamide;

[0071] (R)-1-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-3-(4-methoxyphenyl)urea;

[0072] (R)-1-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-3-(2-ethylphenyl)urea;

[0073] (R)-N-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}acetamide;

[0074] (R)-1-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}guanidine;

[0075] 4'-Chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carbonitrile;

[0076] [4-Chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone;

[0077] {2-Chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}(4-ethoxyphenyl)methanone;

[0078] [4'-Amino-4-chloro-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone;

[0079] [4-Chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone;

[0080] [2-Chloro-5-(piperazin-1-yl)phenyl](4-ethoxyphenyl)methanone;

[0081] N-carbamoyl-4'-chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carboxamide;

[0082] (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-cyclohexylurea;

[0083] (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-(4-methoxyphenyl)urea;

[0084] (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-[4-(trifluoromethoxy)phenyl]urea;

[0085] 1-[2-chloro-5-(4-ethoxybenzoyl)phenyl]-3-cyclohexylurea;

[0086] 1-[2-chloro-5-(4-ethoxybenzoyl)phenyl]-3-(4-methoxyphenyl)urea;

[0087] 1-[2-chloro-5-(4-ethoxybenzoyl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea;

[0088] In one preferred embodiment, the pharmaceutically acceptable salts of the diphenylmethane derivatives include inorganic acid addition salts and organic acid addition salts; the inorganic acids and inorganic acid include: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.

[0089] Based on the same inventive concept, the present invention also claims the preparation method of the diphenylmethane derivatives, wherein the intermediate M1 or M2 undergoes a deprotection reaction in a reaction solvent to obtain the diphenylmethane derivatives.

[0090] The intermediate M1 is:

[0091] The intermediate M2 is:

[0092] In one preferred embodiment, in the above preparation method, Y is a benzene ring, and R 1 is R 2 is H, and R 3 is Cl.

[0093] In one preferred embodiment, the reaction solvent is one or more of tetrahydrofuran, trifluoroacetic acid, hydrochloric acid, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, dichloromethane, methanol, and water.

[0094] The reaction route is Route 1:

[0095]

[0096] In one preferred embodiment, when Y is a benzene ring, R 1 is NH 2 and R 2 is H, and R 3 is Cl, the preparation method is as follows: Intermediate M3 or M4 undergoes a deprotection reaction in the reaction solvent to obtain the diphenylmethane derivative.

[0097] Intermediate M3 is:

[0098] Intermediate M4 is:

[0099] In one preferred embodiment, the reaction solvent is one or more of tetrahydrofuran, trifluoroacetic acid, hydrochloric acid, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, dichloromethane, methanol, or water.

[0100] The reaction route is Route 2:

[0101]

[0102] In one preferred embodiment, when R 1 is H, R 2 is H, and R 3 is Cl, and Y is the preparation method is as follows: Intermediate M5 or M6 undergoes a deprotection reaction in the reaction solvent to obtain the diphenylmethane derivative.

[0103] Intermediate M5 is:

[0104] Intermediate M6 is:

[0105] In one preferred embodiment, the reaction solvent is one or more of tetrahydrofuran, trifluoroacetic acid, hydrochloric acid, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, dichloromethane, methanol, or water.

[0106] The reaction route is Route 3:

[0107]

[0108] In one preferred embodiment, when R 1 is H, R 2 is H, R 3 is Cl, X is CH 2 , Y is , the preparation method is as follows: Intermediate V-1 or IV-3 undergoes Buchwald coupling reaction with N-Boc piperazine to obtain Intermediate M5 or M6; Intermediate M5 or M6 undergoes deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative,

[0109] Intermediate V-1:

[0110] Intermediate V-3:

[0111] Intermediate M5 is:

[0112] Intermediate M6 is:

[0113] In one preferred embodiment, the reaction system used in the Buchwald coupling reaction includes an inorganic base, an organic base, and a solvent; the inorganic base is one or two of potassium carbonate or sodium carbonate; the organic base is one or two of sodium tert-butoxide or potassium tert-butoxide; the solvent is one or two of water or 1,4-dioxane.

[0114] The reaction route for Intermediate V-1 or IV-3 to undergo Buchwald coupling reaction with N-Boc piperazine to obtain Intermediate M5 or M6 is Route 4:

[0115]

[0116] The reaction route for Intermediate M5 or M6 to undergo deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative is Route 3.

[0117] In one preferred embodiment, the synthesis of Intermediate IV-3 is Route 6:

[0118]

[0119] Intermediate V-1 / V-2 is prepared by Friedel-Crafts acylation reaction of starting material II with phenol to obtain Intermediate III, followed by Mitsunobu reaction and reduction reaction. Intermediate IV-3 is prepared by Friedel-Crafts acylation reaction of starting material II with phenetole; the reduction reaction includes: aluminum trichloride / disiloxane system.

[0120] In one preferred embodiment, when R 2 is H, R 3When X is Cl and Y is a C5-C14 heteroaromatic ring, the preparation method is as follows: Intermediate IV and V undergo a Suzuki coupling reaction with a substituted boric acid or a substituted borate ester to obtain Intermediates M1 and M2; Intermediate M1 or M2 undergoes a deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative.

[0121] Intermediate IV:

[0122] Intermediate V:

[0123] Intermediate M1 is:

[0124] Intermediate M2 is:

[0125] In one preferred embodiment, the reaction system used for the Suzuki coupling reaction includes an inorganic base and a solvent; the inorganic base is one or both of potassium carbonate and sodium carbonate; the solvent is one or both of water and 1,4-dioxane.

[0126] The reaction route for Intermediate IV and V to undergo a Suzuki coupling reaction with a substituted boric acid or a substituted borate ester to obtain Intermediates M1 and M2 is Route 5:

[0127]

[0128] The reaction for Intermediate M1 or M2 to undergo a deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative is Route 1.

[0129] In one preferred embodiment, when Y is NHCONH, the preparation method is as follows: Intermediate X undergoes an N-acylation reaction with a carbamate to obtain the diphenylmethane derivative.

[0130] Intermediate X is:

[0131] In one preferred embodiment, the reaction system used for the N-acylation reaction includes an inorganic base and a solvent; the inorganic base is one or both of potassium carbonate and sodium carbonate; the solvent is tetrahydrofuran.

[0132] Its reaction route is Route 7:

[0133]

[0134] In one preferred embodiment, the preparation method of Intermediate X-1 follows Route 8; first, Intermediate VI undergoes a Friedel-Crafts acylation reaction to obtain Intermediate VII, and then Intermediate X-1 is prepared through Mitsunobu reaction, carbonyl reduction reaction, and nitro reduction reaction.

[0135] Its reaction route is Route 8:

[0136]

[0137] In one preferred embodiment, the preparation methods of intermediates X-2 and X-3 are according to Route 9: First, intermediate XI undergoes Friedel-Crafts acylation reaction to obtain intermediate XII, and then through Mitsunobu reaction and reduction reaction to obtain intermediate X-2; intermediate XI undergoes Friedel-Crafts acylation reaction and reduction reaction with phenetole to obtain X-3.

[0138] Its reaction route is Route 9:

[0139]

[0140] In one preferred embodiment, when X is CH 2 , Y is oxadiazole, R 1 is NH 2 , R 2 is H, R 3 is Cl, R 4 is at this time, the preparation method is: The compound of Structural Formula 1 undergoes cyclization reaction in a reaction solvent to obtain the diphenylmethane derivative.

[0141] Structural Formula 1 is:

[0142] In one preferred embodiment, the reaction solvent is one or more of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, and dichloromethane.

[0143] In one preferred embodiment, its reaction route is Route 10:

[0144]

[0145] In one preferred embodiment, when Y is carbonyl, R 1 is guanidine group, R 2 is H, R 3 is Cll, R 4 is at this time, the preparation method is: Intermediate V-1 undergoes formylation reaction with oxalic acid to obtain intermediate XIV, and then through N-acylation reaction to obtain the diphenylmethane derivative.

[0146] Intermediate V-1 is:

[0147] Intermediate XIV:

[0148] In one of the preferred embodiments, the reaction route is Route 11:

[0149]

[0150] In one of the preferred embodiments, when Y is a benzene ring, R1 is an acylguanidine group, R 2 is H, R 3 is Cl, and X is CO, the preparation method is as follows: Compound 2 undergoes base hydrolysis reaction to form a carboxyl compound XV, and then undergoes N-acylation reaction to obtain the diphenylmethane derivative.

[0151] Compound 2 is:

[0152] Compound XV:

[0153] In one of the preferred embodiments, the reaction route is Route 12:

[0154]

[0155] Based on the same inventive concept, the present invention also claims the use of the diphenylmethane derivative in the preparation of a drug for treating heart failure or myocardial hypertrophy.

[0156] Based on the same inventive concept, the present invention also claims the use of the diphenylmethane derivative in the preparation of an NHE1 inhibitor.

[0157] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0158] First, the diphenylmethane derivative of the present invention, its optical isomers, pharmaceutically acceptable salts, solvates or prodrugs have the advantages of stable product structure and easy storage.

[0159] Second, the preparation method is simple, with high purity. The required raw materials are commercially available and inexpensive. The reaction process is green and environmentally friendly, without causing pollution to the environment. The preparation of the compound is easy and has good feasibility.

[0160] Third, through experiments, the present invention proves that the product of the present invention has outstanding in vitro and in vivo pharmacodynamic effects and good safety in the preparation of anti-cardiac protection drugs (heart failure and myocardial hypertrophy). Description of the Drawings

[0161] Figure 1Cell protection data of compound 23 of the present invention; wherein Figure A shows the effect of compound 23 on the survival rate of normal rat cardiomyocytes; Figure B shows the protective effect of compound 23 on glucose-deprivation-induced cells; Figure C shows the protective effect of Cariporide on glucose-deprivation-induced cells; Figure D shows the protective effect of Empagliflozin on glucose-deprivation-induced cells;

[0162] Figure 2 SPR results of compound 23 of the present invention and NHE1 protein;

[0163] Figure 3 Therapeutic effect of compound 23 of the present invention on heart failure; wherein Figure A shows the effect of compound 23 on the left ventricular ejection fraction of an isoproterenol-induced heart failure model; Figure B shows the left ventricular shortening fraction. Detailed implementation manners

[0164] The present invention is not limited to the following specific implementation manners. Those of ordinary skill in the art can implement the present invention in other various specific implementation manners according to the content disclosed in the present invention, or those that adopt the design structure and concept of the present invention and make simple changes or modifications all fall within the protection scope of the present invention. It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other.

[0165] The nuclear magnetic resonance hydrogen spectrum of the compound was measured by Bruker ARX-400 / 600, and the mass spectrum was measured by Agilent 1100 LC / MSD; all the reagents used were of analytical grade or chemical pure grade.

[0166] The halogen is fluorine, chlorine, bromine or iodine; the alkyl is a straight-chain, branched-chain alkyl or cycloalkyl.

[0167] Example 1

[0168] Step A1 Synthesis of Intermediate III

[0169] The structural formula of Intermediate III is:

[0170]

[0171] At room temperature, 5-bromo-2-chlorobenzoic acid (0.5 g, 2.1 mmol) was placed in a 25 mL three-necked flask, 5.0 mL of dichloromethane (DCM) was added and stirred evenly. 0.1 mL of N,N-dimethylformamide (DMF) was added thereto, and thionyl chloride (0.31 mL, 4.3 mmol) was added dropwise under an ice bath (0 °C). After the addition was complete, the temperature was raised to 40 °C and the reaction was refluxed. After detecting that there was no raw material remaining by TLC, the reaction solution was distilled under reduced pressure to obtain a colorless liquid, which was directly put into the next reaction. The above-obtained acyl chloride was placed in a 25 mL three-necked flask, 5.0 mL of nitrobenzene was added and stirred evenly. Aluminum trichloride (0.6 g, 4.3 mmol) and phenol (0.2 g, 2.1 mmol) were slowly added to the mixture under an ice bath (0 °C), and the temperature was raised to 60 °C for reaction, and the reaction was monitored by TLC. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, a small amount of crushed ice was slowly added thereto to quench the reaction, then 10.0 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 min, 2 mL of hydrochloric acid (10 M) was slowly added thereto for acidification, and the reaction solution was extracted with dichloromethane (10.0 mL×3). The organic layers were combined, and dichloromethane was evaporated under reduced pressure to obtain a yellow oil. 10 mL of sodium hydroxide aqueous solution (2 M) was added to the yellow oil and stirred. The extraction was repeated three times with 10 mL of sodium hydroxide aqueous solution (2 M), the aqueous layers were combined, hydrochloric acid (10 M) was added for acidification to adjust the pH to about 2, the aqueous layer was extracted with ethyl acetate (12 mL×3), the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by suction filtration, the filtrate was evaporated to dryness to obtain a yellow oil, and then purified by column chromatography to obtain 0.32 g of a white solid with a yield of 48.5%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.75 (dd, J = 8.6, 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64–7.59 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H).

[0172] Synthesis of Intermediate Ⅳ-1 in Step A2

[0173] The structural formula of Intermediate Ⅳ-1 is:

[0174]

[0175] At room temperature, 0.2 g (0.65 mmol) of Intermediate III was placed in a 25 mL eggplant-shaped flask, 5.0 mL of tetrahydrofuran was added and stirred evenly, (S)-(+)-3-hydroxytetrahydrofuran (0.09 g, 1.0 mmol) and triphenylphosphine (0.25 g, 1.0 mmol) were added, and the mixture was stirred at room temperature for 10 min. Diisopropyl azodicarboxylate (0.2 g, 1.0 mmol) was slowly added dropwise under an ice bath (0 °C). The reaction solution was raised to room temperature and stirred for reaction. After the reaction was completed, 5.0 mL of water was added to the reaction solution to quench the reaction, and extraction was carried out with ethyl acetate (10.0 mL × 3). The organic layers were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by suction filtration, and the solvent was evaporated under reduced pressure to obtain 0.42 g of a yellow oily liquid. Subsequently, purification by column chromatography gave 0.24 g of a white solid with a yield of 79.2%. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 7.9 Hz, 1H), 7.73–7.67 (m, 1H), 7.61–7.54 (m, 1H), 7.13–7.05 (m, 1H), 5.16 (td, J = 5.4, 4.5, 2.1 Hz, 1H), 3.95–3.71 (m, 2H), 2.28 (dtd, J = 14.2, 8.2, 6.3 Hz, 1H), 2.03–1.92 (m, 1H).

[0176] Synthesis of Intermediate V-1 in Step A3

[0177] The structural formula of Intermediate V-1 is:

[0178]

[0179] At room temperature, 0.19 g (0.5 mmol) of Intermediate IV-1 was placed in a 25 mL three-necked flask, 5.0 mL of toluene was added and stirred evenly, aluminum trichloride (0.1 g, 0.75 mmol) was added to the solution, and tetramethyldisiloxane (0.13 mL, 0.75 mmol) was slowly added dropwise to the solution. The temperature was raised to 28 °C and stirred for reaction. After the reaction was completed, 5.0 mL of water was added to the reaction solution and stirred, and extraction was carried out with ethyl acetate (10.0 mL × 3). The organic layers were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by suction filtration, and the filtrate was evaporated to obtain 0.15 g of a yellow oily substance with a yield of 83.3%. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 2.4 Hz, 1H), 7.43–7.29 (m, 2H), 7.12–7.02 (m, 2H), 6.89–6.74 (m, 2H), 4.89 (ddd, J = 6.4, 4.1, 1.9 Hz, 1H), 3.91 (s, 2H), 3.81–3.61 (m, 3H), 2.19–1.80 (m, 1H).

[0180] Synthesis of Intermediate XIV in Step A4

[0181] The structural formula of Intermediate XIV is:

[0182]

[0183] At room temperature, 2.6 g of Intermediate V-1 was placed in a 100 mL three-necked flask, and palladium acetate (0.1 eq), xantphos (0.1 eq), oxalic acid dihydrate (1.5 eq) were added. Under argon protection, 30 mL of DMF, acetic anhydride (1.5 eq), and DIEA (1.5 eq) were added thereto with a syringe. The three-necked flask was placed in an oil bath preheated to 100 °C. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, and a white solid precipitated. The white solid was obtained by suction filtration with a yield of 49.7%. 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.3, 2.1 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.01–4.94 (m, 1H), 4.06 (s, 2H), 3.91–3.69 (m, 4H), 2.19 (dtd, J = 14.4, 8.2, 6.2 Hz, 1H), 2.06–1.88 (m, 1H).

[0184] Synthesis of Compound 1 in Step A5

[0185] The structural formula of Compound 1 is:

[0186]

[0187] At room temperature, 0.1 g of Intermediate XIV was placed in a 25 mL eggplant-shaped flask, 5 mL of DCM was added and stirred evenly, 2 drops of DMF were added and stirred. Oxalyl chloride (3 eq) was added dropwise under ice bath (0 °C). After the addition was completed, the temperature was raised to 40 °C and the reaction was refluxed. The reaction was stopped, and the solvent was evaporated under reduced pressure. The residue was dissolved in 5 mL of tetrahydrofuran and stirred evenly. 0.075 g of guanidine hydrochloride (3 eq) was placed in a 25 mL eggplant-shaped flask, 5 mL of tetrahydrofuran was added and stirred evenly, 0.03 g (3 eq) of sodium hydroxide was added and stirred. The tetrahydrofuran solution of acyl chloride was slowly added dropwise thereto. After the addition was completed, the temperature was raised to 50 °C and the reaction was carried out. After the reaction was completed, 10 mL of water was added to the reaction solution and stirred evenly. The pH of the reaction solution was adjusted to 10 with sodium hydroxide solution, and extracted with DCM (30 mL × 3). The organic layers were combined and evaporated to dryness to obtain 0.12 g of a yellow oil, and then 35 mg of a white solid was obtained by column chromatography with a yield of 54.7%.

[0188] HRMS(ESI) m / z: 374.1272 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.54 (d, J =

[0189] 63.6 Hz, 4H), 8.08–7.60 (m, 3H), 7.27–7.06 (m, 2H), 6.94–6.71 (m, 2H), 5.08–4.87 (m, 1H), 4.08 (s, 2H), 3.90–3.61 (m, 4H), 2.19 (dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 1.92 (dt, J = 13.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 159.55, 159.23, 156.17, 140.13, 139.13, 131.52, 131.14, 130.41, 130.29, 128.15, 115.77, 77.44, 72.73, 66.85, 37.93, 32.90.

[0190] Example 2

[0191] Synthesis of Compound 2

[0192] The structural formula of Compound 2 is:

[0193]

[0194] At room temperature, 30 mg of Example 1 was placed in a 25 mL eggplant-shaped flask, 5 mL of DMF was added and stirred to dissolve. Under ice bath (0 °C) conditions, iodobenzenediacetic acid (1.5 eq) was slowly added. After the addition was completed, the temperature was raised to room temperature (20 °C) for reaction. After the reaction was completed, the reaction solution was poured into 20 mL of water and stirred, extracted with ethyl acetate, and after evaporation to dryness, 15 mg of white solid was obtained by column chromatography, with a yield of 25.1%.

[0195] HRMS(ESI) m / z: 372.1112 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94–7.80 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.42 (s, 2H), 4.98 (td, J = 5.5, 4.5, 2.0 Hz, 1H), 4.09 (s, 2H), 3.91–3.69 (m, 4H), 2.19 (dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 1.93 (dt, J = 11.9, 5.1 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 172.60, 169.46, 156.20, 140.80, 131.14, 130.99, 130.47, 123.57, 115.86, 77.44, 72.74, 66.86, 37.70, 32.92.

[0196] Example 3

[0197] Synthesis of Compound 3

[0198] The structural formula of Compound 3 is as follows:

[0199]

[0200] At room temperature, 0.23 g of Intermediate V-1 was placed in a 25 mL three-necked flask, and 4-hydroxyphenylboronic acid (1.2 eq), tetrakis(triphenylphosphine)palladium (0.1 eq), potassium carbonate (1.5 eq), and a mixed solvent of dioxane and water (8 mL Diox + 2 mL water) were added. The reaction system was slowly heated to 110 °C under nitrogen protection and refluxed. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added and stirred, and extracted with EA (20 mL × 3). The organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness to obtain a black solid, and column chromatography was used to obtain 0.182 g of a yellow oil, with a yield of 76.2%.

[0201] HRMS(ESI) m / z: 403.1077 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.51–7.40 (m, 4H), 7.21–7.12 (m, 2H), 6.88–6.77 (m, 4H), 4.96 (ddt, J = 6.4, 4.0, 1.8 Hz, 1H), 4.03 (s, 2H), 3.88–3.69 (m, 4H), 2.17 (dtd, J = 13.3, 8.2, 6.3 Hz, 1H), 1.92 (dddd, J = 13.2, 7.0, 3.3, 1.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 157.87, 156.00, 139.79, 139.52, 132.10, 131.61, 130.20, 130.13, 130.06, 129.19, 128.20, 125.95, 116.24, 115.72, 77.44, 72.74, 66.85, 38.10, 32.91.

[0202] Example 4

[0203] (R)-5-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-2-(piperidin-1-yl)pyridine - Compound 4

[0204] According to the method in Example 3, using Intermediate V-1 as the raw material, it was prepared by Suzuki coupling reaction with 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine to obtain Example 4, with a yield of 86.3%.

[0205] HRMS(ESI) m / z: 449.2000 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.40 (d, J = 2.6 Hz, 1H), 7.78 (dd, J = 8.9, 2.7 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.51–7.39 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.85 (dd, J = 15.9, 8.7 Hz, 3H), 4.98–4.89 (m, 1H), 4.03 (s, 2H), 3.90–3.69 (m, 4H), 3.55 (t, J = 5.5 Hz, 4H), 2.17 (dtd, J = 14.2, 8.2, 6.2 Hz, 1H), 1.92 (p, J = 6.4 Hz, 1H), 1.57 (dq, J = 33.9, 6.0 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 158.76, 156.02, 145.99, 139.69, 137.32, 135.98, 132.03, 131.66, 130.22, 128.65, 125.43, 123.09, 115.69, 107.17, 77.44, 72.75, 66.85, 46.03, 38.12, 32.92, 25.45, 24.78.

[0206] Example 5

[0207] (R)-4'-Chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-amine - Compound 5

[0208] According to the method in Example 3, using Intermediate V-1 as the raw material, a Suzuki coupling reaction was carried out with 4-(Boc-amino)phenylboronic acid to prepare Intermediate M3, with a yield of 58.1%. 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.54 (s, 4H), 7.53–7.43 (m, 2H), 7.19–7.14 (m, 2H), 6.86–6.81 (m, 2H), 4.95 (ddt, J = 6.4, 4.2, 1.8 Hz, 1H), 4.04 (s, 2H), 3.89–3.69 (m, 4H), 2.23–2.12 (m, 1H), 1.96–1.88 (m, 1H), 1.49 (s, 9H).

[0209] At room temperature, 0.12 g of intermediate M3 was placed in a 25 mL eggplant-shaped flask, and 10 mL of trifluoroacetic acid was added and stirred. After the reaction was completed, the trifluoroacetic acid in the reaction solution was evaporated. 10 mL of water was added to the reaction solution and stirred. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and a solid precipitated. The solid was filtered to obtain a yellow solid, which was purified by column chromatography to obtain 68 mg of a white solid with a yield of 71.6%.

[0210] HRMS(ESI) m / z: 380.1420 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.45–7.28 (m, 4H), 7.16 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 7.7 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 5.28 (s, 2H), 4.94 (s, 1H), 4.02 (s, 2H), 3.91–3.60 (m, 4H), 2.16 (h, J = 7.4 Hz, 1H), 1.99–1.85 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 155.98, 149.15, 140.29, 139.35, 132.20, 130.78, 130.18, 130.01, 128.53, 127.62, 126.48, 125.30, 115.70, 114.67, 77.45, 72.75, 66.85, 38.15, 32.92.

[0211] Example 6

[0212] (R)-1-{4’-Chloro-3’-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1’-biphenyl)-4-yl}piperazine - Compound 6

[0213] According to the method in Example 3, using intermediate V-1 as the raw material, a Suzuki coupling reaction was carried out with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester to prepare intermediate M1-1 with a yield of 51.3%. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 2.3 Hz, 1H), 7.53–7.40 (m, 4H), 7.17 (d, J = 8.6 Hz, 2H), 7.00 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 4.95 (td, J = 6.4, 1.8 Hz, 1H), 4.03 (s, 2H), 3.89–3.67 (m, 4H), 3.46 (t, J = 5.2 Hz, 5H), 3.22–3.04 (m, 3H), 2.23–2.10 (m, 1H), 1.92 (dt, J = 12.5, 5.9 Hz, 1H), 1.42 (s, 9H).

[0214] According to the method in Example 5, using intermediate M1-1 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid, and 18 mg of white solid was obtained after purification by column chromatography, with a yield of 50.3%.

[0215] HRMS(ESI) m / z: 449.2003 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.53–7.38 (m, 4H), 7.17 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 4.95 (d, J = 5.7 Hz, 1H), 4.03 (s, 2H), 3.89–3.66 (m, 4H), 3.10 (d, J = 5.1 Hz, 4H), 2.86 (s, 4H), 2.26–2.09 (m, 1H), 2.00–1.81 (m, 1H), 1.34 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 156.01, 151.49, 139.60, 139.53, 132.10, 131.50, 130.22, 130.14, 129.25, 128.95, 127.54, 125.73, 115.88, 115.72, 77.44, 72.75, 66.85, 49.04, 45.67, 38.10, 32.92.

[0216] Example 7

[0217] Synthesis of Compound 7

[0218] According to the method of Step A1 in Example 1, using intermediate VI as the raw material, a Friedel-Crafts acylation reaction was carried out with phenol to prepare intermediate VII, with a yield of 18.8%. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.39–8.29 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H).

[0219] According to the method of step A2 in Example 1, using intermediate VII as the raw material, a Mitsunobu reaction is carried out with (S)-(+)-3-hydroxytetrahydrofuran to prepare intermediate VIII, and the yield is 93.8%. HRMS(ESI) m / z: 348.0638 [M+H]+. 1H NMR(500 MHz, DMSO-d6) δ 8.46–8.19(m, 2H), 7.91(d, J = 8.7 Hz, 1H), 7.84–7.59(m, 2H), 7.24–6.91(m, 2H), 5.18(tt, J = 4.6, 2.1 Hz, 1H), 4.02–3.59(m, 4H), 2.28(dtd, J = 14.2, 8.2, 6.2 Hz, 1H), 1.98(dt, J = 12.8, 5.8 Hz, 1H).

[0220] According to the method of step A3 in Example 1, using intermediate VIII as the raw material, a carbonyl reduction reaction is carried out to prepare intermediate IX, and the yield is 85.7%. 1H NMR(500 MHz, DMSO-d6) δ 8.19(d, J = 2.7 Hz, 1H), 8.10(dd, J = 8.7, 2.8 Hz, 1H), 7.75(d, J = 8.7 Hz, 1H), 7.17(d, J = 8.5 Hz, 2H), 6.90–6.84(m, 2H), 4.98(ddt, J = 6.4, 4.3, 1.9 Hz, 1H), 4.13(s, 2H), 3.90–3.78(m, 2H), 3.78–3.70(m, 2H), 2.19(dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 1.98–1.89(m, 1H).

[0221] Synthesis of Intermediate X-1

[0222] The structural formula of Intermediate X-1 is:

[0223]

[0224] At room temperature, 1.4 g of intermediate IX was placed in a 100 mL eggplant-shaped flask, 20 mL of absolute ethanol was added and stirred evenly, reduced iron powder (5 eq) was added, the temperature was raised to 50 °C and reacted for 20 min, 10 mL of saturated ammonium chloride aqueous solution was added, and the temperature was raised to 80 °C for reflux reaction. After the reaction was completed, the iron powder was removed by hot filtration with diatomaceous earth as a filter aid. The filtrate was evaporated to dryness. Water was added to the residue and stirred. Ethyl acetate was added for extraction (100 mL × 3). The extraction liquids were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness to obtain 1.012 g of a brown solid. After purification by column chromatography, 1.012 g of a brown solid was obtained with a yield of 79.4%. 1H NMR (400 MHz, DMSO-d6) δ 7.12–7.05 (m, 2H), 7.05–6.95 (m, 1H), 6.91–6.75 (m, 2H), 6.46–6.36 (m, 2H), 5.16 (s, 2H), 4.96 (ddt, J = 6.4, 4.1, 1.9 Hz, 1H), 3.87 (dd, J = 10.1, 4.6 Hz, 1H), 3.83–3.77 (m, 3H), 3.77–3.70 (m, 2H), 2.18 (dtd, J = 13.2, 8.2, 6.2 Hz, 1H), 2.00–1.83 (m, 1H).

[0225] Synthesis of Compound 7

[0226] The structural formula of Compound 7 is:

[0227]

[0228] At room temperature, 0.1 g of intermediate X-1 was placed in a 25 mL eggplant-shaped flask, 10 mL of dichloromethane was added and stirred evenly, triethylamine (2 eq) was added and stirred, acetyl chloride (1.2 eq) was slowly added dropwise, and the reaction was carried out at room temperature after the addition was completed. After the reaction was completed, water was added to the reaction solution and stirred. Dichloromethane was added for extraction (10 mL × 3). The extraction liquids were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness to obtain 55 mg of a white solid. After purification by column chromatography, 30 mg of a white solid was obtained with a yield of 26.5%.

[0229] HRMS(ESI) m / z: 346.1209 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.53 (dd, J = 8.8, 2.6 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 5.02–4.87 (m, 1H), 3.94 (s, 2H), 3.90–3.68 (m, 4H), 2.19 (dq, J = 14.8, 8.2 Hz, 1H), 2.00 (s, 3H), 1.93 (dt, J = 13.1, 6.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 168.84, 156.07, 139.40, 138.91, 131.80, 130.23 (2C), 129.86, 126.96, 121.74, 119.04, 115.76 (2C), 77.45, 72.75, 66.86, 38.07, 32.93, 24.40.

[0230] Example 8

[0231] Synthesis of Compound 8

[0232] The structural formula of Compound 8 is as follows:

[0233]

[0234] At room temperature, 0.1 g of Intermediate X-1 was placed in a 25 mL eggplant-shaped flask, 3 mL of glacial acetic acid was added and stirred evenly, and the temperature was raised to 120 °C. An aqueous solution of monocyanamide (0.030 g of monocyanamide dissolved in 0.5 mL of water) was slowly added dropwise, and the reaction was continued under reflux. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH was adjusted to 8 by slowly adding saturated sodium bicarbonate solution. A solid precipitated out, and the solid was filtered to obtain a yellow solid, which was purified by column chromatography to obtain 15 mg of a white solid with a yield of 46.0%.

[0235] HRMS(ESI) m / z: 346.1321 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.63 (s, 3H), 7.49 (d, J = 8.5 Hz, 1H), 7.20–7.11 (m, 4H), 6.85 (d, J = 8.4 Hz, 2H), 4.97 (t, J = 6.4 Hz, 1H), 3.99 (s, 2H), 3.91–3.68 (m, 4H), 2.19 (td, J = 14.2, 8.2 Hz, 1H), 1.93 (dt, J = 12.6, 5.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 156.48, 156.13, 140.58, 135.10, 131.38, 131.12, 130.88, 130.39, 127.62, 124.71, 115.72, 77.46, 72.74, 66.86, 37.99, 32.92.

[0236] Example 9

[0237] Synthesis of Compound 9

[0238] The structural formula of Compound 9 is as follows:

[0239]

[0240] At room temperature, 0.18 g of Intermediate X-1 was placed in a 25 mL three-necked flask. Under nitrogen protection, 10 mL of tetrahydrofuran was added and stirred evenly. 4-Methoxyphenyl isocyanate (1.2 eq) was slowly added dropwise, and the reaction was carried out at room temperature (60 °C). After the reaction was completed, the reaction solution was cooled to room temperature, a small amount of water was added and stirred, and then extracted with ethyl acetate (10 mL × 3). The extraction solutions were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated. Subsequently, it was purified by column chromatography to obtain 30 mg of a white solid with a yield of 30.2%.

[0241] HRMS(ESI) m / z: 453.1579 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.41 (s, 1H), 7.39 (dd, J = 8.8, 2.6 Hz, 1H), 7.34–7.26 (m, 4H), 7.12 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 4H), 4.97 (t, J = 3.3 Hz, 1H), 3.94 (s, 2H), 3.91–3.72 (m, 4H), 3.71 (s, 3H), 2.19 (dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 2.01–1.82 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 156.06, 155.06, 153.04, 139.55, 139.45, 132.96, 131.91, 130.26, 129.90, 125.59, 120.79, 120.63, 118.07, 115.75, 114.46, 77.45, 72.75, 66.86, 55.65, 38.09, 32.93.

[0242] Example 10

[0243] (R)-1-{4-Chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-3-(2-ethylphenyl)urea - Compound 10

[0244] According to the method in Example 9, using Intermediate X-1 as the raw material, an N-acylation reaction was carried out with 2-ethylphenyl isocyanate to prepare Example 10, with a yield of 45.6%.

[0245] HRMS(ESI) m / z: 451.1785 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.36–7.25 (m, 4H), 7.23 (t, J = 3.1 Hz, 2H), 7.22–7.19 (m, 2H), 7.12–7.07 (m, 1H), 6.88–6.80 (m, 1H), 6.10 (t, J = 5.7 Hz, 1H), 5.87 (t, J = 5.7 Hz, 1H), 4.96 (ddt, J = 6.3, 3.9, 1.8 Hz, 1H), 3.91 (s, 1H), 3.89–3.65 (m, 3H), 3.34–3.13 (m, 4H), 2.69 (dt, J = 25.0, 7.2 Hz, 3H), 2.19 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H), 2.03–1.81 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 158.34, 156.00, 155.39, 140.24, 140.15, 139.95, 139.27, 131.96, 130.22, 129.79, 129.13, 128.83, 128.75, 126.55, 126.42, 124.90, 120.26, 117.58, 115.70, 77.40, 72.74, 66.86, 38.07, 36.65, 36.26, 32.91.

[0246] Example 11

[0247] Synthesis of Intermediate M5

[0248] The structural formula of Intermediate M5 is:

[0249]

[0250] At room temperature, 0.1 g of intermediate V-1 was placed in a 25 mL three-necked flask, and 1-Boc piperazine (1.2 eq), tris(dibenzylideneacetone)dipalladium (0.1 eq), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (0.1 eq), cesium carbonate (1.5 eq), and 10 mL of toluene were added and stirred evenly. Under nitrogen protection, the temperature was raised to 110 °C and refluxed. After the reaction was completed, the reaction solution was cooled to room temperature, filtered by suction, a small amount of water was added to the filtrate and stirred, and extracted with ethyl acetate (10 mL × 3). The extraction solutions were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain intermediate M5 with a yield of 61.9%. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.6 Hz, 3H), 6.98 (d, J = 3.0 Hz, 2H), 6.82 (d, J = 8.6 Hz, 3H), 4.95 (t, J = 5.5 Hz, 1H), 3.93–3.68 (m, 9H), 3.43 (t, J = 5.0 Hz, 7H), 3.06 (d, J = 5.1 Hz, 5H), 2.24–2.11 (m, 1H), 1.92 (dt, J = 12.1, 5.9 Hz, 1H), 1.41 (s, 15H).

[0251] According to the method of compound 5 in Example 5, using intermediate M5 as the raw material, the protecting group was removed under trifluoroacetic acid conditions to prepare compound 11 with a yield of 26.3%.

[0252] HRMS (ESI) m / z: 373.1685 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 3.0 Hz, 1H), 6.86–6.76 (m, 3H), 4.95 (dd, J = 6.4, 4.6 Hz, 1H), 3.91 (s, 2H), 3.88–3.68 (m, 4H), 3.05 (t, J = 5.1 Hz, 4H), 2.92–2.80 (m, 4H), 2.18 (dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 2.01–1.79 (m, 1H), 1.39–1.16 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 155.90, 150.91, 139.31, 132.33, 130.07, 129.95, 122.93, 118.45, 115.61, 115.32, 77.40, 72.74, 66.85, 49.04, 45.50, 38.38, 32.91.

[0253] Example 12

[0254] (R)-4'-Chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carbonitrile - Compound 12

[0255] According to the method in Example 3, using Intermediate IV-1 as the raw material, a Suzuki coupling reaction was carried out with 4-cyanophenylboronic acid to prepare Example 12, with a yield of 83.3%.

[0256] HRMS(ESI) m / z: 404.1050 [M+H]+; 1H NMR(500 MHz, DMSO-d6) δ 7.96(q, J = 8.3 Hz, 5H), 7.90(d, J = 2.3 Hz, 1H), 7.74(d, J = 9.0 Hz, 3H), 7.09(d, J = 8.8 Hz, 2H), 5.15(t, J = 5.4 Hz, 1H), 3.91(dd, J = 10.3, 4.5 Hz, 1H), 3.84(dt, J = 18.2, 9.1 Hz, 2H), 3.76(td, J = 8.3, 4.6 Hz, 1H), 2.27(dtd, J = 14.2, 8.2, 6.3 Hz, 1H), 1.97(dt, J = 12.6, 5.8 Hz, 1H). 13C NMR(126 MHz, DMSO-d6) δ 192.84, 162.49, 142.95, 139.74, 137.72, 133.39, 132.73, 130.99, 130.60, 130.18, 129.12, 128.26, 127.56, 119.15, 116.01, 111.21, 78.32, 72.67, 66.89, 32.90.

[0257] Example 13

[0258] (R)-[4-Chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone - Compound 13

[0259] According to the method in Example 3, using Intermediate IV-1 as the raw material, a Suzuki coupling reaction was carried out with 4-hydroxybenzeneboronic acid to prepare Example 13, with a yield of 83.3%.

[0260] HRMS(ESI) m / z: 395.1050 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.75 (dd, J = 21.1, 9.7 Hz, 3H), 7.66–7.53 (m, 4H), 7.08 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 5.16–5.13 (m, 1H), 3.94–3.72 (m, 4H), 2.27 (dq, J = 14.5, 7.8 Hz, 1H), 1.98 (dt, J = 12.7, 5.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 193.26, 162.38, 158.22, 139.64, 139.36, 132.66, 130.58, 129.26, 129.13, 128.92, 128.43, 127.98, 126.18, 116.33, 115.96, 78.29, 72.67, 66.89, 32.91.

[0261] Example 14

[0262] (R)-{2-Chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone - Compound 14

[0263] According to the method in Example 3, using Intermediate IV-1 as the raw material, it was prepared by Suzuki coupling reaction with 2-(piperidin-1-yl)pyridine-5-boronic acid pinacol ester to obtain Example 14, with a yield of 51.3%.

[0264] HRMS(ESI) m / z: 463.1799 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.6 Hz, 1H), 7.88 (dd, J = 9.0, 2.7 Hz, 1H), 7.81 (dd, J = 8.5, 2.4 Hz, 1H), 7.76–7.71 (m, 2H), 7.70 (d, J = 2.3 Hz, 1H), 7.11–7.04 (m, 2H), 6.88 (d, J = 9.0 Hz, 1H), 5.15 (ddt, J = 6.3, 4.1, 1.8 Hz, 1H), 3.95–3.71 (m, 4H), 3.57 (t, J = 5.4 Hz, 4H), 2.27 (dtd, J = 14.2, 8.2, 6.2 Hz, 1H), 1.97 (dt, J = 12.5, 5.6 Hz, 1H), 1.67–1.43 (m, 6H); 13C NMR (126 MHz, DMSO-d6) δ 193.22, 162.39, 158.89, 146.30, 139.51, 137.32, 136.13, 132.68, 130.64, 129.25, 128.35, 127.91, 125.64, 122.18, 115.96, 107.11, 78.30, 72.67, 66.89, 45.97, 32.91, 25.48, 24.78.

[0265] Example 15

[0266] (R)-[4'-Amino-4-chloro-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone - Compound 15

[0267] According to the method in Example 3, using Intermediate IV-1 as the raw material, it was prepared with 4-(Boc-amino)phenylboronic acid through Suzuki coupling reaction to obtain Intermediate M4-1, with a yield of 78.5%. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.82 (dd, J = 8.5, 2.3 Hz, 1H), 7.76–7.68 (m, 3H), 7.68–7.60 (m, 3H), 7.54 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 5.18–5.11 (m, 1H), 3.94–3.71 (m, 4H), 2.27 (tt, J = 14.2, 7.2 Hz, 1H), 2.03–1.92 (m, 1H), 1.48 (s, 9H).

[0268] According to the synthesis method of Compound 5 in Example 5, using Intermediate M2-1 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid, and 18 mg of white solid was obtained after purification by column chromatography, with a yield of 72.5%.

[0269] HRMS(ESI) m / z: 394.1215 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.72 (dd, J = 9.8, 2.6 Hz, 3H), 7.61–7.52 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 5.40 (s, 2H), 5.16–5.12 (m, 1H), 3.95–3.71 (m, 4H), 2.33–2.20 (m, 1H), 1.98 (h, J = 5.8, 5.1 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 193.42, 162.34, 149.44, 140.11, 139.26, 132.65, 130.46, 129.29, 128.19, 127.82, 127.04, 125.48, 125.43, 115.93, 114.72, 78.28, 72.67, 66.89, 32.90.

[0270] Example 16

[0271] (R)-[4-Chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone - Compound 16

[0272] According to the method in Example 3, using Intermediate IV-1 as the raw material, a Suzuki coupling reaction was carried out with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester to prepare Intermediate M2-1, with a yield of 95.5%. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (dd, J = 8.5, 2.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.5, 4.7 Hz, 3H), 7.05 (dd, J = 22.4, 8.5 Hz, 4H), 5.15 (d, J = 5.6 Hz, 1H), 3.96–3.71 (m, 3H), 3.46 (s, 2H), 3.17 (s, 2H), 2.33–2.20 (m, 0H), 2.01–1.93 (m, 1H), 1.42 (s, 9H).

[0273] According to the synthesis method of Compound 5 in Example 5, using Intermediate M2-1 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid, and 18 mg of white solid was obtained after purification by column chromatography, with a yield of 39.9%.

[0274] HRMS(ESI) m / z: 463.1802 [M+H]+; 1H NMR(600 MHz, DMSO-d6) δ 7.80(d, J = 8.5 Hz, 1H), 7.73(d, J = 8.4 Hz, 2H), 7.68(s, 1H), 7.61(d, J = 5.5 Hz, 2H), 7.08(d, J = 8.5 Hz, 2H), 7.02(d, J = 8.4 Hz, 2H), 3.83(ddd, J = 49.5, 32.3, 7.7 Hz, 3H), 3.22(s, 2H), 2.98(t, J = 5.0 Hz, 3H), 2.27(dq, J = 14.8, 7.7 Hz, 1H), 1.97(dd, J = 13.3, 6.3 Hz, 1H), 1.23(s, 1H). 13C NMR(126 MHz, DMSO-d6) δ 193.30, 162.38, 151.64, 139.46, 139.38, 132.66, 130.58, 129.28, 128.69, 128.25, 127.81, 127.77, 125.95, 115.96, 115.82, 78.30, 72.67, 66.89, 48.70, 45.51, 32.91.

[0275] Example 17

[0276] (R)-N-carbamoyl-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carboxamide - Synthesis of Intermediate XV-1 in Step A14 of Compound 17

[0277] The structural formula of Intermediate XV-1 is:

[0278]

[0279] At room temperature, 0.2 g of Example 12 was placed in a 100 mL eggplant-shaped flask, 10 mL of methanol was added and stirred evenly, 10 mL of sodium hydroxide aqueous solution (4 M) was added, and the temperature was raised to 80 °C for reflux reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and hydrochloric acid was slowly added thereto to adjust the pH to 1. A solid precipitated, and it was filtered by suction to obtain Intermediate XV-1 with a yield of 53.9%. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.06–7.99 (m, 2H), 7.94 (dd, J = 8.5, 2.4 Hz, 1H), 7.91–7.82 (m, 3H), 7.79–7.69 (m, 3H), 7.10 (ddd, J = 8.9, 5.2, 2.5 Hz, 2H), 5.15 (q, J = 4.9, 3.8 Hz, 1H), 3.94–3.69 (m, 4H), 2.27 (td, J = 14.2, 8.2 Hz, 1H), 1.98 (dt, J = 12.5, 5.9 Hz, 1H).

[0280] According to the synthesis method of Compound 1 in Example 1, using Intermediate XV-1 as a raw material, an N-acylation reaction was carried out with guanidine hydrochloride, and after purification by column chromatography, 18 mg of a white solid was obtained with a yield of 31.8%.

[0281] HRMS (ESI) m / z: 464.1375 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.55 (d, J = 109.8 Hz, 4H), 8.16–7.95 (m, 5H), 7.92 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.5, 3.9 Hz, 3H), 7.09 (d, J = 8.4 Hz, 2H), 5.16 (t, J = 5.6 Hz, 1H), 3.99–3.68 (m, 4H), 2.28 (dq, J = 14.6, 7.6 Hz, 1H), 1.98 (dt, J = 13.0, 6.0 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 192.95, 162.51, 143.44, 139.79, 137.97, 132.72, 130.94, 130.42, 130.14, 129.46, 129.13, 127.69, 127.44, 116.03, 78.33, 72.66, 66.89, 32.90.

[0282] Example 18

[0283] 4'-Chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carbonitrile - Compound 18

[0284] According to the method of step A1 in Example 1, using intermediate II as the raw material, a Friedel-Crafts acylation reaction was carried out with phenetole to prepare intermediate IV-3, and the yield was 45.5%. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.7 Hz, 1H), 8.01–7.89 (m, 2H), 7.84–7.75 (m, 2H), 7.17–7.06 (m, 2H), 4.16 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0285] According to the method in Example 3, using intermediate IV-3 as the raw material, a Suzuki coupling reaction was carried out with 4-cyanophenylboronic acid, and after purification by column chromatography, 18 mg of a white solid was obtained, with a yield of 89.7%.

[0286] HRMS (ESI) m / z: 362.0944 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.00–7.91 (m, 1H), 7.89 (d, J = 2.4 Hz, 0H), 7.73 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 8.9 Hz, 0H), 4.14 (q, J = 7.0 Hz, 1H), 1.35 (t, J = 6.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 192.85, 163.83, 142.94, 139.79, 137.69, 133.40, 132.71, 130.98, 130.61, 130.15, 128.89, 128.24, 127.56, 119.17, 115.24, 111.19, 64.26, 14.90.

[0287] Example 19

[0288] [4-Chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone -- Compound 19

[0289] According to the method in Example 3, using intermediate IV-3 as the raw material, a Suzuki coupling reaction was carried out with 4-hydroxyphenylboronic acid, and after purification by column chromatography, 18 mg of a white solid was obtained, with a yield of 87.0%.

[0290] HRMS(ESI) m / z: 353.0944 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.74 (dd, J = 22.8, 8.3 Hz, 3H), 7.64 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 193.27, 163.72, 158.22, 139.62, 139.42, 132.64, 130.57, 129.12, 129.04, 128.88, 128.42, 127.98, 126.18, 116.32, 115.17, 64.22, 14.90.

[0291] Example 20

[0292] {2-Chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}(4-ethoxyphenyl)methanone - Compound 20

[0293] Prepared by the method in Example 3, using Intermediate IV-3 as the raw material, through Suzuki coupling reaction with 2-(piperidin-1-yl)pyridine-5-boronic acid pinacol ester, and purified by column chromatography to obtain 18 mg of white solid, with a yield of 65.9%.

[0294] HRMS(ESI) m / z: 421.1687 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.75–7.68 (m, 3H), 7.60 (d, J = 10.3 Hz, 1H), 7.07 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.57 (s, 4H), 1.61 (s, 2H), 1.53 (d, J = 5.5 Hz, 4H), 1.35 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 193.23, 163.73, 158.87, 146.30, 139.58, 137.30, 136.14, 132.66, 130.63, 129.02, 128.32, 127.90, 125.63, 122.18, 115.19, 107.12, 64.23, 45.96, 25.47, 24.78, 14.91.

[0295] Example 21

[0296] [4'-Amino-4-chloro-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone -- Compound 21

[0297] According to the method in Example 3, using Intermediate IV-3 as the raw material, a Suzuki coupling reaction was carried out with 4-(Boc-amino)phenylboronic acid to prepare Intermediate M4-2. After purification by column chromatography, 18 mg of a white solid was obtained with a yield of 43.4%. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.82 (dd, J = 8.5, 2.4 Hz, 1H), 7.76–7.68 (m, 3H), 7.67–7.60 (m, 3H), 7.54 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 1.48 (s, 9H), 1.35 (t, J = 7.0 Hz, 3H).

[0298] According to the synthesis method of Compound 5 in Example 5, using Intermediate M4-2 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid. After purification by column chromatography, 18 mg of a white solid was obtained with a yield of 81.0%.

[0299] HRMS(ESI) m / z: 352.1106 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, J = 8.3 Hz, 3H), 7.59–7.52 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.2 Hz, 2H), 5.35 (s, 2H), 4.13 (d, J = 7.0 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 193.41, 163.69, 149.57, 140.13, 139.34, 132.61, 130.45, 129.12, 128.15, 127.81, 127.04, 125.43, 125.40, 115.16, 114.66, 64.22, 14.90.

[0300] Example 22

[0301] [4-Chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone -- Compound 22

[0302] According to the method in Example 3, using Intermediate IV-3 as the raw material, a Suzuki coupling reaction was carried out with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester to prepare Intermediate M2-2 with a yield of 87.0%. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.5, 2.4 Hz, 1H), 7.75–7.69 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.6, 5.5 Hz, 3H), 7.11–7.04 (m, 2H), 7.04–6.98 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.46 (t, J = 5.2 Hz, 4H), 3.17 (dd, J = 6.3, 4.1 Hz, 4H), 1.42 (s, 9H), 1.35 (t, J = 7.0 Hz, 3H).

[0303] According to the synthesis method of Compound 5 in Example 5, using Intermediate M2-2 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid, and 18 mg of white solid was obtained after purification by column chromatography with a yield of 82.9%.

[0304] HRMS(ESI) m / z: 421.1693 [M+H]+, 541.3 [M-H]-; 1H NMR (600 MHz, DMSO-d6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.59 (d, J = 8.4 Hz, 3H), 7.07 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.74–3.33 (m, 2H), 3.12 (s, 3H), 2.87 (d, J = 5.0 Hz, 3H), 1.35 (t, J = 6.8 Hz, 3H), 1.23 (s, 1H); 13C NMR (101 MHz, DMSO-d6) δ 193.30, 163.72, 151.24, 139.46, 139.37, 132.64, 130.58, 129.05, 128.71, 128.60, 127.90, 127.81, 125.99, 116.02, 115.19, 64.23, 47.77, 44.77, 14.91.

[0305] Example 23

[0306] N-carbamoyl-4'-chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carboxamide - Compound 23

[0307] According to the method of step A14 in Example 17, using Example 18 as the raw material, a cyano hydrolysis reaction was carried out under the condition of an aqueous sodium hydroxide solution to prepare Intermediate XV-2 with a yield of 95.3%. HRMS(ESI) m / z: 381.0896 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.05–7.99 (m, 2H), 7.94 (dd, J = 8.5, 2.4 Hz, 1H), 7.90–7.81 (m, 3H), 7.73 (t, J = 9.0 Hz, 2H), 7.12–7.04 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.41–1.15 (m, 4H).

[0308] According to the method of step A5 in Example 1, using Intermediate XV-2 as the raw material, an N-acylation reaction was carried out with guanidine hydrochloride to obtain a white solid of 18 mg after purification by column chromatography with a yield of 31.5%.

[0309] HRMS(ESI) m / z: 422.1286 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.58 (d, J = 110.0 Hz, 4H), 8.09–7.97 (m, 5H), 7.91 (d, J = 2.3 Hz, 1H), 7.77–7.71 (m, 3H), 7.11–7.06 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 192.96, 163.85, 159.50, 159.18, 155.80, 143.46, 139.85, 137.94, 132.70, 130.93 (2C), 130.43, 130.11 (2C), 129.45, 128.91 (2C), 127.70, 127.44, 115.26 (2C), 64.27, 14.89.

[0310] Example 24

[0311] [2-Chloro-5-(piperazin-1-yl)phenyl](4-ethoxyphenyl)methanone -- Compound 24

[0312] According to the method of step A13 in Example 11, using intermediate IV-3 as the raw material, a Buchwald coupling reaction was carried out with 1-Boc piperazine to prepare intermediate M6 with a yield of 82.1%. 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.13–7.03 (m, 2H), 6.96 (d, J = 3.0 Hz, 1H), 4.12 (t, J = 6.9 Hz, 1H), 3.43 (s, 1H), 3.16 (s, 1H), 1.41 (s, 5H), 1.35 (t, J = 6.9 Hz, 2H).

[0313] According to the synthesis method of Compound 5 in Example 5, using intermediate M6 as the raw material, the protecting group was removed under the condition of 10 mL of trifluoroacetic acid, and 18 mg of white solid was obtained after purification by column chromatography with a yield of 76.5%.

[0314] HRMS(ESI) m / z: 345.1376 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.9 Hz, 1H), 7.06 (t, J = 6.0 Hz, 3H), 6.90 (d, J = 3.1 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 3.09 (t, J = 5.1 Hz, 4H), 2.83 (t, J = 5.0 Hz, 4H), 1.35 (t, J = 6.8 Hz, 3H), 1.23 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 193.67, 163.60, 150.54, 139.43, 132.54, 130.38, 129.11, 118.53, 117.80, 115.10, 114.85, 64.20, 48.92, 45.62, 14.91.

[0315] Example 25

[0316] (S)-1-{4'-Chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine - Compound 25

[0317] According to the method of step A2 in Example 1, using Intermediate III as the raw material, a Mitsunobu reaction was carried out with (R)-(-)-3-hydroxytetrahydrofuran to prepare Intermediate IV-2 with a yield of 85.1%. 1H NMR (400 MHz, DMSO-d6) δ 7.79–7.73 (m, 1H), 7.72–7.67 (m, 1H), 7.56 (d, J = 8.5 Hz, 0H), 7.12–7.04 (m, 1H), 5.16 (dd, J = 6.2, 4.5 Hz, 0H), 3.95–3.72 (m, 2H), 2.28 (dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 1.98 (dt, J = 13.4, 6.2 Hz, 1H).

[0318] According to the method for synthesizing intermediate V-1 in Example 1, using intermediate IV-2 as the raw material, a reduction reaction occurs under the condition of triethylsilane to prepare intermediate V-2 with a yield of 83.3%. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 2.4 Hz, 1H), 7.48–7.36 (m, 2H), 7.18–7.10 (m, 2H), 6.89–6.81 (m, 2H), 4.97 (ddt, J = 6.3, 4.1, 1.8 Hz, 1H), 3.98 (s, 2H), 3.91–3.69 (m, 4H), 2.19 (dtd, J = 13.5, 8.2, 6.2 Hz, 1H), 1.99–1.88 (m, 1H).

[0319] According to the method in Example 3, using intermediate V-2 as the raw material, 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester undergoes a Suzuki coupling reaction to prepare intermediate M1-2 with a yield of 71.4%. 1H NMR (500 MHz, DMSO-d6) δ 7.60 (d, J = 2.3 Hz, 1H), 7.55–7.41 (m, 4H), 7.20–7.14 (m, 2H), 7.05–7.00 (m, 2H), 6.87–6.81 (m, 2H), 4.96 (ddt, J = 6.5, 4.3, 1.8 Hz, 1H), 4.03 (s, 2H), 3.89–3.69 (m, 4H), 3.46 (t, J = 5.2 Hz, 4H), 3.15 (t, J = 5.3 Hz, 4H), 2.23–2.12 (m, 1H), 1.96–1.88 (m, 1H), 1.42 (s, 9H), 1.31–1.21 (m, 1H).

[0320] According to the synthesis method of compound 5 in Example 5, using intermediate M1-2 as the raw material, the protecting group is removed under the condition of 10 mL of trifluoroacetic acid, and after purification by column chromatography, 18 mg of Example 25 is obtained as a white solid with a yield of 95.2%.

[0321] HRMS(ESI) m / z: 449.2003 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J = 2.3 Hz, 1H), 7.52–7.39 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 5.01–4.89 (m, 1H), 4.03 (s, 2H), 3.91–3.66 (m, 4H), 3.10 (t, J = 5.0 Hz, 4H), 2.93–2.78 (m, 4H), 2.21–2.10 (m, 1H), 1.98–1.83 (m, 1H), 1.40–1.07 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 156.01, 151.59, 139.62, 139.53, 132.09, 131.48, 130.22, 130.14, 129.16, 128.93, 127.53, 125.71, 115.82, 115.71, 77.44, 72.75, 66.85, 49.27, 45.85, 38.11, 32.92.

[0322] Example 26

[0323] (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-cyclohexylurea - Compound 26

[0324] According to the method of step A2 in Example 1, using intermediate XI as the raw material, a Friedel-Crafts acylation reaction with phenol was carried out to prepare intermediate XII, and the yield was 20.0%. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.29 (s, 0H), 7.94 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H).

[0325] According to the method for synthesizing Intermediate Ⅳ-1 in Example 1, using Intermediate XII as the raw material, a Mitsunobu reaction is carried out with (S)-(+)-3-hydroxytetrahydrofuran to prepare Intermediate XIII-1, with a yield of 94.2%. HRMS(ESI) m / z: 348.0636 [M+H]+. 1H NMR(500 MHz, DMSO-d6) δ8.19(d, J = 2.7 Hz, 1H), 8.10(dd, J = 8.7, 2.8 Hz, 1H), 7.75(d, J = 8.7 Hz, 1H), 7.17(d, J = 8.5 Hz, 2H), 6.93–6.77(m, 2H), 4.98(ddt, J = 6.4, 4.3, 1.9 Hz, 1H), 4.13(s, 2H), 3.92–3.67(m, 4H), 2.19(dtd, J = 14.3, 8.2, 6.2 Hz, 1H), 2.05–1.83(m, 1H).

[0326] According to the method for synthesizing Intermediate X1 in Example 7, using Intermediate XIII-1 as the raw material, a reduction reaction is carried out under the conditions of iron / ammonium chloride to prepare Intermediate X-2, with a yield of 72.3%. HRMS(ESI) m / z: 318.0905 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ8.89(s, 1H), 7.87–7.58(m, 2H), 7.35(d, J = 8.2 Hz, 1H), 7.11–7.04(m, 2H), 6.82(dd, J = 8.2, 2.1 Hz, 1H), 5.66(s, 2H), 5.15(ddd, J = 6.3, 4.0, 1.9 Hz, 1H), 4.00–3.69(m, 4H), 2.29(dtd, J = 13.5, 8.2, 6.2 Hz, 1H), 2.06–1.90(m, 1H).

[0327] According to the method of Compound 9 in Example 9, using Intermediate X-2 as the raw material, an N-acylation reaction is carried out with cyclohexyl isocyanate to prepare Example 26, with a yield of 16.5%.

[0328] HRMS(ESI) m / z: 443.1743 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.72–7.66 (m, 2H), 7.54 (d, J = 2.4 Hz, 1H), 7.48–7.37 (m, 2H), 7.11–7.04 (m, 2H), 6.19 (d, J = 7.8 Hz, 1H), 5.19–5.11 (m, 1H), 3.95–3.71 (m, 4H), 3.48–3.37 (m, 1H), 2.34–2.14 (m, 1H), 2.03–1.92 (m, 1H), 1.36–1.09 (m, 10H); 13C NMR (101 MHz, DMSO-d6) δ 193.28, 162.34, 154.60, 140.16, 138.95, 132.61, 130.43, 129.08, 121.09, 120.37, 117.35, 115.91, 78.27, 72.67, 66.89, 48.19, 47.97, 33.82, 33.28, 32.89, 25.79, 25.65, 24.93, 24.80.

[0329] Example 27

[0330] (R)-1-{2-Chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-(4-methoxyphenyl)urea - Compound 27

[0331] According to the method for synthesizing Compound 9 in Example 9, using Intermediate X-2 as the raw material, and carrying out N-acylation reaction with 4-methoxyphenyl isocyanate to prepare Example 27, with a yield of 63.6%.

[0332] HRMS(ESI) m / z: 467.1373 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.55 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.63–7.50 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.15 (d, J = 5.7 Hz, 1H), 3.94–3.72 (m, 4H), 3.71 (s, 3H), 2.27 (dq, J = 14.4, 7.6 Hz, 1H), 1.98 (dt, J = 12.9, 5.8 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 193.18, 162.40, 155.23, 153.08, 139.59, 139.07, 132.77, 132.63, 130.55, 129.11, 121.91, 121.05, 120.88, 118.03, 115.96, 114.48, 78.32, 72.68, 66.90, 55.67, 32.92.

[0333] Example 28

[0334] (R)-1-{2-Chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-[4-(trifluoromethoxy)phenyl]urea - Compound 28

[0335] According to the synthesis method of Compound 9 in Example 9, using Intermediate X-2 as the raw material, an N-acylation reaction was carried out with 4-trifluoromethoxyphenyl isocyanate to prepare Example 27, with a yield of 31.1%.

[0336] HRMS(ESI) m / z: 521.1090 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 15.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.63–7.46 (m, 5H), 7.28 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 5.16 (t, J = 3.3 Hz, 1H), 3.95–3.71 (m, 4H), 2.27 (dtd, J = 14.2, 8.2, 6.3 Hz, 1H), 1.98 (dt, J = 12.9, 6.4 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 193.10, 162.42, 152.86, 143.33, 139.21, 139.11, 132.63, 130.61, 129.09, 122.38, 122.11, 121.66, 121.32, 120.20, 119.64, 118.32, 115.96, 78.32, 72.67, 66.89, 32.91.

[0337] Example 29

[0338] 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-cyclohexylurea - Compound 29

[0339] According to the method of Step A2 in Example 1, using intermediate XI as the raw material, a Friedel-Crafts acylation reaction was carried out with phenetole to prepare intermediate XIII-2, with a yield of 44.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.7 Hz, 1H), 8.01–7.89 (m, 2H), 7.84–7.75 (m, 2H), 7.17–7.06 (m, 2H), 4.16 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

[0340] According to the method for the synthesis of intermediate X1 in Example 7, using intermediate XIII-2 as the raw material, a reduction reaction was carried out under iron / ammonium chloride conditions to prepare intermediate X-3, with a yield of 81.5%. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.81 (dd, J = 8.1, 2.1 Hz, 1H), 5.66 (s, 2H), 4.13 (q, J = 6.9 Hz, 1H), 1.36 (t, J = 6.9 Hz, 2H).

[0341] According to the method for synthesizing Compound 9 in Example 9, using Intermediate X-3 as the raw material, an N-acylation reaction is carried out with cyclohexyl isocyanate to prepare Example 29, with a yield of 96.6%.

[0342] HRMS(ESI)m / z:401.1652[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.68(d,J=8.8Hz,2H),7.54(d,J=2.4Hz,1H),7.48–7.37(m,2H),7.06(d,J=8.9Hz,2H),6.19(d,J=7.8Hz,1H),4.13(q,J=7.0Hz,2H),3.46–3.37(m,1H),1.35(t,J=7.0Hz,3H),1.31–0.82(m,10H);13C NMR(126MHz,DMSO-d6)δ193.27,163.69,154.62,140.16,139.04,132.57,130.41,128.93,121.14,120.36,117.42,115.15,64.23,48.20,33.28,25.66,24.79,14.90.

[0343] Example 30

[0344] 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-(4-methoxyphenyl)urea --- Compound 30

[0345] According to the method for synthesizing Compound 9 in Example 9, using Intermediate X-3 as the raw material, an N-acylation reaction is carried out with p-methoxyphenyl isocyanate to prepare Example 30, with a yield of 39.8%.

[0346] HRMS(ESI) m / z: 425.1275 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68–8.54 (m, 1H), 8.49–8.37 (m, 1H), 7.85–7.58 (m, 2H), 7.44–7.28 (m, 3H), 7.27–7.17 (m, 1H), 7.12–6.98 (m, 3H), 6.91–6.82 (m, 2H), 3.81 (s, 2H), 3.72 (d, J = 3.5 Hz, 3H), 1.46–1.27 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 193.73, 162.95, 159.88, 156.84, 155.62, 153.21, 137.60, 135.78, 132.66, 131.58, 130.66, 129.94, 129.25, 127.25, 125.61, 125.28, 123.40, 122.71, 120.56, 115.39, 114.81, 114.56, 114.18, 114.06, 64.11, 55.82, 55.67, 55.64, 14.96.

[0347] Example 31

[0348] 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea --- Compound 31

[0349] According to the synthesis method of Compound 9 in Example 9, using Intermediate X-3 as the raw material, N-acylation reaction with 4-trifluoromethoxyphenyl isocyanate was carried out to prepare Example 31 with a yield of 68.2%.

[0350] HRMS(ESI) m / z: 479.0994 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 9.00 (s, 1H), 7.77–7.66 (m, 2H), 7.62–7.46 (m, 5H), 7.28 (d, J = 8.6 Hz, 2H), 7.11–7.04 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 193.11, 163.75, 152.85, 143.25, 139.20, 139.13, 132.63, 130.61, 128.82, 122.33, 122.18, 121.91, 121.25, 120.15, 119.37, 118.26, 115.18, 64.24, 14.90.

[0351] The structures of Compounds 1 - 31 are summarized as follows:

[0352] Compounds 1 - 11

[0353] Dibenzyl derivatives:

[0354]

[0355] Among them, R 2 is H, R 3 is Cl, X is CH 2 and R 4 is

[0356]

[0357]

[0358] Compounds 12 - 17

[0359] Diphenylmethane derivatives:

[0360]

[0361] Among them, R 2 is H, R 3 is Cl, X is CO, and R 4 is

[0362] Compounds 18 - 24

[0363] Diphenylmethane derivatives:

[0364]

[0365] Among them, R 2 is H, R 3 is Cl, X is CO, and R 4 is

[0366]

[0367] Compound 25

[0368] Dibenzyl derivatives:

[0369]

[0370] Among them, R 2 is H, R 3 is Cl, X is CH2 , R 4 is

[0371] Compounds 26 - 31

[0372] Diphenylmethane derivatives:

[0373]

[0374] wherein, R 2 is Cl, R 3 is H, X is CO, Y is

[0375] Example 32

[0376] The diphenylmethane derivatives prepared in the above examples were subjected to a myocardial protection activity experiment:

[0377] I. In vitro cytotoxicity test

[0378] The effect of the diphenylmethane derivatives of formula I according to the present invention on the survival rate of normal rat cardiomyocyte cell line H9c2 was investigated in vitro.

[0379] 1. Cell culture

[0380] Using DMEM medium as the basal culture medium, a cell culture medium containing 10% fetal bovine serum was prepared. It was cultured in an incubator at 37°C containing 5% CO 2 . The culture medium was changed daily. When the cells grew to 80% - 90%, the original culture medium was discarded, the cells were rinsed once with PBS, digested with 0.25% trypsin, and subcultured according to the experimental requirements.

[0381] 2. Drug preparation

[0382] The volume of DMSO required for the compound was calculated based on its molecular weight and the weighed mass, and a stock solution (100 mM) of the same concentration was prepared and stored at 4°C.

[0383] 3. Experimental procedure

[0384] (1) Inoculating cells: Taking cells in the logarithmic growth phase with good growth state, digesting the cells with 0.25% trypsin, then blowing and dispersing them into a single cell suspension with the culture medium, and inoculating them into a 96-well plate at an appropriate density (3000 cells / well), 100 μL / well, and culturing them in an incubator at 37°C with saturated humidity and 5% CO 2 .

[0385] (2) Drug treatment: After culturing the cells for 24 h, according to the experimental requirements, 4 different concentration gradients of the drug were set and 100 μL was added to each well. Three replicate wells were set for each group, and a blank group was set for each plate. In this experiment, the test drugs were diluted to the corresponding concentration gradients of 100 μM, 30 μM, 10 μM, and 3 μM for drug addition, and the action time was 48 h. After drug addition, the cells were cultured in a 5% CO 2 incubator at 37 °C for the corresponding time, and the cell status was observed under an inverted microscope;

[0386] (3) Color development and colorimetry: After the drug reached the action time point, the drug was discarded, 100 μL of CCK8 solution was added to each well, and incubation was continued for 1 h; the 96-well plate was placed in an enzyme-linked immunosorbent assay (ELISA) reader, and the absorbance (OD) value of each well was measured at a wavelength of 450 nm and compared with the blank group.

[0387] (4) Data analysis: Calculate the cell proliferation rate and inhibition rate of each group.

[0388] Cell survival rate % = (average OD value of the test group / OD value of the blank group) × 100%

[0389] Inhibition rate = (1 - average OD value of the test group / OD value of the blank group) × 100%

[0390] Calculate the half-maximal inhibitory concentration (IC 50 ) of the drug: According to the drug action concentration and the growth inhibition rate of the drug on the cells, the IC 50 value was calculated using GraphPad Prism statistical analysis software.

[0391] The results of the inhibition of the activity of rat normal cardiomyocyte cell line H9c2 by the compound are shown in the following table.

[0392] Table 1 Inhibition of the activity of rat normal cardiomyocyte cell line H9c2 by the compound

[0393]

[0394] Taking IC50 of 10 μM as the boundary, it shows that most of the compounds have little toxicity to rat normal cardiomyocyte cell line H9c2.

[0395] II. In vitro enzyme inhibition activity

[0396] The cultured cardiomyocytes were seeded in a 96-well plate at a density of 10,000 cells / well and then incubated for 24 hours. On the next day, the culture medium was removed and the cells were washed several times with Hank’s balanced salt solution (HBSS, SH30268.01, Hyclone). Subsequently, HBSS containing 5 mmol / L BCECF-AM, 20 mmol / L NH4Cl and the test compound were added to the cells and incubated for 30 minutes in the dark at 37 °C and 5% CO2. At the end of the incubation, the buffer was removed and the cells were washed twice with HBSS for 5 minutes each time. 100 μL of HBSS was added to each well to prevent the cells from drying. The fluorescence of BCECF-AM (excitation, 488 nm; emission, 535 nm) was detected using a microplate reader (BioTek). All doses were set up in triplicate, and non-linear fitting was performed using GraphPad Prism 9 to calculate the IC 50 value, and the results are shown in the following table.

[0397] Table 2 In vitro NHE1 enzyme inhibitory activity

[0398]

[0399] The structure of Empagliflozin is: The structure of compound 32 is: The structure of compound 33 is:

[0400] The IC 50 values of the compounds against the tested NHE1 were significantly lower than those of the positive control and compounds 32 and 33 (compounds 32 and 33 are existing known compounds). Especially for compound 23, its IC 50 value was lower than 1 μM, showing good targeting activity.

[0401] III. Cell protection assay

[0402] The protective effect of compound 23 was evaluated in a glucose-deprivation-induced H9c2 cell injury model. The cultured cardiomyocytes were digested with trypsin and re-plated in a 96-well plate at a density of 3000 cells per well. After the compounds (0.3, 1, 3, 10, 30 and 100 μmol / L) were added to the cells and incubated for 48 h, the culture medium was removed and the cells were washed once with PBS. Subsequently, glucose-free DMEM medium was added to induce cell injury for 24 hours, and the viability of cardiomyocytes was measured at 450 nm using CCK-8 assay. All doses were set up in triplicate, and non-linear fitting was performed using GraphPad Prism 9. The results are as shown in Figure 1 and the following table, where Figure 1 A is the effect of compound 23 on the survival rate of normal rat cardiomyocytes;Figure 1 Effect of Compound 23 on the protection of cells induced by glucose deprivation; Figure 1 Effect of Cariporide on the protection of cells induced by glucose deprivation; Figure 1 Effect of Empagliflozin on the protection of cells induced by glucose deprivation.

[0403] Table 3 Protective effects of compounds on glucose deprivation-induced H9c2 cells

[0404]

[0405] NA: Not detected

[0406] The results showed that all compounds could increase the viability of cells induced by glucose deprivation.

[0407] Especially, Compound 23 could increase the viability of cells induced by glucose deprivation at a relatively low concentration (1 μM), indicating that as an NHE1 inhibitor, Compound 23 could protect cardiomyocytes from glucose deprivation-induced injury at a relatively low concentration.

[0408] IV. Surface Plasmon Resonance Analysis (SPR)

[0409] The in vitro binding affinity between NHE1 and Compound 23 was evaluated using a Biacore 1K surface plasmon resonance (SPR) instrument (USA). Briefly, the NHE1 protein was diluted with sodium acetate buffer (50 μg / mL in 10 mM sodium acetate at pH 4.5) and flowed into the CM5 biosensor chip at a rate of 10 μL / min for 7 minutes. Uncoupled proteins were washed with ethanolamine hydrochloride. Compounds were serially diluted with a buffer containing 5% DMSO (1×PBS-P). The contact and dissociation times for proteins and small molecules were set at 90 seconds, and the flow rate was 30 μL / min. Finally, the data were analyzed using Biacore evaluation software, and curve fitting was performed using a 1:1 binding model. The results are shown as Figure 2 follows. The SPR experiment showed that the compound could effectively bind to the NHE1 protein. Only the data of Compound 23 are shown in the figure, and the other compounds are similar.

[0410] V. In vivo Pharmacodynamic Experiments

[0411] Male C57BL / 6J mice were purchased from Hunan SJA Laboratory Animal Co., Ltd. The animals were housed under specific pathogen-free conditions with a 12-hour light-dark cycle, a temperature of 25°C, and a humidity of 55%, and had free access to water and food. All experimental procedures were approved by the Laboratory Animal Welfare Ethics Committee and the Animal Management Committee of Central South University (IRB approval number: CSU-2024-0304). For pressure overload-induced HF using isoproterenol infusion, mice (8 weeks old) were divided into 6 groups (n = 6), including a sham operation group (1) control group, (2) model group, (3) ISO + Cariporide (10 mg / kg, once daily), (4) ISO + EMPA (30 mg / kg, once daily), (5) ISO + high-dose compound compound 23 (30 mg / kg, once daily), and (6) ISO + low-dose compound compound 23 (10 mg / kg, once daily). The compounds were administered by gavage. Except for the control group, mice were subcutaneously injected with isoproterenol twice a day for 2 weeks at the following doses: 40 mg / kg on days 1-2, 20 mg / kg on days 3-7, and 10 mg / kg on days 8-14. Mice in the sham operation group were subcutaneously injected with saline. After the experiment, in vivo cardiac ultrasound was performed. Under light anesthesia, cardiac function was evaluated by transthoracic echocardiography (TTE) using a Vevo 2000 high-resolution imaging system (SonicsVisual). The heart was imaged in a two-dimensional parasternal short-axis view, and M-mode echocardiography of the mid-ventricle was recorded at the level of the papillary muscles. Diastolic and systolic left ventricular diameters were measured. The fractional shortening and ejection fraction were calculated as Figure 3 shown. Among them Figure 3 A shows the effect of compound 23 on the left ventricular ejection fraction in an isoproterenol-induced heart failure model; Figure 3 B shows the left ventricular fractional shortening.

[0412] The results showed that: After 14 days of administration, compound 23 showed a significant inhibitory effect on pressure overload-induced HF by isoproterenol infusion, effectively reducing the degree of heart failure in isoproterenol-induced C57BL / 6J mice, increasing their left ventricular ejection fraction and left ventricular fractional shortening. Additionally, there were no significant changes in the body weights of the animals in the experimental groups compared to the blank group, and there were no death samples during the experiment, demonstrating that compound 23 has no obvious toxicity. This fully indicates that compound 23 is an effective inhibitor against NHE1.

[0413] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the implementation manners here. Any obvious changes or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A diphenylmethane derivative, characterized in that It is a compound represented by formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: Wherein, X is CH2; Y is selected from: -NH-, -CO-, -NHCONH-, The Y is , may be substituted by 0-3 R7; R7 is selected from hydrogen, halogen, C1-C6 alkyl; R1 is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, carboxyl, -CONHC(=NH)NH2, -C(=NH)NH2, Acylguanidine, substituted acylguanidine, guanidine, substituted guanidine, imide amide, C1-C6 alkyl, substituted C1-C6 alkyl, CO-(C1-C6 alkyl), substituted CO-(C1-C6 alkyl), C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, C5-C14 aromatic heterocycle, substituted C5-C14 aromatic heterocycle, aryl, substituted aryl; the substituent is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy; R2 is selected from: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl; R3 is selected from: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl; R4 is OR5; R5 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C5-C14 aromatic heterocycle, substituted C5-C14 aromatic heterocycle; Wherein, the C5-C14 aromatic heterocycle contains 1-3 heteroatoms, and the heteroatoms are N, O or S atoms; wherein, the substituted C5-C14 aromatic heterocycle is substituted by 1-3 identical or different R6; R6 is selected from hydrogen, halogen, C1-C6 alkyl.

2. The diphenylmethane derivative according to claim 1, characterized in that When R1 or R5 is a C5-C14 aromatic heterocycle or a substituted C5-C14 aromatic heterocycle, the C5-C14 aromatic heterocycle is selected from: pyridine, pyrazine, pyrimidine, pyrazine, pyridazine, pyran, piperidine, piperazine, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, dioxane, hexahydropyrazine, morpholine, and dithiane.

3. The diphenylmethane derivative according to claim 1, characterized in that When R1 is a C1-C6 alkoxy group, the C1-C6 alkoxy group is selected from: -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH2(CH3)2, -O-CH2CH2CH2CH3; when R1 is a C1-C6 alkyl group, the C1-C6 alkyl group is selected from: -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -CH2CH2CH2CH3; R4 is 4. A diphenylmethane derivative, characterized in that It is a compound represented by formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: Wherein, X is CO; Y is selected from: -NH-, -CO-, -NHCONH-, The Y is , may be substituted by 1-3 R7; R7 is selected from hydrogen, halogen, C1-C6 alkyl; R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, -CONHC(=NH)NH2, -C(=NH)NH2, acylguanidine, substituted acylguanidine, guanidine, substituted guanidine, imide amido, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, C5-C14 aromatic heterocycle, substituted C5-C14 aromatic heterocycle, aryl, substituted aryl; the substituent is selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy; R2 is selected from: hydrogen, halogen, C1-C6 alkyl; R3 is selected from: hydrogen, halogen, C1-C6 alkyl; R4 is OR5; R5 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C5-C14 aromatic heterocycle, substituted C5-C14 aromatic heterocycle; Wherein, the C5-C14 aromatic heterocycle contains 1-3 heteroatoms, and the heteroatoms are N, O or S atoms; wherein, the substituted C5-C14 aromatic heterocycle is substituted by 1-3 identical or different R6; R6 is selected from hydrogen, halogen, C1-C6 alkyl.

5. The diphenylmethane derivative according to claim 4, characterized in that When R1 is a substituted aryl group, the substituent is selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy; preferably, when R1 is a substituted aryl group, the substituent is selected from monohalomethoxy, dihalomethoxy, trihalomethoxy, monohaloethoxy, dihaloethoxy, trihaloethoxy, monohalopropoxy, dihalopropoxy, trihalopropoxy; the halogen element is selected from: fluorine, chlorine, bromine, iodine.

6. The diphenylmethane derivative according to claim 4, characterized in that R1 is -NHC(=NH)NH2, Preferably, when R1 or R5 is a C5-C14 aromatic heterocycle or a substituted C5-C14 aromatic heterocycle, the C5-C14 aromatic heterocycle is selected from: pyridine, pyrazine, pyrimidine, pyrazine, pyridazine, pyran, piperidine, piperazine, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, dioxane, hexahydropyrazine, morpholine, dithiane; substituted C5-C14 aromatic heterocycle is a substitute of C5-C14 aromatic heterocycle.

7. The diphenylmethane derivative according to claim 4, characterized in that When R1 is a C1-C6 alkoxy group, the C1-C6 alkoxy group is selected from: -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH2(CH3)2, -O-CH2CH2CH2CH3; when R1 is a C1-C6 alkyl group, the C1-C6 alkyl group is selected from: -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -CH2CH2CH2CH3; R4 is 8. The diphenylmethane derivative according to any one of claims 1 to 7, characterized in that The diphenylmethane derivative is the following compound, its optical isomer or its pharmaceutically acceptable salt: (R)-4-chloro-N-(diaminomethylene)-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}benzamide; (R)-5-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-1,2,4-oxadiazol-3-amine; (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carbonitrile; (R)-[4-chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone; (R)-{2-chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone; (R)-[4'-amino-4-chloro-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone; (R)-[4-chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methanone; (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-ol; (R)-5-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-2-(piperidin-1-yl)pyridine; (R)-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-amine; (R)-1-{4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine; (S)-1-{4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine; (R)-1-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}piperazine; (R)-N-Carbamoyl-4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}-(1,1'-biphenyl)-4-carboxamide; (R)-1-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-3-(4-methoxyphenyl)urea; (R)-1-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}-3-(2-ethylphenyl)urea; (R)-N-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}acetamide; (R)-1-{4-chloro-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}phenyl}guanidine; 4'-Chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carbonitrile; [4-Chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone; {2-chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}(4-ethoxyphenyl)methanone; [4'-amino-4-chloro-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone; [4-Chloro-4'-(piperazin-1-yl)-(1,1'-biphenyl)-3-yl](4-ethoxyphenyl)methanone; [2-Chloro-5-(piperazin-1-yl)phenyl](4-ethoxyphenyl)methanone; N-Carbamoyl-4'-chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-carboxamide; (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-cyclohexylurea; (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-(4-methoxyphenyl)urea; (R)-1-{2-chloro-5-{4-[(tetrahydrofuran-3-yl)oxy]benzoyl}phenyl}-3-[4-(trifluoromethoxy)phenyl]urea; 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-cyclohexylurea; 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-(4-methoxyphenyl)urea; 1-[2-Chloro-5-(4-ethoxybenzoyl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea.

9. The method for preparing a diphenylmethane derivative according to any one of claims 1 to 8, characterized in that: The intermediate M1 or M2 undergoes a deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative. Intermediate M1 is: Intermediate M2 is:

10. Use of the diphenylmethane derivative according to any one of claims 1 to 8 in the preparation of a drug for treating heart failure or myocardial hypertrophy, or in the preparation of an NHE1 inhibitor.

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