Diphenylmethane derivatives, processes for their preparation and use

Abstract

This invention belongs to the field of pharmaceutical technology, and relates to diphenylmethane derivatives, their preparation methods, and applications. The diphenylmethane derivative is a compound represented by Formula I, its optical isomer, or a pharmaceutically acceptable salt thereof: wherein X is CH2; Y is selected from: -NH-, -CO-, -NHCONH-. The diphenylmethane derivative of this invention is stable, easy to store, and readily prepared, exhibiting good feasibility. It demonstrates outstanding in vitro and in vivo efficacy and good safety profile when used to prepare anticardioprotective drugs (for heart failure and myocardial hypertrophy).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to diphenylmethane derivatives, their preparation methods, and applications. Background Technology

[0002] Heart failure (HF) is considered the end-stage of various cardiovascular diseases, characterized by poor prognosis and high mortality. HF primarily occurs in elderly patients over 60 years of age, but can sometimes occur in younger patients who have survived acute myocardial infarction (MI). HF can be triggered by a variety of factors, including coronary artery disease (CAD), hypertension, diabetes, a family history of heart disease, obesity, chronic lung disease, or the use of cardiac toxins. Ischemic heart disease caused by impaired myocardial perfusion is considered the most common cause of HF. Despite advances in the combined use of several drugs (including RASi, beta-blockers, MRA, and SGLT2 inhibitors) to treat HF, no single drug can reduce mortality in HF.

[0003] Sodium-hydrogen exchanger 1 (NHE1) is encoded by the SLC9A1 gene and belongs to the mammalian Na+ / H+ exchanger (NHE) gene family of membrane transporters. The NHE family has been reported to contain at least nine isoforms, all functioning to exchange extracellular Na+ for intracellular H+. NHE1 is the only isoform present in cardiomyocytes and regulates sodium and calcium ion homeostasis. Animal studies have shown that NHE1 gene knockout has a cardioprotective effect during ischemia and reperfusion, with better recovery of left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVDP), and coronary blood flow. This makes NHE1 a promising target for cardioprotective activity.

[0004] Current clinical treatments for heart failure are effective, but overall, they are not satisfactory. Developing more anti-heart failure drugs and improving patient cure rates remain urgent scientific challenges. Summary of the Invention

[0005] The purpose of this invention is to provide a diphenylmethane derivative, its preparation method, and its application in the treatment of heart failure.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] Diphenylmethane derivatives, which are compounds of Formula I, their optical isomers, or pharmaceutically acceptable salts thereof:

[0008]

[0009] Where X is CH2;

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

[0011] The Y is At this time, it can be replaced by 1-3 R7s; R7s are selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0012] R1 is selected from: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, -C(=NH)NH2, acylguanidine, substituted acylguanidine, guanidine, substituted guanidine, iminoamide, 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;

[0013] R2 is selected from: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl;

[0014] R3 is selected from: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl;

[0015] R4 is OR5;

[0016] R5 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C5-C14 aromatic heterocycle, and 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 R6s;

[0017] R6 is selected from hydrogen, halogen, and C1-C6 alkyl.

[0018] In one preferred embodiment, the aryl group is selected from: phenyl, naphthyl, anthraceneyl, phenanthryl, pyreneyl.

[0019] Substituted aryl groups, namely phenyl, naphthyl, anthracene, phenanthryl, and pyrene.

[0020] In one preferred embodiment, CO-(C1-C6 alkyl) is selected from: -CO-CH3, -CO-CH2CH3, -CO-CH2CH2CH3, -CO-CH2(CH3)2, -CO-CH2CH2CH2CH3.

[0021] In one preferred embodiment, R1 is -NHC(=NH)NH2.

[0022] In one preferred embodiment, 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, pyran, piperidine, piperazine, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, tetrahydrothiaran, dioxane, hexahydropyrazine, morpholine, dithiane; the substituted C5-C14 aromatic heterocycle is a substituted product of the C5-C14 aromatic heterocycle.

[0023] In one preferred embodiment, 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.

[0024] In one preferred embodiment, when R1 is a C1-C6 alkyl group, the C1-C6 alkyl group is selected from: -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -CH2CH2CH2CH3.

[0025] In one preferred embodiment, R2 is selected from C1-C4 alkyl groups;

[0026] In one preferred embodiment, R3 is selected from C1-C4 alkyl groups;

[0027] In one preferred embodiment, R6 is selected from C1-C4 alkyl groups.

[0028] In one preferred embodiment, when Y is -NHCONH- and R1 is a substituted phenyl group, the substituent is not a methoxy group.

[0029] In one preferred embodiment, Y is R1 is not piperazine.

[0030] In one preferred embodiment, R4 is

[0031] Based on the same inventive concept, this invention also claims protection for another diphenylmethane derivative, which is a compound of formula I, its optical isomer, or a pharmaceutically acceptable salt thereof:

[0032]

[0033] Where X is CO;

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

[0035] The Y is At this time, it can be replaced by 0-3 R7s; R7s are selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0036] R1 is selected from: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, -CONHC(=NH)NH2, -C(=NH)NH2, acylguanidine, substituted acylguanidine, guanidine, substituted guanidine, imine amide, 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 halogen, C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy;

[0037] R2 is selected from: hydrogen, halogen, C1-C6 alkyl;

[0038] R3 is selected from: hydrogen, halogen, C1-C6 alkyl;

[0039] R4 is OR5;

[0040] R5 is selected from C1-C6 alkyl, substituted C1-C6 alkyl, C5-C14 aromatic heterocycle, and 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 R6s;

[0041] R6 is selected from hydrogen, halogen, and C1-C6 alkyl.

[0042] In one preferred embodiment, the aryl group is selected from: phenyl, naphthyl, anthraceneyl, phenanthryl, pyreneyl.

[0043] Substituted aryl groups, namely phenyl, naphthyl, anthracene, phenanthryl, and pyrene.

[0044] In one preferred embodiment, when R1 is a substituted aryl group, the substituent is selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkoxy, and C1-C4 alkoxy.

[0045] In one preferred embodiment, when R1 is a substituted aryl group, the substituent is selected from monohalomethoxyalkylene, dihalomethoxyalkylene, trihalomethoxyalkylene, monohaloethoxyalkylene, dihaloethoxyalkylene, trihaloethoxyalkylene, monohalopropoxyalkylene, dihalopropoxyalkylene, and trihalopropoxyalkylene; the halogen element is selected from fluorine, chlorine, bromine, and iodine.

[0046] In one preferred embodiment, R1 is -NHC(=NH)NH2,

[0047] In one preferred embodiment, 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, pyran, piperidine, piperazine, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, tetrahydrothiaran, dioxane, hexahydropyrazine, morpholine, dithiane; the substituted C5-C14 aromatic heterocycle is a substituted product of the C5-C14 aromatic heterocycle.

[0048] In one preferred embodiment, 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.

[0049] In one preferred embodiment, when R1 is a C1-C6 alkyl group, the C1-C6 alkyl group is selected from: -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -CH2CH2CH2CH3.

[0050] In one preferred embodiment, R2 is selected from C1-C4 alkyl groups;

[0051] In one preferred embodiment, R3 is selected from C1-C4 alkyl groups;

[0052] In one preferred embodiment, R6 is selected from C1-C4 alkyl groups.

[0053] In one preferred embodiment, R4 is

[0054] In one preferred embodiment, Y is -NHCONH- and R4 is When R1 is not cyclohexyl or

[0055]

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

[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-nitrile;

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

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

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

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

[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-nitrile;

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

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

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

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

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

[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, pharmaceutically acceptable salts of the diphenylmethane derivative include inorganic acid addition salts and organic acid addition salts; the inorganic acids and organic acids 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, and benzoic acid.

[0089] Based on the same inventive concept, this invention also claims a method for preparing the diphenylmethane derivative, wherein intermediate M1 or M2 undergoes a deprotection reaction in a reaction solvent to obtain the diphenylmethane derivative.

[0090] Intermediate M1 is:

[0091] Intermediate M2 is:

[0092] In one preferred embodiment, in the above preparation method, Y is a benzene ring, and R1 is... R2 is H, and R3 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] Its reaction route is Route 1:

[0095]

[0096] In one preferred embodiment, when Y is a benzene ring, R1 is NH2, R2 is H, and R3 is Cl, the preparation method is as follows: intermediate M3 or M4 undergoes a deprotection reaction in a 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] Its reaction route is Route 2:

[0101]

[0102] In one preferred embodiment, when R1 is H, R2 is H, and R3 is Cl, Y is The preparation method is as follows: intermediate M5 or M6 undergoes a deprotection reaction in a 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] Its reaction route is route 3:

[0107]

[0108] In one preferred embodiment, when R1 is H, R2 is H, R3 is Cl, X is CH2, and Y is... The preparation method is as follows: intermediate V-1 or IV-3 undergoes a Buchwald coupling reaction with N-Boc piperazine to obtain intermediate M5 or M6; intermediate M5 or M6 undergoes a 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 for the Buchwald coupling reaction includes an inorganic base, an organic base, and a solvent; the inorganic base is one or both of potassium carbonate or sodium carbonate; the organic base is one or both of sodium tert-butyloxide or potassium tert-butyloxide; and the solvent is one or both of water or 1,4-dioxane.

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

[0115]

[0116] The reaction route for obtaining the diphenylmethane derivative by the deprotection reaction of intermediate M5 or M6 in the reaction solvent is route 3.

[0117] In one preferred embodiment, the synthesis of intermediate IV-3 follows route 6:

[0118]

[0119] Intermediate V-1 / V-2 is prepared by Friedel-Crafts acylation of starting material II with phenol to obtain intermediate III, which is then obtained by photoelongation and reduction reactions. Intermediate IV-3 is prepared by Friedel-Crafts acylation of starting material II with phenethyl ether; the reduction reaction includes an aluminum trichloride / disiloxane system.

[0120] In one preferred embodiment, when R2 is H, R3 is Cl, and Y is a C5-C14 aromatic heterocycle, the preparation method is as follows: intermediates IV and V undergo a Suzuki coupling reaction with substituted boric acid or substituted boric ester to obtain intermediates M1 and M2; intermediates M1 or M2 undergo 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 in the Suzuki coupling reaction comprises an inorganic base and a solvent; the inorganic base is one or both of potassium carbonate or sodium carbonate; and the solvent is one or both of water or 1,4-dioxane.

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

[0127]

[0128] The intermediate M1 or M2 undergoes a deprotection reaction in the reaction solvent to obtain the diphenylmethane derivative, which 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 or sodium carbonate; and the solvent is tetrahydrofuran.

[0132] Its reaction route is route 7:

[0133]

[0134] In one preferred embodiment, intermediate X-1 is prepared according to route 8; firstly, intermediate VII is obtained by Friedel-Crafts acylation of intermediate VI, and then intermediate X-1 is obtained by photoelongation reaction, carbonyl reduction reaction and nitro reduction reaction.

[0135] Its reaction route is route 8:

[0136]

[0137] In one preferred embodiment, intermediates X-2 and X-3 are prepared according to route 9; firstly, intermediate XII is obtained by Friedel-Crafts acylation of intermediate XI, followed by photoelongation and reduction reactions to obtain intermediate X-2; intermediate XI undergoes Friedel-Crafts acylation and reduction reactions with phenylethyl ether to obtain X-3.

[0138] Its reaction route is route 9:

[0139]

[0140] In one preferred embodiment, when X is CH2, Y is oxadiazole, R1 is NH2, R2 is H, R3 is Cl, and R4 is... The preparation method is as follows: structural formula 1 undergoes a cyclization reaction in a reaction solvent to obtain the diphenylmethane derivative.

[0141] Structure 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, the reaction route is route 10:

[0144]

[0145] In one preferred embodiment, when Y is carbonyl, R1 is guanidine, R2 is H, R3 is C11, and R4 is... The preparation method is as follows: intermediate V-1 undergoes a formylation reaction with oxalic acid to obtain intermediate XIV, followed by an N-acylation reaction to obtain the diphenylmethane derivative.

[0146] Intermediate V-1 is:

[0147] Intermediate XIV:

[0148] In one preferred embodiment, the reaction route is route 11:

[0149]

[0150] In one preferred embodiment, when Y is a benzene ring, R1 is an acylguanidine group, R2 is H, R3 is Cl, and X is CO, the preparation method is as follows: compound 2 undergoes an alkaline hydrolysis reaction to generate a carboxyl compound XV, followed by an N-acylation reaction to obtain the diphenylmethane derivative.

[0151] Compound 2 is:

[0152] Compound XV:

[0153] In one preferred embodiment, 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 medicaments for treating heart failure or myocardial hypertrophy.

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

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

[0158] I. The diphenylmethane derivatives and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs of the present invention have the advantages of stable properties and easy storage.

[0159] Second, the preparation method is simple, the purity is high, the required raw materials are all available on the market and are cheap and readily available, the reaction process is green and environmentally friendly and will not cause pollution to the environment, the preparation of the compound is easy and has good feasibility.

[0160] Third, experiments have demonstrated that the product of this invention has outstanding in vitro and in vivo efficacy and good safety when used to prepare anticardioprotective drugs (for heart failure and myocardial hypertrophy). Attached Figure Description

[0161] Figure 1 The following are cell protection data for compound 23 of the present invention; Figure A shows the effect of compound 23 on the survival rate of normal rat cardiomyocytes; Figure B shows the effect of compound 23 on glucose-induced cell protection; Figure C shows the effect of cariporide on glucose-induced cell protection; and Figure D shows the effect of empagliflozin on glucose-induced cell protection.

[0162] Figure 2 The SPR results of compound 23 of this invention with NHE1 protein;

[0163] Figure 3 The therapeutic effect of compound 23 of the present invention on heart failure is shown in Figure A, whereby compound 23 has an effect on the left ventricular ejection fraction in an isoproterenol-induced heart failure model; and Figure B shows the left ventricular shortening fraction. Detailed Implementation

[0164] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0165] The proton NMR spectra of the compounds were determined using a Bruker ARX-400 / 600, and the mass spectra were determined using an Agilent 1100LC / MSD. All reagents used were of analytical or chemical purity.

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

[0167] Example 1

[0168] Synthesis of intermediate III in step A1

[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, and 5.0 mL of dichloromethane (DCM) was added and stirred until homogeneous. Then, 0.1 mL of N,N-dimethylformamide (DMF) was added, and thionyl chloride (0.31 mL, 4.3 mmol) was added dropwise under ice bath (0 °C). After the addition was complete, the temperature was raised to 40 °C and the mixture was refluxed. After a half-day test showed no remaining starting material, the reaction solution was distilled under reduced pressure to obtain a colorless liquid, which was directly added to the next reaction. The obtained acyl chloride was placed in a 25 mL three-necked flask, and 5.0 mL of nitrobenzene was added and stirred until homogeneous. Under ice bath (0 °C), aluminum trichloride (0.6 g, 4.3 mmol) and phenol (0.2 g, 2.1 mmol) were slowly added to the mixture, and the temperature was raised to 60 °C. The reaction was monitored by TLC. After the reaction was monitored to complete, the reaction solution was cooled to room temperature. A small amount of crushed ice was slowly added to quench the reaction, followed by 10.0 mL of saturated sodium bicarbonate aqueous solution and stirring for 10 min. 2 mL of hydrochloric acid (10 M) was slowly added for acidification, and dichloromethane (10.0 mL × 3) was added to extract the reaction solution. The organic layers were combined, and the dichloromethane was evaporated to dryness 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, and the pH was adjusted to approximately 2 by acidification with hydrochloric acid (10 M). Ethyl acetate (12 mL × 3) was added to extract the aqueous layer, and the organic layers were combined. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated to dryness to obtain a yellow oil. Subsequent column chromatography purification yielded 0.32 g of a white solid, with a yield of 48.5%. 1 H NMR(600MHz,DMSO-d6)δ10.69(s,1H),7.75(dd,J=8.6,2.4Hz,1H),7.71(d,J =2.4Hz,1H),7.64–7.59(m,2H),7.55(d,J=8.6Hz,1H),6.90(d,J=8.8Hz,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 round-bottom flask, and 5.0 mL of tetrahydrofuran was added and stirred until homogeneous. Then, (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 azodicarbonate (0.2 g, 1.0 mmol) was slowly added dropwise under ice bath (0 °C). The reaction mixture was then brought to room temperature and stirred. After the reaction was complete, 5.0 mL of water was added to quench the reaction mixture, and the mixture was extracted 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 filtration, and the solvent was evaporated under reduced pressure to obtain 0.42 g of a yellow oily liquid. Subsequent column chromatography purification yielded 0.24 g of a white solid, with a yield of 79.2%. 1H NMR(400MHz,DMSO-d6)δ7.77(d,J=7.9Hz,1H),7.73–7.67(m,1H),7.61–7.54(m,1H),7.13–7.05(m,1H),5 .16(td,J=5.4,4.5,2.1Hz,1H),3.95–3.71(m,2H),2.28(dtd,J=14.2,8.2,6.3Hz,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, and 5.0 mL of toluene was added and stirred until homogeneous. Aluminum trichloride (0.1 g, 0.75 mmol) was added to the solution, followed by slow dropwise addition of tetramethyldisiloxane (0.13 mL, 0.75 mmol). The mixture was heated to 28 °C and stirred. After the reaction was complete, 5.0 mL of water was added to the reaction solution and stirred. Ethyl acetate (10.0 mL × 3) was added for extraction, and the organic layers were combined. The mixture was washed twice with saturated brine and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was evaporated to dryness to give 0.15 g of a yellow oily substance, with a yield of 83.3%. 1H NMR(400MHz, DMSO-d6)δ7.46(d,J=2.4Hz,1H),7.43–7.29(m,2H),7.12–7.02(m,2H),6.89–6.7 4(m,2H),4.89(ddd,J=6.4,4.1,1.9Hz,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), and 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 using a syringe. The three-necked flask was then placed in an oil bath preheated to 100 °C. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water. A white solid precipitated, which was obtained by filtration, yielding a white solid with a yield of 49.7%. 1H NMR (400MHz, DMSO-d6) δ13.14(s,1H),7.84(d,J=2.1Hz,1H),7.79(dd,J=8.3,2.1Hz,1H),7.57(d,J=8.3Hz,1H),7.13(d,J=8.7Hz,2 H),6.86(d,J=8.7Hz,1H),5.01–4.94(m,1H),4.06(s,2H),3.91–3.69(m,4H),2.19(dtd,J=14.4,8.2,6.2Hz,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 flask, 5 mL of DCM was added and stirred until homogeneous, then 2 drops of DMF were added and stirred. Oxaloyl chloride (3 eq) was added dropwise under ice bath (0 °C). After the addition was complete, 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 until homogeneous. 0.075 g of guanidine hydrochloride (3 eq) was placed in a 25 mL flask, 5 mL of tetrahydrofuran was added and stirred until homogeneous, then 0.03 g (3 eq) of sodium hydroxide was added and stirred. The tetrahydrofuran solution of acyl chloride was slowly added dropwise until the addition was complete, and the temperature was raised to 50 °C and the reaction was carried out. After the reaction was complete, 10 mL of water was added to the reaction solution and stirred until homogeneous. Sodium hydroxide solution was added to the reaction solution to adjust the pH to 10, and the mixture was extracted with DCM (30 mL × 3). The organic layers were combined and evaporated to dryness to give 0.12 g of a yellow oil. Column chromatography then yielded 35 mg of a white solid, with a yield of 54.7%.

[0188] HRMS(ESI) m / z: 374.1272 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 8.54 (d, J=

[0189] 63.6Hz,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),4.0 8(s,2H),3.90–3.61(m,4H),2.19(dtd,J=14.3,8.2,6.2Hz,1H),1.92(dt,J=13.4,6.4Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ159.55,159.23,156.17,140.13,139.13,131.52,1 31.14,130.41,130.29,128.15,115.77,77.44,72.73,66.85,37.93,32.90.

[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 round-bottom flask, and 5 mL of DMF was added and stirred to dissolve. Iodophenyl diacetic acid (1.5 eq) was slowly added under ice bath (0 °C). After the addition was complete, the temperature was raised to room temperature (20 °C) for the reaction. After the reaction was complete, the reaction solution was poured into 20 mL of water and stirred. The solution was extracted with ethyl acetate, evaporated to dryness, and then subjected to column chromatography to obtain 15 mg of white solid, with a yield of 25.1%.

[0195] HRMS(ESI)m / z:372.1112[M+H]+; 1H NMR (400MHz, DMSO-d6) δ7.94–7.80(m,2H),7.67(d,J=8.3Hz,1H),7.17(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6.42(s,2H),4.98 13C NMR (101MHz, DMSO-d6) δ172.60,169.46,156.20,140.80,131.14,130.99,130.47,123.57,115.86,77.44,72.74,66.86,37.70,32.92.

[0196] Example 3

[0197] Synthesis of Compound 3

[0198] The structural formula of compound 3 is:

[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 EA was added for extraction (20 mL × 3). The organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a black solid. Column chromatography yielded 0.182 g of a yellow oil, with a yield of 76.2%.

[0201] HRMS(ESI)m / z:403.1077[M+H]+; 1H NMR (500MHz, DMSO-d6) δ9.60 (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. 4,4.0,1.8Hz,1H),4.03(s,2H),3.88–3.69(m,4H),2.17(dtd,J=13.3,8.2,6.3Hz,1H),1.92(dddd,J=13.2,7.0,3.3,1.3Hz,1H).13C NMR(126MHz,DMSO-d6)δ157.87,156.00,139.79,139.52,132.10,131.61,130.20,130.1 3,130.06,129.19,128.20,125.95,116.24,115.72,77.44,72.74,66.85,38.10,32.91.

[0202] Example 4

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

[0204] Following the method described in Example 3, using intermediate V-1 as a starting material, Example 4 was prepared by a Suzuki coupling reaction with 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine, with a yield of 86.3%.

[0205] HRMS(ESI)m / z:449.2000[M+H]+; 1H NMR(500MHz,DMSO-d6)δ8.40(d,J=2.6Hz,1H),7.78(dd,J=8.9,2.7Hz,1H),7.61(d, J=2.3Hz,1H),7.51–7.39(m,2H),7.17(d,J=8.3Hz,2H),6.85(dd,J=15.9,8.7Hz,3H ),4.98–4.89(m,1H),4.03(s,2H),3.90–3.69(m,4H),3.55(t,J=5.5Hz,4H),2.17(d td,J=14.2,8.2,6.2Hz,1H),1.92(p,J=6.4Hz,1H),1.57(dq,J=33.9,6.0Hz,6H).13C NMR(126MHz,DMSO-d6)δ158.76,156.02,145.99,139.69,137.32,135.98,132.03,131.66,130.22, 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] Following the method described in Example 3, intermediate M3 was prepared by a Suzuki coupling reaction between intermediate V-1 and 4-(Boc-amino)phenylboronic acid, 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 flask, and 10 mL of trifluoroacetic acid was added with stirring. After the reaction was complete, the trifluoroacetic acid was distilled off from the reaction solution, and 10 mL of water was added to the reaction solution with stirring. Saturated sodium bicarbonate solution was added to adjust the pH to 8, 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 (500MHz, DMSO-d6) δ7.52(s,1H),7.45–7.28(m,4H),7.16(d,J=8.1Hz,2H),6.83(d,J=7.7Hz,2H),6.64(d,J=8 .0Hz,2H),5.28(s,2H),4.94(s,1H),4.02(s,2H),3.91–3.60(m,4H),2.16(h,J=7.4Hz,1H),1.99–1.85(m,1H).13C NMR(126MHz,DMSO-d6)δ155.98,149.15,140.29,139.35,132.20,130.78,130.18,130.0 1,128.53,127.62,126.48,125.30,115.70,114.67,77.45,72.75,66.85,38.15,32.92.

[0211] Example 6

[0212] (R)-1-{4'-chloro-3'-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}-(1,1'-biphenyl)-4-yl}piperazine-compound 6

[0213] Following the method in Example 3, intermediate M1-1 was prepared by reacting intermediate V-1 with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester via a Suzuki coupling reaction, with a yield of 51.3%. 1H NMR (400MHz, DMSO-d6) δ7.59(d,J=2.3Hz,1H),7.53–7.40(m,4H),7.17(d,J=8.6Hz,2H),7.00(s,1H),6.83(d,J=8.7Hz,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 = 5.2Hz, 5H), 3.22–3. 04(m,3H),2.23–2.10(m,1H),1.92(dt,J=12.5,5.9Hz,1H),1.42(s,9H).

[0214] Following the method in Example 5, intermediate M1-1 was used as the raw material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 50.3%.

[0215] HRMS(ESI)m / z:449.2003[M+H]+; 1H NMR (500MHz, DMSO-d6) δ7.58(s,1H),7.53–7.38(m,4H),7.17(d,J=8.1Hz,2H),6.98(d,J=8.4Hz,2H),6.84(d,J=8.2Hz,2H),4.95(d,J= 13C NMR (126MHz, DMSO-d6) δ156.01,151.49,139.60,139.53,132.10,131.50,130.22,130.14,129. 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] Following the method in step A1 of Example 1, intermediate VII was prepared by Friedel-Crafts acylation reaction of intermediate VI with phenol, 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] Following the method in step A2 of Example 1, intermediate VIII was prepared by photoelectrophoresis of intermediate VII with (S)-(+)-3-hydroxytetrahydrofuran, with a yield of 93.8%. HRMS (ESI) m / z: 348.0638 [M+H]+.1H NMR (500MHz, DMSO-d6) δ 8.46–8.19 (m, 2H), 7.91 (d, J = 8.7Hz, 1H), 7.84–7.59 (m, 2H), 7.24–6.91 (m, 2H), 5.18 (tt, J = 4.6, 2.1Hz, 1H), 4.02–3.59 (m, 4H), 2.28 (dtd, J = 14.2, 8.2, 6.2Hz, 1H), 1.98 (dt, J = 12.8, 5.8Hz, 1H).

[0220] Following the method in step A3 of Example 1, intermediate IX was prepared by carbonyl reduction reaction using intermediate VIII as the raw material, with a yield of 85.7%. 1H NMR(500MHz,DMSO-d6)δ8.19(d,J=2.7Hz,1H),8.10(dd,J=8.7,2.8Hz,1H),7.75(d,J=8.7Hz,1H),7.17(d,J=8.5Hz,2H),6.90–6.84(m,2H), 4.98(ddt,J=6.4,4.3,1.9Hz,1H),4.13(s,2H),3.90–3.78(m,2H),3.78–3.70(m,2H),2.19(dtd,J=14.3,8.2,6.2Hz,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 round-bottom flask, 20 mL of anhydrous ethanol was added and stirred until homogeneous, then reduced iron powder (5 eq) was added, and the mixture was heated to 50 °C and reacted for 20 min. Then, 10 mL of saturated ammonium chloride aqueous solution was added, and the mixture was refluxed to 80 °C. After the reaction was complete, the iron powder was removed by filtration through a hot diatomaceous earth pad. The filtrate was evaporated to dryness, water was added to the residue and stirred, and ethyl acetate was added for extraction (100 mL × 3). The extracts were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness to obtain 1.012 g of brown solid. This was purified by column chromatography to obtain 1.012 g of brown solid, with a yield of 79.4%. 1H NMR (400MHz, DMSO-d6) δ7.12–7.05(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 ,1.9Hz,1H),3.87(dd,J=10.1,4.6Hz,1H),3.83–3.77(m,3H),3.77–3.70(m,2H),2.18(dtd,J=13.2,8.2,6.2Hz,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 round-bottom flask, 10 mL of dichloromethane was added and stirred until homogeneous, then triethylamine (2 eq) was added and stirred, followed by the slow addition of acetyl chloride (1.2 eq). After the addition was complete, the reaction proceeded at room temperature. Once the reaction was complete, water was added to the reaction mixture and stirred. Dichloromethane was added for extraction (10 mL × 3 times), and the extracts were combined. The mixture was dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain 55 mg of white solid. This was purified by column chromatography to obtain 30 mg of white solid, with a yield of 26.5%.

[0229] HRMS(ESI)m / z:346.1209[M+H]+; 1H NMR (500MHz, DMSO-d6) δ9.97(s,1H),7.53(dd,J=8.8,2.6Hz,1H),7.42(d,J=2.6Hz,1H),7.34(d,J=8.6Hz,1H),7.09(d,J=8.1Hz,2H),6.85(d, J=8.1Hz,2H),5.02–4.87(m,1H),3.94(s,2H),3.90–3.68(m,4H),2.19(dq,J=14.8,8.2Hz,1H),2.00(s,3H),1.93(dt,J=13.1,6.1Hz,1H).13C NMR(126MHz,DMSO-d6)δ168.84,156.07,139.40,138.91,131.80,130.23(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:

[0233]

[0234] At room temperature, 0.1 g of intermediate X-1 was placed in a 25 mL round-bottom flask, and 3 mL of glacial acetic acid was added and stirred until homogeneous. The mixture was then heated to 120 °C. An aqueous solution of cyanamide (0.030 g of cyanamide dissolved in 0.5 mL of water) was slowly added dropwise, and the reaction was continued under reflux. After the reaction was complete, the reaction solution was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added to adjust the pH to 8. A solid precipitated out; this 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(500MHz,DMSO-d6)δ9.99(s,1H),7.63(s,3H),7.49(d,J=8.5Hz,1H),7.20–7.11(m,4H),6.85(d,J=8.4Hz,2H),4 .97(t,J=6.4Hz,1H),3.99(s,2H),3.91–3.68(m,4H),2.19(td,J=14.2,8.2Hz,1H),1.93(dt,J=12.6,5.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ156.48,156.13,140.58,135.10,131.38,131.12,1 30.88,130.39,127.62,124.71,115.72,77.46,72.74,66.86,37.99,32.92.

[0236] Example 9

[0237] Synthesis of Compound 9

[0238] The structural formula of compound 9 is:

[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 until homogeneous. 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 complete, the reaction solution was cooled to room temperature, a small amount of water was added and stirred, and ethyl acetate was added for extraction (10 mL × 3). The extracts were combined, dried over anhydrous sodium sulfate, and the organic solvent was evaporated. The solution was then 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 (500MHz, DMSO-d6) δ8.64(s,1H),8.41(s,1H),7.39(dd,J=8.8,2.6Hz,1H),7.34–7.26(m,4H),7.12(d,J=8.6Hz,2H),6.85(d,J=8.8 Hz,4H),4.97(t,J=3.3Hz,1H),3.94(s,2H),3.91–3.72(m,4H),3.71(s,3H),2.19(dtd,J=14.3,8.2,6.2Hz,1H),2.01–1.82(m,1H).13C NMR (126MHz, DMSO-d6) δ156.06,155.06,153.04,139.55,139.45,132.96,131.91,130.26,129. 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] Following the method in Example 9, Example 10 was prepared by N-acylation of intermediate X-1 with 2-ethylphenyl isocyanate, with a yield of 45.6%.

[0245] HRMS(ESI)m / z:451.1785[M+H]+; 1H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 7.36–7.25 (m, 4H), 7.23 (t, J = 3.1Hz, 2H), 7.22–7.1 9(m,2H),7.12–7.07(m,1H),6.88–6.80(m,1H),6.10(t,J=5.7Hz,1H),5.87(t,J=5.7Hz,1 H),4.96(ddt,J=6.3,3.9,1.8Hz,1H),3.91(s,1H),3.89–3.65(m,3H),3.34–3.13(m,4H) ,2.69(dt,J=25.0,7.2Hz,3H),2.19(dtd,J=13.3,8.2,6.2Hz,1H),2.03–1.81(m,1H).13C NMR(101MHz,DMSO-d6)δ158.34,156.00,155.39,140.24,140.15,139.95,139.27,131.96,130.22,129.79,129.13, 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(dibenzylacetone)palladium (0.1 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.1 eq), cesium carbonate (1.5 eq), and 10 mL of toluene were added. The mixture was stirred until homogeneous, and then refluxed at 110 °C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and a small amount of water was added to the filtrate. The mixture was then extracted with ethyl acetate (10 mL × 3), and the extracts 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 (400MHz, DMSO-d6) δ7.22(d,J=8.8Hz,2H),7.12(d,J=8.6Hz,3H),6.98(d,J=3.0Hz,2H),6.82(d,J=8.6Hz,3H),4.95(t,J=5.5Hz, 1H),3.93–3.68(m,9H),3.43(t,J=5.0Hz,7H),3.06(d,J=5.1Hz,5H),2.24–2.11(m,1H),1.92(dt,J=12.1,5.9Hz,1H),1.41(s,15H).

[0251] Following the method for compound 5 in Example 5, compound 11 was prepared by deprotecting intermediate M5 under trifluoroacetic acid conditions, with a yield of 26.3%.

[0252] HRMS(ESI)m / z:373.1685[M+H]+; 1H NMR (400MHz, DMSO-d6) δ7.20(d,J=8.8Hz,1H),7.12(d,J=8.6Hz,2H),6.93(d,J=3.0Hz,1H),6.86–6.76(m,3H),4.95(dd,J=6.4,4.6Hz,1H),3.91( s,2H),3.88–3.68(m,4H),3.05(t,J=5.1Hz,4H),2.92–2.80(m,4H),2.18 (dtd,J=14.3,8.2,6.2Hz,1H),2.01–1.79(m,1H),1.39–1.16(m,1H).13C NMR (101MHz, DMSO-d6) δ155.90,150.91,139.31,132.33,130.07,129.95,122. 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-nitrile-compound 12

[0255] Following the method described in Example 3, Example 12 was prepared by reacting intermediate IV-1 with 4-cyanobenzoboric acid via a Suzuki coupling reaction, with a yield of 83.3%.

[0256] HRMS(ESI)m / z:404.1050[M+H]+; 1H NMR (500MHz, DMSO-d6) δ7.96(q,J=8.3Hz,5H),7.90(d,J=2.3Hz,1H),7.74(d,J=9.0Hz,3H),7.09(d,J=8.8Hz,2H),5.15(t,J=5.4Hz,1H),3.91(dd, J=10.3,4.5Hz,1H),3.84(dt,J=18.2,9.1Hz,2H),3.76(td,J=8.3,4.6Hz, 1H),2.27(dtd,J=14.2,8.2,6.3Hz,1H),1.97(dt,J=12.6,5.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ192.84,162.49,142.95,139.74,137.72,133.39,132.73,130.99,13 0.60,130.18,129.12,128.26,127.56,119.15,116.01,111.21,78.32,72.67,66.89,32.90.

[0257] Example 13

[0258] (R)-[4-chloro-4'-hydroxy-(1,1'-biphenyl)-3-yl]{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methyl ketone--compound 13

[0259] Following the method described in Example 3, Example 13 was prepared by reacting intermediate IV-1 with 4-hydroxyphenylboronic acid via a Suzuki coupling reaction, with a yield of 83.3%.

[0260] HRMS(ESI)m / z:395.1050[M+H]+; 1H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.75(dd,J=21.1,9.7Hz,3H),7.66–7.53(m,4H),7.08(d,J=8.5Hz,2H),6.84(d ,J=8.0Hz,2H),5.16–5.13(m,1H),3.94–3.72(m,4H),2.27(dq,J=14.5,7.8Hz,1H),1.98(dt,J=12.7,5.3Hz,1H).13C NMR (126MHz, DMSO-d6) δ193.26,162.38,158.22,139.64,139.36,132.66,130.58,129.2 6,129.13,128.92,128.43,127.98,126.18,116.33,115.96,78.29,72.67,66.89,32.91.

[0261] Example 14

[0262] (R)-{2-chloro-5-[6-(piperidin-1-yl)pyridin-3-yl]phenyl}{4-[(tetrahydrofuran-3-yl)oxy]phenyl}methyl ketone--compound 14

[0263] Following the method described in Example 3, using intermediate IV-1 as a starting material, and subjecting it to a Suzuki coupling reaction with 2-(piperidin-1-yl)pyridine-5-boronic acid pinacol ester, Example 14 was prepared with a yield of 51.3%.

[0264] HRMS(ESI)m / z:463.1799[M+H]+; 1H NMR (400MHz, DMSO-d6) δ8.48 (d, J=2.6Hz, 1H), 7.88 (dd, J=9.0, 2.7Hz, 1H), 7.81 (dd, J= 8.5,2.4Hz,1H),7.76–7.71(m,2H),7.70(d,J=2.3Hz,1H),7.11–7.04(m,2H),6.88(d,J= 9.0Hz,1H),5.15(ddt,J=6.3,4.1,1.8Hz,1H),3.95–3.71(m,4H),3.57(t,J=5.4Hz,4H), 2.27(dtd,J=14.2,8.2,6.2Hz,1H),1.97(dt,J=12.5,5.6Hz,1H),1.67–1.43(m,6H); 13C NMR (126MHz, DMSO-d6) δ193.22,162.39,158.89,146.30,139.51,137.32,136.13,132.68,130.64,129. 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}methyl ketone--compound 15

[0267] Following the method described in Example 3, intermediate M4-1 was prepared by a Suzuki coupling reaction with 4-(Boc-amino)phenylboronic acid using intermediate IV-1 as the starting material, 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] Following the synthesis method of compound 5 in Example 5, intermediate M2-1 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 72.5%.

[0269] HRMS(ESI)m / z:394.1215[M+H]+; 1H NMR (400MHz, DMSO-d6) δ7.72(dd,J=9.8,2.6Hz,3H),7.61–7.52(m,2H),7.42(d,J=8.3Hz,2H),7.07(d,J =8.6Hz,2H),6.64(d,J=8.1Hz,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=5.8,5.1Hz,1H);13CNMR(101MHz,DMSO-d6)δ193.42,162.34,149.44,140.11,139.26,132.65 ,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}methyl ketone--compound 16

[0272] Following the method in Example 3, intermediate M2-1 was prepared by reacting intermediate IV-1 with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester via a Suzuki coupling reaction, with a yield of 95.5%. 1H NMR (400MHz, DMSO-d6) δ7.80(dd,J=8.5,2.3Hz,1H),7.73(d,J=8.6Hz,2H),7.68(d,J=2.3Hz,1H),7.60(dd,J=8.5,4.7Hz,3H),7.05(dd,J =22.4,8.5Hz,4H),5.15(d,J=5.6Hz,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] Following the synthesis method of compound 5 in Example 5, intermediate M2-1 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 39.9%.

[0274] HRMS(ESI)m / z:463.1802[M+H]+; 1H NMR (600MHz, DMSO-d6) δ7.80(d,J=8.5Hz,1H),7.73(d,J=8.4Hz,2H),7.68(s,1H),7.61(d,J=5.5Hz,2H),7.08(d,J=8.5Hz, 2H),7.02(d,J=8.4Hz,2H),3.83(ddd,J=49.5,32.3,7.7Hz,3H),3.22(s,2H),2.98(t,J=5.0Hz,3H),2.27(dq,J=14.8,7.7H z,1H),1.97(dd,J=13.3,6.3Hz,1H),1.23(s,1H).13CNMR(126MHz,DMSO-d6)δ193.30,162.38,151.64,139.46,139.38,132 .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--compound 17 step A14 intermediate XV-1 synthesis

[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 round-bottom flask, 10 mL of methanol was added and stirred until homogeneous, then 10 mL of sodium hydroxide aqueous solution (4 M) was added, and the mixture was heated to 80 °C and refluxed. After the reaction was completed, the reaction solution was cooled to room temperature, and hydrochloric acid was slowly added to adjust the pH to 1. A solid precipitated out, and the solid was filtered to obtain intermediate XV-1, with a yield of 53.9%. 1H NMR (400MHz, DMSO-d6) δ13.04(s,1H),8.06–7.99(m,2H),7.94(dd,J=8.5,2.4Hz,1H),7.91–7.82(m,3H),7.79–7.69(m,3H),7.10(dd d,J=8.9,5.2,2.5Hz,2H),5.15(q,J=4.9,3.8Hz,1H),3.94–3.69(m,4H),2.27(td,J=14.2,8.2Hz,1H),1.98(dt,J=12.5,5.9Hz,1H).

[0280] Following the method for synthesizing compound 1 in Example 1, intermediate XV-1 was used as a starting material and reacted with guanidine hydrochloride in an N-acylation reaction. The resulting product was purified by column chromatography to obtain 18 mg of a white solid, with a yield of 31.8%.

[0281] HRMS(ESI)m / z:464.1375[M+H]+; 1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),8.55(d,J=109.8Hz,4H),8.16–7.95(m,5H),7.92(d,J=2.4Hz,1H),7.75(dd,J=8.5,3.9Hz,3 H),7.09(d,J=8.4Hz,2H),5.16(t,J=5.6Hz,1H),3.99–3.68(m,4H),2.28(dq,J=14.6,7.6Hz,1H),1.98(dt,J=13.0,6.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ192.95,162.51,143.44,139.79,137.97,132.72,130.94,13 0.42,130.14,129.46,129.13,127.69,127.44,116.03,78.33,72.66,66.89,32.90.

[0282] Example 18

[0283] 4'-Chloro-3'-(4-ethoxybenzoyl)-(1,1'-biphenyl)-4-nitrile--compound 18

[0284] Following the method in step A1 of Example 1, intermediate IV-3 was prepared by Friedel-Crafts acylation reaction of intermediate II with phenethyl ether, with a yield of 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] Following the method in Example 3, intermediate IV-3 was used as a raw material and reacted with 4-cyanobenzonic acid via a Suzuki coupling reaction to prepare the product. The product was purified by column chromatography to obtain 18 mg of a white solid, with a yield of 89.7%.

[0286] HRMS(ESI)m / z:362.0944[M+H]+; 1H NMR(500MHz,DMSO-d6)δ8.00–7.91(m,1H),7.89(d,J=2.4Hz,0H),7.73(d,J=9.0 Hz,1H),7.08(d,J=8.9Hz,0H),4.14(q,J=7.0Hz,1H),1.35(t,J=6.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ192.85,163.83,142.94,139.79,137.69,133.40,132.71,130 .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)methyl ketone -- Compound 19

[0289] Following the method in Example 3, intermediate IV-3 was used as a raw material and reacted with 4-hydroxyphenylboronic acid via a Suzuki coupling reaction to prepare the product. The product was purified by column chromatography to obtain 18 mg of a white solid, with a yield of 87.0%.

[0290] HRMS(ESI)m / z:353.0944[M+H]+; 1H NMR (600MHz, DMSO-d6) δ9.67(s,1H),7.74(dd,J=22.8,8.3Hz,3H),7.64(s,1H),7.59(d,J=8.5Hz,1H),7.55(d ,J=8.2Hz,2H),7.07(d,J=8.5Hz,2H),6.85(d,J=8.1Hz,2H),4.13(q,J=7.0Hz,2H),1.35(t,J=6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ193.27,163.72,158.22,139.62,139.42,132.64,130.57 ,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)methyl ketone - Compound 20

[0293] Following the method in Example 3, intermediate IV-3 was used as the starting material and prepared by a Suzuki coupling reaction with 2-(piperidin-1-yl)pyridine-5-boronic acid pinacol ester. The product was purified by column chromatography to obtain 18 mg of a white solid, with a yield of 65.9%.

[0294] HRMS(ESI)m / z:421.1687[M+H]+; 1H NMR (600MHz, DMSO-d6) δ8.48(s,1H),7.88(d,J=9.0Hz,1H),7.81(d,J=8.5Hz,1H),7.75–7.68(m,3H),7.60(d,J=10.3Hz,1H),7.07(d, J=7.5Hz,2H),6.88(d,J=9.0Hz,1H),4.14(q,J=7.0Hz,2H),3.57(s,4H),1.61(s,2H),1.53(d,J=5.5Hz,4H),1.35(t,J=6.9Hz,3H).13C NMR (126MHz, DMSO-d6) δ193.23,163.73,158.87,146.30,139.58,137.30,136.14,132.66,130.6 3,129.02,128.32,127.90,125.63,122.18,115.19,107.12,64.23,45.96,25.47,24.78,14.91.

[0295] Example 21

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

[0297] Following the method described in Example 3, intermediate M4-2 was prepared by a Suzuki coupling reaction between intermediate IV-3 and 4-(Boc-amino)phenylboronic acid. The intermediate was purified by column chromatography to obtain 18 mg of a white solid, 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] Following the synthesis method of compound 5 in Example 5, intermediate M4-2 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 81.0%.

[0299] HRMS(ESI)m / z:352.1106[M+H]+; 1H NMR(500MHz,DMSO-d6)δ7.72(d,J=8.3Hz,3H),7.59–7.52(m,2H),7.41(d,J=8.1Hz,2H),7.07(d,J =8.5Hz,2H),6.63(d,J=8.2Hz,2H),5.35(s,2H),4.13(d,J=7.0Hz,2H),1.35(t,J=6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ193.41,163.69,149.57,140.13,139.34,132.61,130.45 ,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)methyl ketone -- Compound 22

[0302] Following the method in Example 3, intermediate M2-2 was prepared by reacting intermediate IV-3 with 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester via a Suzuki coupling reaction, with a yield of 87.0%. 1H NMR (400MHz, DMSO-d6) δ7.79(dd,J=8.5,2.4Hz,1H),7.75–7.69(m,2H),7.67(d,J=2.3Hz,1H),7.60(dd,J=8.6,5.5Hz,3H),7.11–7.04( m,2H),7.04–6.98(m,2H),4.13(q,J=7.0Hz,2H),3.46(t,J=5.2Hz,4H),3.17(dd,J=6.3,4.1Hz,4H),1.42(s,9H),1.35(t,J=7.0Hz,3H).

[0303] Following the synthesis method of compound 5 in Example 5, intermediate M2-2 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 82.9%.

[0304] HRMS(ESI)m / z:421.1693[M+H]+,541.3[MH]-; 1H NMR (600MHz, DMSO-d6) δ7.79(d,J=8.6Hz,1H),7.72(d,J=8.4Hz,2H),7.66(s,1H),7.59(d,J=8.4Hz,3H),7.07(d,J=8.5Hz,2H),6.99( 13C NMR(101MHz,DMSO-d6)δ193.30,163.72,151.24,139.46,139.37,132.64,130.58,129.0 5,128.71,128.60,127.90,127.81,125.99,116.02,115.19,64.23,47.77,44.77,14.91.

[0305] Example 23

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

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

[0308] Following the method in step A5 of Example 1, intermediate XV-2 was used as a raw material and reacted with guanidine hydrochloride via an N-acylation reaction to obtain the product. After purification by column chromatography, 18 mg of a white solid was obtained, with a yield of 31.5%.

[0309] HRMS(ESI)m / z:422.1286[M+H]+; 1H NMR (400MHz, DMSO-d6) δ11.51(s,1H),8.58(d,J=110.0Hz,4H),8.09–7.97(m,5H),7.91(d,J=2. 3Hz,1H),7.77–7.71(m,3H),7.11–7.06(m,2H),4.14(q,J=7.0Hz,2H),1.35(t,J=7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ192.96,163.85,159.50,159.18,155.80,143.46,139.85,137.94,132.70, 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)methyl ketone -- Compound 24

[0312] Following the method in step A13 of Example 11, intermediate M6 was prepared by reacting intermediate IV-3 with 1-Boc piperazine via a Buchwald coupling reaction, 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] Following the synthesis method of compound 5 in Example 5, intermediate M6 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid, with a yield of 76.5%.

[0314] HRMS(ESI)m / z:345.1376[M+H]+; 1H NMR (500MHz, DMSO-d6) δ7.68(d,J=8.4Hz,2H),7.34(d,J=8.9Hz,1H),7.06(t,J=6.0Hz,3H),6.90(d,J=3.1Hz,1 H),4.13(q,J=6.9Hz,2H),3.09(t,J=5.1Hz,4H),2.83(t,J=5.0Hz,4H),1.35(t,J=6.8Hz,3H),1.23(s,1H).13C NMR (126MHz, DMSO-d6) δ193.67,163.60,150.54,139.43,132.54,130.38,129.11,118.53,117.80,115.10,114.85,64.20,48.92,45.62,14.91.

[0315] Example 25

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

[0317] Following the method in step A2 of Example 1, intermediate IV-2 was prepared by photoelectrophoresis of intermediate III with (R)-(-)-3-hydroxytetrahydrofuran, with a yield of 85.1%. ¹H NMR (400MHz, DMSO-d6) δ 7.79–7.73 (m, 1H), 7.72–7.67 (m, 1H), 7.56 (d, J = 8.5Hz, OH), 7.12–7.04 (m, 1H), 5.16 (dd, J = 6.2, 4.5Hz, OH), 3.95–3.72 (m, 2H), 2.28 (dtd, J = 14.3, 8.2, 6.2Hz, 1H), 1.98 (dt, J = 13.4, 6.2Hz, 1H).

[0318] Following the method for synthesizing intermediate V-1 in Example 1, intermediate V-2 was prepared by reduction reaction of intermediate IV-2 under triethylsilane conditions, with a yield of 83.3%. ¹H NMR (400MHz, DMSO-d6) δ 7.54 (d, J = 2.4Hz, 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, 1.8Hz, 1H), 3.98 (s, 2H), 3.91–3.69 (m, 4H), 2.19 (dtd, J = 13.5, 8.2, 6.2Hz, 1H), 1.99–1.88 (m, 1H).

[0319] Following the method in Example 3, intermediate M1-2 was prepared by Suzuki coupling reaction of 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester using intermediate V-2 as the starting material, with a yield of 71.4%. 1H NMR(500MHz,DMSO-d6)δ7.60(d,J=2.3Hz,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=6.5,4.3,1.8Hz, 1H),4.03(s,2H),3.89–3.69(m,4H),3.46(t,J=5.2Hz,4H),3.15(t,J=5.3Hz ,4H),2.23–2.12(m,1H),1.96–1.88(m,1H),1.42(s,9H),1.31–1.21(m,1H).

[0320] Following the synthesis method of compound 5 in Example 5, intermediate M1-2 was used as the starting material. The protecting group was removed under 10 mL of trifluoroacetic acid, and the product was purified by column chromatography to obtain 18 mg of white solid as shown in Example 25, with a yield of 95.2%.

[0321] HRMS(ESI)m / z:449.2003[M+H]+; 1H NMR(500MHz,DMSO-d6)δ7.58(d,J=2.3Hz,1H),7.52–7.39(m,4H),7.17(d,J=8.0Hz,2H),6.98(d,J=8.5Hz,2H),6.83(d,J=8.2Hz,2H),5.01–4.8 9(m,1H),4.03(s,2H),3.91–3.66(m,4H),3.10(t,J=5.0Hz,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 (126MHz, DMSO-d6) δ156.01,151.59,139.62,139.53,132.09,131.48,130.22,130.14,129. 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] Following the method in step A2 of Example 1, intermediate XII was prepared by Friedel-Crafts acylation reaction of intermediate XI with phenol, with a yield of 20.0%. ¹H NMR (400MHz, DMSO-d6) δ 10.62 (s, ¹H), 8.29 (s, OH), 7.94 (s, ¹H), 7.72 (d, J = 8.7Hz, 2H), 6.92 (d, J = 8.7Hz, 2H).

[0325] Following the method for synthesizing intermediate IV-1 in Example 1, intermediate XIII-1 was prepared by photo-extending reaction of intermediate XII with (S)-(+)-3-hydroxytetrahydrofuran, with a yield of 94.2%. HRMS(ESI)m / z:348.0636[M+H]+.1H NMR (500MHz, DMSO-d6) δ8.19(d,J=2.7Hz,1H),8.10(dd,J=8.7,2.8Hz,1H),7.75(d,J=8.7Hz,1H),7.17(d,J=8.5Hz,2H),6.93–6.7 7(m,2H),4.98(ddt,J=6.4,4.3,1.9Hz,1H),4.13(s,2H),3.92–3.67(m,4H),2.19(dtd,J=14.3,8.2,6.2Hz,1H),2.05–1.83(m,1H).

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

[0327] Following the method for compound 9 in Example 9, using intermediate X-2 as a starting material, N-acylation reaction was 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 (400MHz, DMSO-d6) δ8.61(s,1H),7.72–7.66(m,2H),7.54(d,J=2.4Hz,1H),7.48–7.37(m,2H),7.11–7.04(m,2H),6.19(d,J=7 13C NMR(101MHz,DMSO-d6)δ193.28,162.34,154.60,140.16,138.95,132.61,130.43,129.08,121.09,120.3 7,117.35,115.91,78.27,72.67,66.89,48.19,47.97,33.82,33.28,32.89,25.79,25.65,24.93,24.80.

[0329] Example 27

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

[0331] Following the method for synthesizing compound 9 in Example 9, using intermediate X-2 as a starting material, N-acylation reaction was carried out with p-methoxyphenyl isocyanate to prepare Example 27, with a yield of 63.6%.

[0332] HRMS(ESI)m / z:467.1373[M+H]+; 1H NMR(500MHz,DMSO-d6)δ8.87(s,1H),8.55(s,1H),7.71(d,J=8.6Hz,2H),7. 63–7.50(m,2H),7.46(d,J=8.8Hz,1H),7.33(d,J=8.6Hz,2H),7.08(d,J=8. 5Hz,2H),6.86(d,J=8.6Hz,2H),5.15(d,J=5.7Hz,1H),3.94–3.72(m,4H),3 .71(s,3H),2.27(dq,J=14.4,7.6Hz,1H),1.98(dt,J=12.9,5.8Hz,1H); 13C NMR(126MHz,DMSO-d6)δ193.18,162.40,155.23,153.08,139.59,139.07,132.77,132.63,130.5 5,129.11,121.91,121.05,120.88,118.03,115.96,114.48,78.32,72.68,66.90,55.67,32.92.

[0333] Example 28

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

[0335] Following the method for synthesizing compound 9 in Example 9, using intermediate X-2 as a starting material, 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 (400MHz, DMSO-d6) δ9.03(d,J=15.9Hz,2H),7.71(d,J=8.9Hz,2H),7.63–7.46(m,5H),7.28(d,J=8.6Hz,2H ),7.09(d,J=8.9Hz,2H),5.16(t,J=3.3Hz,1H),3.95–3.71(m,4H),2.27(dtd,J=14.2,8.2,6.3Hz,1H),1.98(d t,J=12.9,6.4Hz,1H);13CNMR(126MHz,DMSO-d6)δ193.10,162.42,152.86,143.33,139.21,139.11,132.63,1 30.61,129.09,122.38,122.11,121.66,121.32,120.20,119.64,118.32,115.96,78.32,72.67,66.89,32.91.

[0337] Example 29

[0338] 1-[2-chloro-5-(4-ethoxybenzoyl)phenyl]-3-cyclohexylurea--compound 29

[0339] Following the method in step A2 of Example 1, intermediate XIII-2 was prepared by Friedel-Crafts acylation reaction of intermediate XI with phenethyl ether, 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] Following the method for synthesizing intermediate X1 in Example 7, intermediate X-3 was prepared by reduction reaction of intermediate XIII-2 under iron / ammonium chloride conditions, with a yield of 81.5%. ¹H NMR (400MHz, 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] Following the method for synthesizing compound 9 in Example 9, using intermediate X-3 as a starting material, N-acylation reaction was 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=8.9H 13C NMR(126MHz,DMSO-d6)δ193.27,163.69,154.62,140.16,139.04,132.57,130.41,1 28.93,121.14,120.36,117.42,115.15,64.23,48.20,33.28,25.66,24.79,14.90.

[0343] Example 30

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

[0345] Following the method for synthesizing compound 9 in Example 9, using intermediate X-3 as a starting material, N-acylation reaction was 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(400MHz, DMSO-d6)δ8.68–8.54(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=3.5Hz,3H),1.46–1.27(m,3H); 13C NMR(101MHz,DMSO-d6)δ193.73,162.95,159.88,156.84,155.62,153.21,137.60,135.78,132.66,131.58,130.66,129.94,129.2 5,127.25,125.61,125.28,123.40,122.71,120.56,115.39,114.81,114.56,114.18,114.06,64.11,55.82,55.67,55.64,14.96.

[0347] Example 31

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

[0349] Following the method for synthesizing compound 9 in Example 9, using intermediate X-3 as a starting material, N-acylation reaction was carried out with 4-trifluoromethoxyphenyl isocyanate to prepare Example 31, with a yield of 68.2%.

[0350] HRMS(ESI)m / z:479.0994[M+H]+; 1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),9.00(s,1H),7.77–7.66(m,2H),7.62–7.46(m,5H),7 .28(d,J=8.6Hz,2H),7.11–7.04(m,2H),4.14(q,J=7.0Hz,2H),1.35(t,J=7.0Hz,3H); 13C NMR(101MHz,DMSO-d6)δ193.11,163.75,152.85,143.25,139.20,139.13,132.63,130.61 ,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 below:

[0352] Compounds 1-11

[0353] Diphenylmethyl derivatives:

[0354]

[0355] Where R2 is H, R3 is Cl, X is CH2, and R4 is

[0356]

[0357]

[0358] Compounds 12-17

[0359] Diphenylmethane derivatives:

[0360]

[0361] Where R2 is H, R3 is Cl, X is CO, and R4 is...

[0362] Compounds 18-24

[0363] Diphenylmethane derivatives:

[0364]

[0365] Where R2 is H, R3 is Cl, X is CO, and R4 is...

[0366]

[0367] Compound 25

[0368] Diphenylmethyl derivatives:

[0369]

[0370] Where R2 is H, R3 is Cl, X is CH2, and R4 is

[0371] Compounds 26-31

[0372] Diphenylmethane derivatives:

[0373]

[0374] Where R2 is Cl, R3 is H, X is CO, and Y is

[0375] Example 32

[0376] Cardioprotective activity experiments were conducted on the diphenylmethane derivatives prepared in the above examples:

[0377] I. In vitro cytotoxicity test

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

[0379] 1. Cell Culture

[0380] Using DMEM medium as the basal culture medium, a cell culture medium containing 10% fetal bovine serum was prepared. The cells were cultured in a 37°C incubator containing 5% CO2. The culture medium was changed daily. When the cells reached 80%-90% confluence, the original culture medium was discarded, the cells were washed once with PBS, digested with 0.25% trypsin, and passaged according to experimental requirements.

[0381] 2. Drug preparation

[0382] The required volume of DMSO was calculated based on the compound's molecular weight and the mass weighed to prepare a stock solution of the same concentration (100 mM), which was then stored at 4°C.

[0383] 3. Experimental Procedure

[0384] (1) Cell seeding: Take cells in good growth condition during the logarithmic growth phase, digest the cells with 0.25% trypsin, then disperse them into a single cell suspension by pipetting with culture medium. After counting, seed them into a 96-well plate at an appropriate density (3000 cells / well), 100 μL / well, and incubate in a saturated humidity, 37℃, 5% CO2 incubator.

[0385] (2) Drug treatment: After 24 hours of cell culture, four different concentration gradients of drug were added according to experimental needs, 100 μL per well, with three replicates per group and a blank group per plate. In this experiment, the test drug was diluted to the corresponding concentration gradients of 100 μM, 30 μM, 10 μM, and 3 μM and added for 48 hours. After drug addition, the cells were cultured in a 5% CO2, 37℃ constant temperature cell culture incubator for the corresponding time, and the cell state was observed under an inverted microscope.

[0386] (3) Color development and colorimetric analysis: After the drug reaches the action time point, discard the drug, add 100 μL of CCK8 solution to each well, and continue incubation for 1 h; place the 96-well plate in a microplate reader, detect the absorbance (OD) value of each well at a wavelength of 450 nm and compare it with the blank group.

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

[0388] Cell viability % = (Average OD value of test group / OD value of blank group) × 100%

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

[0390] Calculate the half-maximal inhibitory concentration (IC50) of the drug. 50 IC50 was calculated using GraphPad Prism statistical analysis software based on the drug's effective concentration and its growth inhibition rate on cells. 50 value.

[0391] The results of the compounds inhibiting the activity of the normal rat cardiomyocyte cell line H9c2 are shown in the table below.

[0392] Table 1. Inhibitory activity of compounds in rat normal cardiomyocyte H9c2 cells.

[0393]

[0394] Using an IC50 value of 10 μM as the cutoff, it can be concluded that most of the compounds have low toxicity to the normal rat cardiomyocyte cell line H9c2.

[0395] II. In vitro enzyme inhibitory activity

[0396] Cultured cardiomyocytes were seeded at 10,000 cells / well in 96-well plates and incubated for 24 hours. 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 the cells were incubated in the dark at 37°C and 5% CO2 for 30 minutes. At the end of the culture, the buffer was removed, and the cells were washed twice with HBSS for 5 minutes each time, with 100 μL of HBSS added to each well to prevent cell drying. Fluorescence of BCECF-AM (excitation, 488 nm; emission, 535 nm) was detected using a microplate reader (BioTek). All doses were set in triplicate, and IC50 was calculated using a GraphPad Prism 9 for nonlinear fitting. 50 The values ​​are shown in the table below.

[0397] Table 2 In vitro NHE1 enzyme inhibitory activity

[0398]

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

[0400] The compound's effect on the IC50 of NHE1 testing 50 The values ​​were all significantly lower than those of the positive control and compounds 32 and 33 (compounds 32 and 33 are currently known compounds), especially compound 23, whose IC50 value for NHE1 was significantly lower. 50 With a value below 1 μM, it exhibits good targeting activity.

[0401] III. Cell Protection Assay

[0402] The protective effect of compound 23 was evaluated in a glucose-deficiency-induced H9c2 cell injury model. Cultured cardiomyocytes were digested with trypsin and reseeded in 96-well plates at a density of 3000 cells per well. Compounds (0.3, 1, 3, 10, 30, and 100 μmol / L) were added to the cells and incubated for 48 h. After removing the culture medium, the cells were washed once with PBS, and then DMEM medium without glucose was added to induce cell injury for 24 h. Cardiomyocyte viability was measured at 450 nm using a CCK-8 assay. All doses were used in triplicate. Nonlinear fitting was performed using GraphPad Prism 9, and the results are shown below. Figure 1 And as shown in the table below, where Figure 1 A represents the effect of compound 23 on the survival rate of normal rat cardiomyocytes; Figure 1 B represents the effect of compound 23 on the protective effect of glucose-deficiency-induced cells; Figure 1 C represents the effect of cariporide on the protective effect of glucose-deficiency-induced cells; Figure 1 D represents the effect of empagliflozin on the protective effect of glucose-deficiency-induced cells.

[0403] Table 3. Protective effects of the compounds on glucose-deficiency-induced H9c2 cells.

[0404]

[0405] NA: Not detected

[0406] The results showed that all compounds could increase glucose-deficiency-induced cell viability.

[0407] In particular, compound 23 can increase glucose deficiency-induced cell viability at a low concentration (1 μM), indicating that compound 23, as an NHE1 inhibitor, can protect cardiomyocytes from glucose deficiency-induced damage at a low concentration.

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

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

[0410] V. In vivo pharmacodynamic experiments

[0411] Male C57BL / 6J mice were purchased from Hunan SJA Laboratory Animal Co., Ltd. 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%, with free access to water and food. All experimental procedures were approved by the Laboratory Animal Welfare and Ethics Committee and the Animal Management Committee of Central South University (IRB Approval No.: 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-operated 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 23 (30 mg / kg, once daily), and (6) ISO + low-dose 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 daily for two 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-operated group were subcutaneously injected with saline. After the experiment, in vivo cardiac ultrasound was performed under mild anesthesia using a Vevo 2000 high-resolution imaging system (SonicsVisual) via transthoracic echocardiography (TTE) to assess cardiac function. The heart was imaged in a two-dimensional parasternal short-axis view, and M-mode echocardiography of the mid-ventricle was recorded at the papillary muscle level. Diastolic and systolic left ventricular diameters were measured. Fractional shortening and ejection fraction were calculated. Figure 3 As shown. Among them Figure 3 A represents the effect of compound 23 on the left ventricular ejection fraction in an isoproterenol-induced heart failure model. Figure 3 B represents the left ventricular shortening fraction.

[0412] The results showed that compound 23 significantly inhibited pressure overload-induced heart failure (HF) induced by isoproterenol infusion after 14 days of administration. It effectively reduced the severity of HF induced by isoproterenol in C57BL / 6J mice, increased left ventricular ejection fraction and left ventricular shortening fraction, and showed no significant change in body weight compared to the control group. Furthermore, no animals died during the experiment, demonstrating that compound 23 has no significant toxicity. This fully demonstrates that compound 23 is an effective inhibitor of NHE1.

[0413] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is impossible to exhaustively list all possible implementations here. All obvious variations or modifications derived from the technical solutions of this invention are still within the scope of protection of this invention.

Claims

1. A diphenylmethane derivative, characterized in that, It is a compound represented by Formula I or a pharmaceutically acceptable salt thereof: ； Where X is CH2; Y is -CO-; R1 is -NHC(=NH)NH2; R2 is selected from: hydrogen, C1-C6 alkyl; R3 is selected from: halogen; R4 is or .

2. The diphenylmethane derivative according to claim 1, characterized in that, The diphenylmethane derivative is one of the following compounds or a pharmaceutically acceptable salt thereof: ( R )-4-chloro- N -(diaminomethylene)-3-{4-[(tetrahydrofuran-3-yl)oxy]benzyl}benzamide.

3. The method for preparing the diphenylmethane derivative according to claim 1 or 2, characterized in that, Intermediate M1 undergoes a deprotection reaction in the reaction solvent to yield the diphenylmethane derivative. Intermediate M1 is: .

4. The use of the diphenylmethane derivative according to claim 1 or 2 in the preparation of a medicament for treating heart failure or myocardial hypertrophy by inhibiting NHE1 enzyme.

5. The use of the diphenylmethane derivative according to claim 1 or 2 in the preparation of NHE1 inhibitors.

Images