A class of small molecule organic compounds with double-substituted nitrogen atoms on the aromatic ring, their derivatives, and their applications in the preparation of antibacterial drugs

Abstract

The present invention discloses a class of small molecule compounds of nitrogen atom double-substituted aromatic rings represented by formula (I-VI), or their hydrates or pharmaceutically acceptable salts, and pharmaceutical compositions. The present invention also discloses the use of the compounds or their pharmaceutical compositions of the present invention in the preparation of antibacterial drugs. The compounds of the present invention can effectively inhibit Gram-negative bacteria (such as Escherichia coli) and Gram-positive bacteria (such as Staphylococcus aureus), and at the same time also have good antibacterial and rapid bactericidal effects on multi-drug resistant Staphylococcus aureus and Staphylococcus hominis, etc., which are difficult to treat clinically. At the same time, the compounds of the present invention also have properties such as low toxicity and not easily inducing drug resistance, and have good application prospects for treating diseases caused by bacterial infections.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine and its applications, and specifically relates to a series of small molecule compounds and analogs of aromatic rings with double nitrogen atom substitutions, as well as the use of such compounds or pharmaceutical compositions containing such compounds in the preparation of drugs for treating various bacterial infections. Background Art

[0002] Since the discovery of penicillin, antibiotics have saved tens of thousands of lives. However, due to the overuse and abuse of antibiotics or other factors, antibiotic resistance is increasing rapidly. Currently, most "new" antibacterial drugs are still based on traditional antibacterial molecular scaffolds, which makes cross-resistance inevitable. Therefore, in order to effectively solve the problem of bacterial resistance, it is urgent to develop new antibiotics with a structural backbone different from traditional antibiotics. Summary of the Invention

[0003] The present invention relates to a novel class of small molecule compounds of aromatic rings with double nitrogen atom substitutions having antibacterial activity, and the mechanism of action thereof has been studied, laying a foundation for subsequent new drug research and development, and having important theoretical significance and broad application prospects.

[0004] The present invention provides a novel small molecule organic compound of aromatic rings with double nitrogen atom substitutions having antibacterial activity and its analogs, including pharmaceutically acceptable salts and esters thereof.

[0005] The small molecule organic compound of aromatic rings with double nitrogen atom substitutions or related analogs or pharmaceutically acceptable salts provided by the present invention has a structure as shown in (I):

[0006]

[0007] Wherein,

[0008] n = 0 - 5.

[0009] is phenyl, heteroaryl, naphthalene ring, quinoline.

[0010] is selected from any one of the following aromatic groups or heteroaromatic groups, including monocyclic aromatic groups, polycyclic aromatic groups, and polyheterocyclic aromatic groups; the monocyclic aromatic groups include phenyl, heteroaromatic groups, thioaromatic groups, and oxoaromatic groups; the polycyclic aromatic groups and polyheterocyclic aromatic groups refer to groups containing two or more monocyclic aromatic groups.

[0011] R1 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde group, alkoxy, amino, cycloalkoxy, cycloamino, benzyloxy, phenethyloxy, C2 - C12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl;

[0012] R2 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester, alkyl, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde, alkoxy, amino, cycloalkoxy, cycloamino, benzyloxy, phenethyloxy, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C4-C 12 Cycloalkenyl, C4-C 12 Cycloalkynyl, Wherein X, Y, Z, and W are each independently selected from one or more of CH, CH=CH, CH=NH, NH, N, O, or S; R4 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester, alkyl, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde, alkoxy, amino, cycloalkoxy, cycloamino, benzyloxy, phenethyloxy, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C4-C 12 Cycloalkenyl, C4-C 12 Cycloalkynyl.

[0013] R3 is selected from any one of the following groups: C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C1-C 12 Alkoxy, C1-C 12 Halogenated alkyl, C1-C 12 Trifluoroalkyl, C1-C 12 Trichloroalkyl, aryl, heteroaryl.

[0014] In the formula (I) of the present invention, when is a naphthalene ring, the structure is as shown in the following formula (II):

[0015]

[0016] Wherein,

[0017] n = 0-5;

[0018] Any one selected from the following aryl groups or heteroaryl groups, including monocyclic aryl groups, polycyclic aryl groups, and polyheterocyclic aryl groups; the monocyclic aryl groups include phenyl, azoaromatic groups, thioaromatic groups, and oxoaromatic groups; the polycyclic aryl groups and polyheterocyclic aryl groups refer to those containing two or more monocyclic aryl groups.

[0019] R1 is selected from one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl group, trifluoromethoxy group, trifluorobenzyloxy group, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy group, phenethyloxy group, C2-C 12 alkenyl group, C2-C 12 alkynyl group, C3-C 12 cycloalkyl group;

[0020] R2 is selected from one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl group, trifluoromethoxy group, trifluorobenzyloxy group, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy group, phenethyloxy group, C2-C 12 alkenyl group, C2-C 12 alkynyl group, C3-C 12 cycloalkyl group, C4-C 12 cycloalkenyl group, C4-C 12 cycloalkynyl group;

[0021] R3 is selected from any one of the following groups: C1-C 12 alkyl group, C2-C 12 alkenyl group, C2-C 12 alkynyl group, C3-C 12 cycloalkyl group, C1-C 12 alkoxy group, C1-C 12 haloalkyl group, C1-C 12 trifluoroalkyl group, C1-C 12 trichloroalkyl group, aryl group, heteroaryl group;

[0022] In formula (I) of the present invention, when is benzene and R2 is its structure is shown as the following formula (III):

[0023]

[0024] wherein,

[0025] n = 0 - 5;

[0026] Any one selected from the following aryl groups or heteroaryl groups, including monocyclic aryl groups, polycyclic aryl groups, and polyheterocyclic aryl groups; the monocyclic aryl groups include phenyl, azoheteroaryl groups, thiaheteroaryl groups, and oxaheteroaryl groups; the polycyclic aryl groups and polyheterocyclic aryl groups refer to those containing two or more monocyclic aryl groups;

[0027] R1 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy, phenethyloxy, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl;

[0028] R3 is selected from any one of the following groups: C1-C 12 alkyl group, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C1-C 12 alkoxy group, C1-C 12 haloalkyl, C1-C 12 trifluoroalkyl, C1-C 12 trichloroalkyl, aryl, heteroaryl;

[0029] X, Y, Z, and W are each independently selected from one or more of CH, CH=CH, CH=NH, NH, N, O, or S;

[0030] R4 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy, phenethyloxy, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C4-C 12 cycloalkenyl, C4-C 12 cycloalkynyl;

[0031] In the formula (III) of the present invention, when R3 is C1-C 12 trifluoroalkyl, its structure is shown in the following formula (IV):

[0032]

[0033] wherein,

[0034] n = 0-5;

[0035] n1 = 1 - 12;

[0036] Any one selected from the following aryl groups or heteroaryl groups, including monocyclic aryl groups, polycyclic aryl groups, and polyheterocyclic aryl groups; the monocyclic aryl groups include phenyl, azoheteroaryl groups, thiaheteroaryl groups, and oxaheteroaryl groups; the polycyclic aryl groups and polyheterocyclic aryl groups refer to groups containing two or more monocyclic aryl groups.

[0037] R1 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy group, phenethyloxy group, C2 - C 12 alkenyl, C2 - C 12 alkynyl, C3 - C 12 cycloalkyl group;

[0038] X, Y, Z, and W are each independently selected from one or more of CH, CH=CH, CH=NH, NH, N, O, or S;

[0039] R4 selects one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester group, alkyl group, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde group, alkoxy group, amino group, cycloalkoxy group, cycloamino group, benzyloxy group, phenethyloxy group, C2 - C 12 alkenyl, C2 - C 12 alkynyl, C3 - C 12 cycloalkyl group, C4 - C 12 cycloalkenyl group, C4 - C 12 cycloalkynyl group;

[0040] In the formula (IV) of the present invention, when R1 is a hydroxyl group, its structure is as shown in the following formula (V):

[0041]

[0042] Among them,

[0043] n = 0 - 5;

[0044] n1 = 1 - 12;

[0045] Any one selected from the following aryl groups or heteroaryl groups, including monocyclic aryl groups, polycyclic aryl groups, and polyheterocyclic aryl groups; the monocyclic aryl groups include phenyl, azoheteroaryl groups, thiaheteroaryl groups, and oxaheteroaryl groups; the polycyclic aryl groups and polyheterocyclic aryl groups refer to groups containing two or more monocyclic aryl groups.

[0046] X, Y, Z, and W are each independently selected from one or more of CH, CH═CH, CH═NH, NH, N, O, or S;

[0047] R4 is selected from one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester, alkyl, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde, alkoxy, amino, cycloalkoxy, cycloamino, benzyloxy, phenethyloxy, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C4-C 12 cycloalkenyl, C4-C 12 cycloalkynyl;

[0048] In the formula (V) of the present invention, when n = 1, its structure is as shown in the following formula (VI):

[0049]

[0050] wherein,

[0051] n1 = 1-12;

[0052] is selected from any one of the following aromatic groups or heteroaromatic groups, including monocyclic aromatic groups, polycyclic aromatic groups, and polyheterocyclic aromatic groups; the monocyclic aromatic groups include phenyl, azoaromatic groups, thioaromatic groups, and oxoaromatic groups; the polycyclic aromatic groups and polyheterocyclic aromatic groups refer to groups containing two or more monocyclic aromatic groups;

[0053] X, Y, Z, and W are each independently selected from one or more of CH, CH═CH, CH═NH, NH, N, O, or S;

[0054] R4 is selected from one or more of the following groups: hydrogen, hydroxyl, hydroxymethyl, cyano, nitro, halogen, carboxyl, ester, alkyl, trifluoromethyl, trifluoromethoxy, trifluorobenzyloxy, aldehyde, alkoxy, amino, cycloalkoxy, cycloamino, benzyloxy, phenethyloxy, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C4-C 12 cycloalkenyl, C4-C 12 cycloalkynyl;

[0055] The present invention also provides the nitrogen atom double-substituted aromatic ring small molecule compound or its related analogs or pharmaceutically acceptable salts, and the nitrogen atom double-substituted aromatic ring small molecule organic compound forms an acid addition salt with an acid; wherein, the acid includes but is not limited to: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, pyruvic acid, maleic acid, succinic acid.

[0056] The present invention also provides the nitrogen atom double-substituted aromatic ring small molecule organic compound or its hydrate or pharmaceutically acceptable salts, characterized in that the nitrogen atom double-substituted aromatic ring small molecule organic compound is combined with a radioactive fluorescent group or biotin.

[0057] The present invention also provides the nitrogen atom double-substituted aromatic ring small molecule organic compound or its hydrate or pharmaceutically acceptable salts, including:

[0058] N-(1-Hydroxy-2-naphthyl)-N-(phenanthrene-9-methyl)pentanamide

[0059] N-(3,5-Di-tert-butylbenzyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0060] N-((2,3-Dihydrobenzofuranyl)-5-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0061] N-((2,3-Dihydrobenzo[b][1,4]dioxanyl)-6-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0062] N-(Benzo[d][1,3]dioxol-5-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0063] N-(Benzo[b]thiophen-5-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0064] N-(Benzo[b]thiophen-2-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0065] N-(Benzo[b]furan-2-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide

[0066] N-(Benzo[b]thiophen-2-methyl)-N-(1-hydroxy-2-naphthyl)butanamide

[0067] N-(Benzo[b]thiophen-2-methyl)-N-(1-hydroxy-2-naphthyl)hexanamide

[0068] N-(Benzo[b]thiophen-2-methyl)-N-(1-hydroxy-2-naphthyl)acrylamide

[0069] N-(Benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)-4-pentenamide

[0070] N-(Benzo[b]thiophen-2-ylmethyl)-4-chloro-N-(1-hydroxy-2-naphthyl)butyramide

[0071] N-(Benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)-4,4,4-trifluorobutyramide

[0072] N-(Benzo[b]thiophen-2-ylmethyl-N-(3-hydroxy-[1,1'-biphenyl]-4-yl-4,4,4-trifluorobutyramide

[0073] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0074] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0075] N-(Benzo[b]thiophen-2-ylmethyl)-N-(3-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0076] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutyramide

[0077] N-(Benzo[b]thiophen-2-ylmethyl)-N-(3-methoxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutyramide

[0078] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0079] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4'-chloro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0080] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4'-bromo-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0081] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4'-tert-butyl-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutyramide

[0082] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0083] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0084] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0085] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0086] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-3'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0087] N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-4'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide

[0088] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(4-pyridyl)phenyl)-4,4,4-trifluorobutanamide

[0089] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(5-pyridyl)phenyl)-4,4,4-trifluorobutanamide

[0090] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(2-thienyl)phenyl)-4,4,4-trifluorobutanamide

[0091] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(2-furyl)phenyl)-4,4,4-trifluorobutanamide

[0092] N-(Benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,4,4-trifluorobutanamide

[0093] The present invention also provides a pharmaceutical composition, which comprises a small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a hydrate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition is formulated into an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, a transdermal patch or an excipient.

[0094] The present invention also provides the use of the small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in the preparation of an antibacterial agent for preventing and / or treating diseases related to infection by pathogenic bacteria.

[0095] In the present invention, the pathogenic bacteria include Gram-positive bacteria, Gram-negative bacteria and their respective drug-resistant bacteria; the Gram-positive bacteria include staphylococcus, streptococcus, erysipelothrix, mycobacterium, bacillus anthracis, etc.; the Gram-negative bacteria include escherichia coli, pasteurella, riemerella, salmonella, haemophilus, brucella, etc.

[0096] In the present invention, the drug-resistant bacteria include, but are not limited to, methicillin-resistant staphylococcus aureus, vancomycin-resistant staphylococcus aureus, norfloxacin-resistant staphylococcus aureus, multidrug-resistant staphylococcus aureus, and multidrug-resistant staphylococcus hominis.

[0097] In the present invention, the diseases include yellow and white diarrhea, enzootic pneumonia, erysipelas, edema disease, clostridial enteritis, proliferative enteritis, tuberculosis, pasteurellosis, anthrax, salmonellosis.

[0098] In the present invention, the small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is used to inhibit the growth, reproduction, migration and infiltration of pathogenic bacteria, and quickly kill pathogenic bacteria and their drug-resistant bacteria.

[0099] In the present invention, the small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, destroys the integrity of the cell membrane of pathogenic bacteria, affects the morphology of the cell membrane of pathogenic bacteria, deforms the outer membrane of pathogenic bacteria, and appears dents and holes, thereby quickly killing bacteria.

[0100] In the present invention, the small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, can kill 99% of pathogenic bacteria and their drug-resistant bacteria within 180 min.

[0101] In the present invention, the small molecule organic compound with a nitrogen atom disubstituted aromatic ring, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is not likely to produce drug resistance.

[0102] In the present invention, the nitrogen atom double-substituted aromatic ring small molecule organic compound, pharmaceutically acceptable salt or pharmaceutical composition thereof does not cause red blood cell hemolysis, has no obvious toxicity to mammalian cells, and has high safety.

[0103] In the present invention, the nitrogen atom double-substituted aromatic ring small molecule organic compound, pharmaceutically acceptable salt or pharmaceutical composition thereof clears the bacteria in the body of mice infected with methicillin-resistant Staphylococcus aureus through the injection administration route, and significantly prolongs the survival period of the diseased mice.

[0104] The nitrogen atom double-substituted aromatic ring small molecule organic compound, pharmaceutically acceptable salt or pharmaceutically acceptable carrier, etc. shown in formulas (I)-(VI) of the present invention also have the same effects as the nitrogen atom double-substituted aromatic ring small molecule organic compound shown in formulas (I)-(VI).

[0105] The antibacterial drug of the present invention can be used alone or in combination with other drugs.

[0106] The beneficial effects of the present invention are as follows: The nitrogen atom double-substituted aromatic ring small molecule organic compound shown in formulas (I)-(VI) of the present invention can inhibit the growth and reproduction of bacteria, quickly kill bacteria and drug-resistant bacteria and are not easy to generate drug resistance; it can treat the peritonitis disease in mice caused by methicillin-resistant Staphylococcus aureus, and animal experiments also show that the nitrogen atom double-substituted aromatic ring small molecule organic compound shown in formulas (I)-(VI) of the present invention can clear the bacteria in the infected mice and significantly prolong the survival period of the mice. The present invention provides an important reference for the research and development of new antibacterial agents and has good application prospects for treating diseases caused by bacterial infections. Description of the Drawings

[0107] Figure 1 The bactericidal effect diagram of some compounds of the present invention against Staphylococcus aureus ATCC6538 is shown.

[0108] Figure 2 The hemolytic activity of some compounds of the present invention against mammalian red blood cells is shown.

[0109] Figure 3 The effect diagram of the change of MIC value after some compounds of the present invention are treated with Staphylococcus aureus ATCC6538 for a long time is shown.

[0110] Figure 4 The bactericidal effect diagrams of some compounds of the present invention against methicillin-resistant Staphylococcus aureus, multi-drug resistant human Staphylococcus aureus, norfloxacin-resistant Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus are shown.

[0111] Figure 5The effects of some compounds of the present invention on the morphology and integrity of bacterial cell membranes are shown. Among them, (A) is the scanning electron micrograph of Staphylococcus aureus treated or untreated with the compounds of the present invention; (B) is the immunofluorescence micrograph of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus treated or untreated with the compounds of the present invention; (C) is the flow cytometry result graph of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus treated or untreated with the compounds of the present invention; (D) is the effect on the DNA leakage of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus treated or untreated with the compounds of the present invention.

[0112] Figure 6 The in vivo effect diagrams of the compounds of the present invention on mice infected with methicillin-resistant Staphylococcus aureus are shown. Among them, (A) is the number of bacteria in the main organs (heart, liver, spleen, lung, kidney) of mice after administration of different doses of the compounds of the present invention; (B) is the statistical graph of the survival period of mice after administration of different doses of the compounds of the present invention.

[0113] Combined with the following specific embodiments and drawings, the present invention will be further described in detail. The protection scope of the present invention is not limited to the following embodiments. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be conceived by those skilled in the art are included in the present invention, and the appended claims are used as the protection scope. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no special restrictive content.

[0114] 1 1H-NMR was measured using a Bruker AV-400 instrument; all solvents were redistilled before use, and the anhydrous solvents used were all obtained by drying treatment according to standard methods; except as otherwise stated, all reactions were carried out under nitrogen protection and monitored by TLC, and during post-treatment, they were all washed with saturated brine and dried with anhydrous sodium sulfate; the purification of the products was carried out by column chromatography using silica gel (200 - 300 mesh) except as otherwise stated; the silica gel used, including 200 - 300 mesh and GF254, was produced by Qingdao Ocean Chemical Factory or Yantai Yuanbo Silica Gel Company.

[0115] Example 1: Preparation of small molecule organic compounds with double-substituted aromatic rings by nitrogen atoms

[0116] Example 1-01: Preparation of N-(1-hydroxy-2-naphthyl)-N-(phenanthrene-9-methyl)pentanamide (YZ-001)

[0117] (1) 2-Nitro-1-naphthol (1.135 g, 6.0 mmol) and anhydrous K2CO3 (1.650 g, 12.0 mmol) were dissolved in anhydrous DMF (10 mL). Then, benzyl bromide (2.14 mL, 18.0 mmol) was added dropwise to the reaction system. The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was completed as detected by TLC, it was extracted three times with ethyl acetate and H2O. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the intermediate 1-(benzyloxy)-2-nitronaphthalene (1.6683 g, 99.6% yield) was obtained by column chromatography.

[0118] (2) 1-(Benzyloxy)-2-nitronaphthalene (1.6683 g, 5.97 mmol) was dissolved in a mixed solution of 20 mL of EtOH / H2O (4:1). Subsequently, Fe (3.024 g, 54.0 mmol) and NH4Cl (991.2 mg, 18.0 mmol) were added to the reaction system. The reaction mixture was stirred at 85 °C for 2 hours, and then ethanol was removed under reduced pressure. The residue was extracted 3 times with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the intermediate 1-(benzyloxy)-2-naphthylamine (1.422 g, 95% yield).

[0119] (3) 1-(Benzyloxy)-2-naphthylamine (247.5 mg, 0.99 mmol) and 9-phenanthraldehyde (170.6 mg, 0.83 mmol) were dissolved in toluene. A water separator was added, and the system was heated to 100 °C and stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in 10 mL of 1,4-dioxane solution, and NaBH3CN (124.4 mg) was added portionwise at room temperature. After the reaction was completed as detected by TLC, the reaction was quenched with a small amount of water, the solvent was removed under reduced pressure, and it was extracted three times with CH2Cl2 and H2O. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the intermediate 1-(benzyloxy)-N-(phenanthren-9-ylmethyl)-2-naphthylamine (191.8 mg, 52.5% yield) was obtained by column chromatography.

[0120] (4) 1-(Benzyloxy)-N-(phenanthren-9-ylmethyl)-2-naphthylamine (191.8 mg, 0.436 mmol) and valeryl chloride (105.3 mg, 0.872 mmol) were dissolved in 10 mL of 1,4-dioxane solution. Subsequently, the system was heated to 105 °C and stirred for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure, and it was extracted three times with CH2Cl2 and H2O. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the intermediate N-(1-(benzyloxy)-2-naphthalenyl)-N-(phenanthren-9-ylmethyl)valeramide (133.3 mg, 58.4% yield) was obtained by column chromatography.

[0121] (5) Dissolve N-(1-(benzyloxy)-2-naphthalenyl)-N-(phenanthren-9-ylmethyl)pentanamide (133.3 mg, 0.25 mmol) in 2.5 mL of anhydrous dichloromethane. Then, dropwise add BCl3 at 0 °C. The mixture is stirred at room temperature until TLC shows the reaction is complete, and the reaction is quenched with a small amount of water. The residue is extracted with CH2Cl2 and H2O, washed with saturated brine, dried over anhydrous Na2SO4, concentrated, and then N-(1-hydroxy-2-naphthalenyl)-N-(phenanthren-9-ylmethyl)pentanamide (61.1 mg, 55.4% yield) is obtained by column chromatography. 1 H NMR (300 MHz, CDCl3) δ 8.76 (d, J = 8.6 Hz, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.73 - 7.67 (m, 3H), 7.63 - 7.53 (m, 2H), 7.49 - 7.35 (m, 3H), 7.29 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 5.70 (d, J = 14.3 Hz, 1H), 5.39 (d, J = 14.1 Hz, 1H), 2.12 - 2.07 (m, 2H), 1.65 - 1.64 (m, 2H), 1.24 - 1.16 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).

[0122] Preparation of Example 1-02, N-(3,5-Di-tert-butylbenzyl)-N-(1-hydroxy-2-naphthalenyl)pentanamide (YZ-002)

[0123] Dissolve 1-(benzyloxy)-2-naphthylamine (277.1 mg, 1.11 mmol) and K2CO3 (306.82 mg, 2.22 mmol) in 2.0 mL of anhydrous DMF. Dropwise add 3,5-di-tert-butylbenzyl bromide (229.0 mg, 1.05 mmol) under ice-cooling, and then restore the reaction system to room temperature and stir for 1 hour. After the reaction is complete, extract three times with CH2Cl2 and H2O, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and then purify by column chromatography to obtain the key intermediate 1-(benzyloxy)-N-(3,5-di-tert-butylbenzyl)-2-naphthylamine (214.7 mg, 45.6% yield). Subsequently, according to the method of Example 1-01, compound N-(3,5-di-tert-butylbenzyl)-N-(1-hydroxy-2-naphthalenyl)pentanamide (90% yield) is obtained, with the difference that intermediate 1-(benzyloxy)-N-(3,5-di-tert-butylbenzyl)-2-naphthylamine is used instead of intermediate 1-(benzyloxy)-N-(9-methylphenanthrene)-2-naphthylamine. 1HNMR (300 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.54 - 7.42 (m, 2H), 7.40 - 7.30 (m, 2H), 7.02 (s, 2H), 6.95 (d, J = 8.6 Hz, 1H), 5.82 (s, 1H), 5.22 (d, J = 13.5 Hz, 1H), 4.57 (d, J = 13.6 Hz, 1H), 2.13 - 1.99 (m, 2H), 1.59 - 1.51 (m, 2H), 1.26 - 1.24 (m, 2H), 1.19 (s, 18H), 0.78 (t, J = 7.3 Hz, 3H).

[0124] Example 1 - 15N-(Benzo[b]thiophen-2-ylmethyl)-N-(3-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (YZ-015)

[0125] (1) 5-Bromo-2-nitrophenol (327.0 mg, 1.5 mmol) and K2CO3 (618.0 mg, 4.5 mmol) were dissolved in 2 mL of anhydrous DMF, and then benzyl bromide (0.53 mL, 4.5 mmol) was added dropwise under ice bath conditions. Subsequently, the reaction system was heated to 60 °C and stirred for 1 hour. After the reaction was completed, it was extracted three times with ethyl acetate and water. The organic phases were combined and dried over anhydrous sodium sulfate, and after concentration, the intermediate 2-(benzyloxy)-4-bromo-1-nitrobenzene (433.6 mg, 93.8% yield) was obtained by column chromatography.

[0126] (2) 2-(Benzyloxy)-4-bromo-1-nitrobenzene (433.6 mg, 1.42 mmol) was dissolved in a mixed solution of 20 mL of EtOH / H2O (4:1). Subsequently, Fe (715.68 mg, 12.78 mmol) and NH4Cl (991.2 mg, 227.86 mmol) were added to the reaction system. After the reaction mixture was stirred at 85 °C for 2 hours, ethanol was removed under reduced pressure. The residue was extracted 3 times with ethyl acetate and water. The organic phases were combined and dried over anhydrous sodium sulfate, and after evaporation to dryness, the intermediate 2-(benzyloxy)-4-bromoaniline (380.6 mg, 96.4% yield) was obtained.

[0127] (3) 2-(Benzyloxy)-4-bromoaniline (380.6 mg, 1.37 mmol) and K2CO3 (378.17 mg, 2.74 mmol) were dissolved in 2.0 mL of anhydrous DMF. 2-(Bromomethyl)benzo[b]thiophene (211.23 mg, 0.82 mmol) was slowly added thereto under ice-cooling, and then the reaction system was allowed to return to room temperature and stirred for 5 hours. After completion of the reaction, the mixture was extracted three times with CH2Cl2 and H2O. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain the key intermediate N-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-bromoaniline (142.7 mg, 24.6% yield).

[0128] (4) N-(Benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-bromoaniline (142.7 mg, 0.34 mmol) and 4,4,4-trifluorobutyryl chloride (163.7 mg, 1.02 mmol) were dissolved in 10 mL of 1,4-dioxane. Subsequently, the system was heated to 105 °C and stirred for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure. The mixture was extracted three times with CH2Cl2 and H2O. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and then the intermediate N-(benzo[b]thiophen-2-ylmethyl)-N-(2-(benzyloxy)-4-bromophenyl)-4,4,4-trifluorobutanamide (157.3 mg, 84.4% yield) was obtained by column chromatography.

[0129] (5) A dry round-bottom flask was sealed and protected with nitrogen. (Benzo[b]thiophen-2-ylmethyl)-N-(2-(benzyloxy)-4-bromophenyl)-4,4,4-trifluorobutanamide (157.3 mg, 0.29 mmol), Pd(PPh3)4 (35 mg) were added to 2 mL of DME and 4 mL of Na2CO3 (2.0 mol / L). The system was stirred at room temperature for 10 min under nitrogen protection. Phenylboronic acid (70.7 mg, 0.58 mmol) and 3 mL of ethanol were added to the mixture, and it was sealed and heated to 85 °C under nitrogen protection and reacted overnight. Post-treatment: The solvent was evaporated under reduced pressure, and the mixture was extracted three times with dichloromethane and water. The combined organic phases were dried over anhydrous sodium sulfate, concentrated to obtain N-(benzo[b]thiophen-2-ylmethyl)-N-(3-(benzyloxy)-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (151.7 mg, 98.5% yield).

[0130] (6) Dissolve N-(benzothiophen-2-ylmethyl)-N-(3-(benzyloxy)-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (151.7 mg, 0.29 mmol) in 2.5 mL of anhydrous dichloromethane. Then add BCl3 dropwise at 0 °C. The mixture was stirred at room temperature until TLC showed the reaction was complete, and the reaction was quenched with a small amount of water. The residue was extracted with CH2Cl2 and H2O, washed with saturated brine, dried over anhydrous Na2SO4, concentrated, and N-(benzo[b]thiophen-2-ylmethyl-N-(3-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (111.4 mg, 83% yield) was obtained by column chromatography. 1 1H NMR (300 MHz, CDCl3) δ 7.84 - 7.75 (m, 1H), 7.71 - 7.64 (m, 1H), 7.57 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.08 (dd, J = 24.1, 10.7 Hz, 2H), 5.23 (s, 1H), 5.18 - 4.93 (m, 2H), 2.59 - 2.46 (m, 2H), 2.40 - 2.33 (m, 2H).

[0131] Example 1 - 35 N-(benzo[b]thiophen-2-ylmethyl-N-(3-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (YZ-035)

[0132] (1) First, prepare the key intermediate N-(benzothiophen-2-ylmethyl)-N-(2-(benzyloxy)-5-cyanophenyl)-4,4,4-trifluorobutanamide according to the method for preparing intermediate N-(benzothiophen-2-ylmethyl)-N-(2-(benzyloxy)-4-bromophenyl)-4,4,4-trifluorobutanamide in Examples 1-15, except that 4-hydroxy-3-nitrobenzonitrile is used instead of 4-bromo-2-nitrophenol. Subsequently, dissolve N-(benzothiophen-2-ylmethyl)-N-(2-(benzyloxy)-5-cyanophenyl)-4,4,4-trifluorobutanamide (224.7 mg, 0.454 mmol) and DIEA (0.24 mL, 1.41 mmol) in 20 mL of ethanol, then add hydroxylamine hydrochloride (65.09 mg, 0.94 mmol), and stir the mixture at 80 °C for 4 hours. Concentrate the residue and extract it with CH2Cl2 and H2O. Wash the separated organic layer with saturated sodium chloride, dry it with Na2SO4, concentrate it, dissolve the obtained residue in pyridine (10 mL), add trifluoroacetic anhydride (0.2 mL, 1.41 mmol) dropwise, and then stir the mixture at 50 °C until TLC shows that the reaction is complete. Extract the residue with CH2Cl2 and H2O, wash it with saturated brine, dry it with anhydrous Na2SO4, concentrate it, and obtain N-(benzothiophen-2-ylmethyl)-N-(2-(benzyloxy)-5-(5-(trifluoromethyl)-3-(1,2,4-oxadiazolyl)phenyl)-4,4,4-trifluorobutanamide (120 mg, 50.1% yield) by column chromatography.

[0133] (2) Dissolve N-(benzothiophen-2-ylmethyl)-N-(2-(benzyloxy)-5-(5-(trifluoromethyl)-3-(1,2,4-oxadiazolyl)phenyl)-4,4,4-trifluorobutanamide (120.0 mg, 0.2 mmol) in 2.5 mL of anhydrous dichloromethane. Then add BCl3 dropwise at 0 °C. Stir the mixture at room temperature until TLC shows that the reaction is complete, and quench the reaction with a small amount of water. Extract the residue with CH2Cl2 and H2O, wash it with saturated brine, dry it with anhydrous Na2SO4, concentrate it, and obtain N-(benzo[b]thiophen-2-ylmethyl-N-(3-hydroxy-[1,1'-biphenyl]-4-yl)-4,4-4-trifluorobutanamide (75.5 mg, 75.4% yield) by column chromatography.

[0134] The preparation methods of the compounds YZ-001 to YZ-035 corresponding to Examples 1-01 to 1-35 are shown in Table 1.

[0135]

[0136]

[0137]

[0138]

[0139] The following examples provide the preparation methods and product detection results of some compounds of the present invention from 001 to 035.

[0140] Example 1-03. Preparation of N-((2,3-dihydrobenzofuranyl)-5-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ-003)

[0141] Replace 3,5-di-tert-butylbenzyl bromide with 5-(bromomethyl)-2,3-dihydrobenzofuran, and prepare compound YZ-003 according to the method of Example 1-02. 1 H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 7.0 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.58 - 7.43 (m, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 6.92 (dd, J = 8.1, 3.3 Hz, 2H), 6.65 (d, J = 8.2 Hz, 1H), 5.98 (s, 1H), 4.99 (d, J = 13.8 Hz, 1H), 4.64 (d, J = 13.9 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.14 (t, J = 8.6 Hz, 2H), 2.09 - 1.94 (m, 2H), 1.42 - 1.37 (m, 1H), 1.57 - 1.51 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H).

[0142] Example 1-04. Preparation of N-((2,3-dihydrobenzo[b][1,4]dioxanyl)-6-methyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ-004)

[0143] Replace 3,5-di-tert-butylbenzyl bromide with 6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane, and prepare compound YZ-004 according to the method of Example 1-02. 11H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.58 - 7.46 (m, 2H), 7.35 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.83 - 6.68 (m, 3H), 6.45 (s, 1H), 4.80 (q, J = 13.8 Hz, 2H), 4.23 (s, 4H), 2.16 - 1.95 (m, 2H), 1.60 - 1.52 (m, 2H), 1.22 - 1.12 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H).

[0144] Example 1 - 05, Preparation of N-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ - 005)

[0145] Replace 3,5 - di - tert - butylbenzyl bromide with 5-(bromomethyl)benzo[d][1,3]dioxole, and prepare YZ - 005 according to the method of Example 1 - 02. 1 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 7.31 - 7.30 (m, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.74 (s, 1H), 5.17 (d, J = 13.5 Hz, 1H), 4.47 (d, J = 13.9 Hz, 1H), 4.26 - 4.18 (m, 1H), 2.16 - 2.02 (m, 2H), 1.58 - 1.50 (m, 2H), 1.20 - 1.12 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H).

[0146] Example 1 - 06, Preparation of N-(benzo[b]thiophen-5-ylmethyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ - 006)

[0147] Replace 3,5 - di - tert - butylbenzyl bromide with 5-(bromomethyl)benzo[d][1,3]dioxole, and prepare compound YZ - 006 according to the method of Example 1 - 02. 11H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 7.9 Hz, 1H), 7.85 - 7.71 (m, 3H), 7.51 (t, J = 7.4 Hz, 2H), 7.44 (d, J = 5.1 Hz, 1H), 7.38 - 7.28 (m, 3H), 6.90 (d, J = 9.0 Hz, 1H), 5.76 (s, 1H), 5.12 (d, J = 13.9 Hz, 1H), 4.91 (d, J = 13.4 Hz, 1H), 2.10 - 1.96 (m, 2H), 1.37 - 1.33 (m, 2H), 1.23 - 1.14 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H).

[0148] Example 1 - 07. Preparation of N-(benzothiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ - 007)

[0149] Replace 3,5 - di - tert - butylbenzyl bromide with 2-(bromomethyl)benzothiophene, and prepare compound YZ - 007 according to the method of Example 1 - 02. 1 1H NMR (300 MHz, DMSO - d6) δ 10.16 (s, 1H), 8.32 - 8.20 (m, 1H), 7.96 - 7.88 (m, 1H), 7.82 - 7.73 (m, 1H), 7.73 - 7.64 (m, 1H), 7.57 - 7.47 (m, 2H), 7.33 - 7.23 (m, 3H), 7.11 (s, 1H), 6.82 (d, J = 8.6 Hz, 1H), 5.66 (d, J = 15.1 Hz, 1H), 4.35 (d, J = 15.1 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.53 - 1.41 (m, 2H), 1.16 (dd, J = 14.6, 7.3 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H).

[0150] Example 1 - 08. Preparation of N-(benzofuran-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)pentanamide (YZ - 008)

[0151] Replace 3,5 - di - tert - butylbenzyl bromide with 2-(bromomethyl)benzofuran, and prepare compound YZ - 008 according to the method of Example 1 - 02. 11H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.53 (dd, J = 4.2, 1.9 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 6.57 (s, 1H), 5.38 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 2.12 - 2.07 (m, 2H), 1.63 - 1.51 (m, 4H), 0.79 (t, J = 7.3 Hz, 3H).

[0152] Example 1 - 09. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)butanamide (YZ-009)

[0153] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with butyryl chloride, and prepare compound YZ-009 according to the method of Example 1 - 02. 1 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 7.5 Hz, 1H), 7.80 (dd, J = 8.2, 5.0 Hz, 2H), 7.64 (dd, J = 6.1, 3.3 Hz, 1H), 7.53 (dd, J = 7.6, 5.3 Hz, 2H), 7.39 - 7.33 (m, 2H), 7.33 - 7.30 (m, 1H), 7.07 - 6.95 (m, 2H), 6.43 (s, 1H), 5.20 - 5.07 (m, 2H), 2.11 - 2.05 (m, 2H), 1.70 - 1.63 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H).

[0154] Example 1 - 10. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)hexanamide (YZ-010)

[0155] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with hexanoyl chloride, and prepare YZ-010 according to the method of Example 1 - 02. 11H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 6.0 Hz, 2H), 7.68 - 7.60 (m, 1H), 7.59 - 7.46 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 6.0, 3.1 Hz, 2H), 7.16 - 6.91 (m, 2H), 6.13 (s, 1H), 5.21 (d, J = 14.7 Hz, 1H), 5.04 (d, J = 14.9 Hz, 1H), 2.08 (t, J = 7.2 Hz, 2H), 1.65 - 1.59 (m, 2H), 1.23 - 1.12 (m, 4H), 0.81 (t, J = 6.8 Hz, 3H).

[0156] Example 1 - 11. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)acrylamide (YZ-011)

[0157] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with acryloyl chloride, and prepare YZ-011 according to the method of Example 1 - 02. 1 1H NMR (300 MHz, DMSO-d6) δ 10.23 (d, J = 5.5 Hz, 1H), 8.27 (t, J = 4.8 Hz, 1H), 7.91 (dd, J = 6.3, 2.8 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.71 - 7.66 (m, 1H), 7.53 (t, J = 4.7 Hz, 2H), 7.31 (d, J = 3.4 Hz, 2H), 7.28 (d, J = 2.6 Hz, 1H), 7.15 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.82 - 5.48 (m, 2H), 4.51 - 4.43 (m, 1H), 3.88 - 3.64 (m, 2H).

[0158] Example 1 - 12. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)-4-pentenamide (YZ-012)

[0159] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with pentenoyl chloride, and prepare compound YZ-012 according to the method of Example 1 - 02. 11H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.30 - 8.22 (m, 1H), 7.95 - 7.88 (m, 1H), 7.83 - 7.78 (m, 1H), 7.68 (dd, J = 6.3, 2.7 Hz, 1H), 7.52 (dd, J = 5.9, 3.7 Hz, 2H), 7.32 - 7.24 (m, 3H), 7.13 (s, 1H), 6.85 (d, J = 8.6 Hz, 1H), 5.77 - 5.61 (m, 2H), 4.89 (dd, J = 23.8, 6.1 Hz, 2H), 4.94 - 4.83 (m, 1H), 2.31 - 2.19 (m, 2H), 2.13 - 2.03 (m, 2H).

[0160] Example 1 - 13, Preparation of N-(Benzo[b]thiophen-2-ylmethyl)-4-chloro-N-(1-hydroxy-2-naphthyl)butanamide (YZ-013)

[0161] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with 4-chlorobutyryl chloride, and prepare compound YZ-013 according to the method of Example 1 - 02. 1 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.1 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.52 (d, J = 6.9 Hz, 2H), 7.33 - 7.24 (m, 3H), 7.13 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.65 (d, J = 15.0 Hz, 1H), 4.39 (d, J = 14.8 Hz, 1H), 3.59 (t, J = 6.0 Hz, 2H), 2.20 - 2.09 (m, 2H), 1.99 - 1.91 (m, 2H).

[0162] Example 1 - 14, Preparation of N-(Benzo[b]thiophen-2-ylmethyl)-N-(1-hydroxy-2-naphthyl)-4,4,4-trifluorobutanamide (YZ-014)

[0163] Replace 3,5-di-tert-butylbenzyl bromide with 2-(bromomethyl)benzo[b]thiophene and valeryl chloride with 4,4,4-trifluorobutyryl chloride, and prepare compound YZ-014 according to the method of Example 1 - 02. 11H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.66 - 7.61 (m, 1H), 7.53 (dd, J = 13.8, 7.1 Hz, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 5.9, 3.1 Hz, 2H), 7.06 - 6.97 (m, 2H), 6.04 (s, 1H), 5.28 (d, J = 14.4 Hz, 1H), 5.02 (d, J = 14.6 Hz, 1H), 2.59 - 2.45 (m, 2H), 2.38 - 2.23 (m, 2H).

[0164] Example 1 - 16. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-016)

[0165] Replace 5-bromo-2-nitrophenol with 5-bromo-2-nitrophenol, and prepare compound YZ-016 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.86 - 7.76 (m, 1H), 7.74 - 7.61 (m, 1H), 7.57 - 7.46 (m, 1H), 7.38 - 7.29 (m, 6H), 7.18 (d, J = 1.8 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.49 (s, 1H), 5.19 - 5.03 (m, 2H), 2.63 - 2.42 (m, 2H), 2.43 - 2.28 (m, 2H).

[0166] Example 1 - 17. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-017)

[0167] Replace 5-bromo-2-nitrophenol with 2-bromo-6-nitrophenol, and prepare compound YZ-017 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.82 - 7.76 (m, 1H), 7.71 - 7.64 (m, 1H), 7.53 - 7.40 (m, 5H), 7.31 (dd, J = 8.8, 5.1 Hz, 3H), 7.10 (s, 1H), 6.99 - 6.91 (m, 2H), 5.54 (s, 1H), 5.42 (d, J = 14.9 Hz, 1H), 4.77 (d, J = 14.9 Hz, 1H), 2.66 - 2.45 (m, 2H), 2.42 - 2.35 (m, 2H).

[0168] Examples 1-18, Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(3-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-018)

[0169] Replace 5-bromo-2-nitrophenol with 3-bromo-2-nitrophenol, and prepare compound YZ-018 according to the method of Examples 1-15. 1 H NMR (300 MHz, CDCl3) δ 7.81-7.71 (m, 1H), 7.69-7.59 (m, 1H), 7.48-7.37 (m, 3H), 7.37-7.27 (m, 4H), 7.09-6.98 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 5.35 (d, J = 14.8 Hz, 1H), 5.04 (s, 1H), 3.80 (d, J = 14.8 Hz, 1H), 2.68-2.36 (m, 4H). Example 1-19, Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (YZ-019)

[0170] Replace 5-bromo-2-nitrophenol with 2-bromo-5-nitrophenol, and prepare compound YZ-019 according to the method of Examples 1-15. 1 H NMR (300 MHz, CDCl3) δ 7.88-7.79 (m, 1H), 7.79-7.68 (m, 1H), 7.60-7.45 (m, 5H), 7.39-7.33 (m, 2H), 7.14 (s, 1H), 6.86-6.71 (m, 2H), 5.14 (s, 2H), 2.57 (dd, J = 17.2, 8.2 Hz, 2H), 2.47 (dd, J = 8.7, 5.4 Hz, 2H).

[0171] Examples 1-20, Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(3-methoxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide (YZ-020)

[0172] Replace 5-bromo-2-nitrophenol with 4-bromo-2-methoxynitrobenzene, and prepare compound YZ-020 according to the method of Examples 1-15. 11H NMR (300 MHz, CDCl3) δ 7.83 - 7.75 (m, 1H), 7.69 - 7.63 (m, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.31 (dd, J = 8.8, 4.8 Hz, 2H), 7.16 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 7.07 - 7.00 (m, 2H), 5.54 (d, J = 14.9 Hz, 1H), 4.54 (d, J = 14.9 Hz, 1H), 3.83 (s, 3H), 2.56 - 2.45 (m, 2H), 2.41 - 2.24 (m, 2H).

[0173] Example 1 - 21. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(4'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-021)

[0174] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-fluorophenylboronic acid, and prepare compound YZ-021 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 4.9 Hz, 1H), 7.68 (dd, J = 6.3, 3.1 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.36 - 7.28 (m, 4H), 7.10 (s, 2H), 7.03 (t, J = 7.8 Hz, 3H), 5.25 (s, 1H), 5.10 (d, J = 1.8 Hz, 1H), 2.57 - 2.49 (m, 2H), 2.40 - 2.28 (m, 2H).

[0175] Example 1 - 22. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(4'-chloro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-022)

[0176] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-chlorophenylboronic acid, and prepare compound YZ-022 according to the method of Example 1 - 15. 11H NMR (300 MHz, CDCl3) δ 7.81 - 7.71 (m, 1H), 7.67 - 7.58 (m, 1H), 7.42 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 - 7.23 (m, 4H), 7.21 (s, 2H), 7.09 - 7.02 (m, 2H), 6.99 (d, J = 8.5 Hz, 1H), 5.46 (s, 1H), 5.05 (dd, J = 44.7, 14.8 Hz, 2H), 2.58 - 2.38 (m, 2H), 2.36–2.20 (m, 2H).

[0177] Preparation of Examples 1 - 23, N-(benzo[b]thiophen-2-ylmethyl)-N-(4'-bromo-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-023)

[0178] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-bromophenylboronic acid, and prepare compound YZ-023 according to the method of Examples 1 - 15. 1 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.93 - 7.89 (m, 1H), 7.78 - 7.68 (m, 2H), 7.52 (dd, J = 8.4, 5.5 Hz, 1H), 7.37 (dd, J = 8.9, 2.5 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.24 (d, J = 2.3 Hz, 1H), 7.21 (s, 1H), 6.93 (d, J = 8.7 Hz, 1H), 5.29 (d, J = 15.3 Hz, 1H), 4.67 (d, J = 15.6 Hz, 1H), 4.03 (dd, J = 14.4, 7.3 Hz, 1H), 2.37 (dd, J = 15.7, 8.2 Hz, 1H), 2.21 (dd, J = 16.0, 7.0 Hz, 1H), 1.20 - 1.14 (m, 1H).

[0179] Preparation of Examples 1 - 24, N-(benzo[b]thiophen-2-ylmethyl)-N-(4'-tert-butyl-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-024)

[0180] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-tert-butylphenylboronic acid, and prepare compound YZ-024 according to the method of Examples 1 - 15. 11H NMR (300 MHz, CDCl3) δ 7.80 - 7.70 (m, 1H), 7.66 - 7.57 (m, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.22 (d, J = 10.3 Hz, 1H), 7.12 (d, J = 1.1 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.69 (s, 1H), 5.11 (d, J = 14.7 Hz, 1H), 4.98 (d, J = 14.8 Hz, 1H), 2.52 - 2.41 (m, 2H), 2.34 - 2.28 (m, 2H), 1.27 (s, 9H).

[0181] Preparation of Examples 1 - 25, N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-025)

[0182] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and replace phenylboronic acid with 2-methoxyphenylboronic acid, and prepare compound YZ-025 according to the method of Examples 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.82 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.48 (dd, J = 8.5, 1.6 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.23 (s, 2H), 7.15 (d, J = 1.7 Hz, 1H), 7.07 (s, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.83 (s, 1H), 5.32 (s, 1H), 5.08 (q, J = 14.7 Hz, 2H), 3.68 (s, 3H), 2.58 - 2.42 (m, 2H), 2.40 - 2.23 (m, 2H).

[0183] Preparation of Examples 1 - 26, N-(Benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-026)

[0184] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and replace phenylboronic acid with 3-methoxyphenylboronic acid, and prepare compound YZ-026 according to the method of Examples 1 - 15. 11H NMR (300 MHz, CDCl3) δ 7.86 - 7.77 (m, 1H), 7.72 - 7.65 (m, 1H), 7.46 (dd, J = 8.4, 1.3 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.29 (d, J = 5.1 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.04 (d, J = 8.5 Hz, 1H), 7.01 - 6.90 (m, 2H), 5.23 (d, J = 14.8 Hz, 1H), 5.03 (d, J = 14.8 Hz, 1H), 3.67 (s, 3H), 2.62 - 2.36 (m, 4H).

[0185] Preparation of Examples 1 - 27, N-(benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-027)

[0186] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-methoxyphenylboronic acid, and prepare compound YZ-027 according to the method of Examples 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.86 - 7.76 (m, 1H), 7.71 - 7.64 (m, 1H), 7.46 (dd, J = 8.2, 1.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.16 - 7.08 (m, 2H), 7.01 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 3.82 (s, 3H), 2.61 - 2.42 (m, 2H), 2.39 - 2.33 (m, 2H).

[0187] Preparation of Examples 1 - 28, N-(benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-028)

[0188] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 2-trifluoromethylphenylboronic acid, and prepare compound YZ-028 according to the method of Examples 1 - 15. 11H NMR (300 MHz, DMSO-d6) δ 10.36 (d, J = 24.2 Hz, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.71 (t, J = 7.2 Hz, 2H), 7.61 - 7.45 (m, 2H), 7.36 - 7.29 (m, 2H), 7.24 - 7.14 (m, 3H), 7.04 (d, J = 8.2 Hz, 1H), 6.95 - 6.84 (m, 1H), 5.45 - 5.26 (m, 1H), 4.63 (dd, J = 26.5, 14.9 Hz, 1H), 2.46 - 2.32 (m, 2H), 2.32 - 2.11 (m, 2H). Preparation of Example 1 - 29, N-(benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-3'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-029)

[0189] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol, and replace phenylboronic acid with 3-trifluoromethylphenylboronic acid, and prepare compound YZ-029 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.85 - 7.76 (m, 1H), 7.67 (dd, J = 12.0, 5.9 Hz, 2H), 7.59 - 7.45 (m, 3H), 7.34 (dd, J = 5.7, 3.3 Hz, 2H), 7.31 - 7.26 (m, 2H), 7.23 - 7.03 (m, 2H), 5.24 (s, 1H), 5.17 - 5.06 (q, J = 14.7 Hz, 2H), 2.55 - 2.49 (m, 2H), 2.43 - 2.26 (m, 2H).

[0190] Preparation of Example 1 - 30, N-(benzo[b]thiophen-2-ylmethyl)-N-(4-hydroxy-4'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide (YZ-030)

[0191] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol, and replace phenylboronic acid with 4-trifluoromethylphenylboronic acid, and prepare compound YZ-030 according to the method of Example 1 - 15. 11H NMR (300 MHz, CDCl3) δ 7.85 - 7.78 (m, 1H), 7.71 - 7.65 (m, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.52 (dd, J = 8.5, 1.1 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 5.9, 3.0 Hz, 2H), 7.15 (d, J = 1.4 Hz, 1H), 7.09 (t, J = 4.0 Hz, 2H), 5.25 (d, J = 14.7 Hz, 1H), 4.97 (d, J = 14.7 Hz, 1H), 2.58 - 2.45 (m, 2H), 2.42 - 2.32 (m, 2H).

[0192] Example 1 - 31. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(pyridin-4-yl)phenyl)-4,4,4-trifluorobutanamide (YZ-031)

[0193] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 4-pyridylphenylboronic acid, and prepare compound YZ-031 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 4.6 Hz, 2H), 7.86 - 7.76 (m, 1H), 7.68 - 7.65 (m, 1H), 7.57 (dd, J = 8.5, 1.8 Hz, 1H), 7.34 (dd, J = 5.9, 3.0 Hz, 2H), 7.28 (s, 1H), 7.21 (d, J = 1.7 Hz, 1H), 7.13 - 7.09 (m, 2H), 5.31 (d, J = 14.8 Hz, 1H), 4.91 (d, J = 14.8 Hz, 1H), 2.60 - 2.47 (m, 2H), 2.40 - 2.32 (m, 2H).

[0194] Example 1 - 32. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(pyridin-5-yl)phenyl)-4,4,4-trifluorobutanamide (YZ-032)

[0195] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and phenylboronic acid with 5-pyrimidinylphenylboronic acid, and prepare compound YZ-032 according to the method of Example 1 - 15. 11H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 8.73 (s, 2H), 7.84 - 7.76 (m, 1H), 7.70 - 7.63 (m, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.20 (s, 1H), 7.18 - 7.02 (m, 2H), 6.29 (s, 1H), 5.26 (d, J = 14.5 Hz, 1H), 4.98 (d, J = 14.6 Hz, 1H), 2.63 - 2.47 (m, 2H), 2.45 - 2.27 (m, 2H).

[0196] Example 1 - 33. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(2-thienyl)phenyl)-4,4,4-trifluorobutanamide (YZ-033)

[0197] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and replace phenylboronic acid with 2-thienylphenylboronic acid, and prepare compound YZ-033 according to the method of Example 1 - 15. 1 1H NMR (300 MHz, CDCl3) δ 7.83 - 7.77 (m, 1H), 7.71 - 7.63 (m, 1H), 7.51 (d, J = 6.7 Hz, 1H), 7.33 (dd, J = 5.8, 3.1 Hz, 2H), 7.25 - 7.17 (m, 2H), 7.10 (s, 1H), 7.08 (d, J = 3.2 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.59 (s, 1H), 5.19 - 5.00 (m, 2H), 2.57 - 2.45 (m, 2H), 2.41 - 2.29 (m, 2H).

[0198] Example 1 - 34. Preparation of N-(benzo[b]thiophen-2-ylmethyl)-N-(2-hydroxy-5-(2-furyl)phenyl)-4,4,4-trifluorobutanamide (YZ-034)

[0199] Replace 5-bromo-2-nitrophenol with 4-bromo-2-nitrophenol and replace phenylboronic acid with 2-furylphenylboronic acid, and prepare compound YZ-034 according to the method of Example 1 - 15. 11H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 4.1 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 15.1 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.07 (d, J = 12.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 4.2 Hz, 1H), 5.49 (s, 1H), 5.26 (d, J = 14.7 Hz, 1H), 5.09 - 4.81 (m, 1H), 2.58 - 2.43 (m, 2H), 2.42 - 2.25 (m, 2H).

[0200] Example 2: Inhibitory Experiment of the Compounds of the Present Invention against Various Bacteria

[0201] (1) Inhibitory effect of the compounds of the present invention on the growth and reproduction of Gram-positive bacteria and Gram-negative bacteria. The compounds of the present invention have obvious inhibitory effects on the growth and reproduction of different strains (such as Staphylococcus aureus ATCC6538, Staphylococcus albus D11158, and Escherichia coli AB1157, etc.).

[0202] Experimental protocol: Dissolve the compounds of the present invention in DMSO, configure the stock solution concentration to 10 mg / mL, store it in a -20 °C refrigerator. During the experiment, first pick a single colony of the strain and shake it overnight, then dilute the OD 600 to 0.01 and continue shaking for 5 - 8 h, then dilute the bacterial solution to OD 0.6 and then dilute it 400 times, and then add it to the culture medium containing the compounds of the present invention in equal proportion, and detect the growth status of the bacteria after growing at 37 °C for 24 h.

[0203] Result analysis: By comparing with positive compounds (vancomycin and methicillin), it was found that the compounds of the present invention have obvious inhibitory effects on Gram-positive bacteria: Staphylococcus aureus ATCC6538 strain, Staphylococcus albus D11158 and Gram-negative bacteria: Escherichia coli AB1157. Table 2 shows the inhibitory activities of some compounds of the present invention against the above strains. It can be seen from Table 2 that the compounds of the present invention have obvious antibacterial activities against the above strains, and the MIC values of some compounds are less than 1 μg / mL.

[0204] Table 2 Antibacterial Effects of Some Compounds of the Present Invention against Staphylococcus aureus, Staphylococcus albus and Escherichia coli

[0205]

[0206] (2) Inhibitory effect of the compounds of the present invention on the growth and reproduction of drug-resistant bacteria

[0207] The compounds of the present invention have significant inhibitory activities against methicillin-resistant Staphylococcus strains MRS1, MRS23, MRS70, MRS207, MRS108, MRS153, MRS200, MRS273, MRS153, MRS84, MRS121, MRS97 isolated clinically, vancomycin-resistant Staphylococcus VRS-01, and multi-drug resistant human Staphylococcus strains isolated clinically. Table 3 shows the inhibitory activities of some compounds of the present invention against the above strains. As can be seen from Table 3, the compounds of the present invention have significant antibacterial activities against the above strains, and the MIC values of some compounds are less than 1 μg / mL.

[0208] Table 3 Antibacterial effects of some compounds of the present invention against methicillin-resistant bacteria

[0209]

[0210]

[0211] Example 3: The compounds of the present invention can kill bacteria rapidly

[0212] Experimental protocol: Staphylococcus aureus ATCC6538 and clinical isolates were incubated in 2×YT culture medium at 37 °C until the mid-log phase (OD 600 = 0.3). Then, the bacterial suspension was stimulated with the specified concentration of the compounds of the present invention at 37 °C and 200 rpm, and the colony counts were measured at the specified time.

[0213] Result analysis: As shown in the appendix Figure 1 The compounds of the present invention can rapidly eliminate Staphylococcus aureus ATCC6538 within 2 hours, showing a strong bactericidal effect.

[0214] Example 4: The compounds of the present invention do not induce erythrocyte hemolysis

[0215] Experimental protocol: A certain amount of rabbit whole blood was collected in a heparinized centrifuge tube, centrifuged, the supernatant was discarded, washed, and centrifuged again. After discarding the supernatant, it was prepared into a 2% erythrocyte suspension. Subsequently, the compounds of the present invention were added at a concentration gradient and incubated, centrifuged, the supernatant was taken, and the absorbance at 450 nm was measured with an enzyme-linked immunosorbent assay (ELISA) reader to calculate the hemolysis rate.

[0216] Result analysis: As shown in the appendix Figure 2 The compounds of the present invention do not cause hemolysis of rabbit erythrocytes at a concentration of 20xMI, showing high safety.

[0217] Example 5: The compounds of the present invention have low cytotoxicity to mammalian cells and show strong selectivity

[0218] Experimental protocol: Appropriate amounts of mammalian cells in the logarithmic growth phase were digested, counted, and inoculated into 96-well plates. After culturing in a 37 °C incubator for 24 h, the original culture medium was discarded, and a culture medium containing different concentrations of the compound to be tested was added. The control group was added with the same culture medium containing an equal amount of DMSO. After 72 h, pre-cooled TCA was added to fix the cells, and the cells were left standing in a 4 °C refrigerator for 1 h. After washing with double-distilled water and air-drying, SRB dye was added. After 15 min, the cells were washed with 1% acetic acid solution until there was no floating color. After air-drying, an equal amount of Tris was added to each well. After shaking, the OD value was measured at a wavelength of 515 nm using a microplate reader. The statistical data was analyzed using GraphPad Prism software, and the half-maximal inhibitory concentration (IC 50 ) of the target compound measured against cell proliferation was calculated.

[0219] Result analysis: To further detect the selectivity of the compounds of the present invention against mammalian cells, we used the SRB method to detect the toxicity of some of the compounds of the present invention against Hela, HacaT, HEK293, and A549 cells. The results are shown in Table 4. The compounds of the present invention have low toxicity to the above cells and have a selectivity of more than 20 times compared to their corresponding antibacterial activities.

[0220] Table 4 Toxicity of some compounds of the present invention against mammalian cells

[0221]

[0222] Example 6: The compounds of the present invention are not easily induced to develop drug resistance

[0223] Experimental protocol: The initial MIC value of the compound of the present invention against Staphylococcus aureus ATCC6538 was obtained according to the method in Example 2. Then, bacteria from the 0.5xMIC concentration well were used to prepare a bacterial suspension for the next MIC value test, and the experiment was repeated daily for 10 consecutive days.

[0224] Result analysis: As shown in the appendix Figure 3 , the MIC of the positive compound norfloxacin increased by 256 times within ten days. Compared with the positive compound, the MIC value of the compound of the present invention changed little, and the MIC values of some of the compounds of the present invention did not change at all, indicating that the compounds of the present invention have a low tendency to develop drug resistance.

[0225] Example 7: The compounds of the present invention can rapidly kill multidrug-resistant bacteria

[0226] Experimental protocol: The same as the protocol in Example 3.

[0227] Result analysis: As shown in the appendix Figure 4As shown, the compounds of the present invention can rapidly eliminate methicillin-resistant Staphylococcus aureus, multi-drug resistant human Staphylococcus aureus, norfloxacin-resistant Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus within 150 minutes. Figure A shows the bactericidal effects of the compounds of the present invention on Staphylococcus aureus ATCC6538, multi-drug resistant human Staphylococcus aureus, and the bactericidal effects of methicillin and vancomycin on Staphylococcus aureus ATCC6538 and multi-drug resistant human Staphylococcus aureus. It can be seen from the figure that the compounds of the present invention and methicillin have obvious killing effects on the above strains, while vancomycin cannot kill the above strains. Figures B-D show the bactericidal effects of the compounds of the present invention on different clinically isolated methicillin-resistant Staphylococcus aureus. It can be seen from the figure that the compounds of the present invention can rapidly kill the above strains, while methicillin has no killing effect on methicillin-resistant Staphylococcus aureus. Figures E-F show the bactericidal effects of the compounds of the present invention on norfloxacin-resistant Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus. It can be seen from the figure that the compounds of the present invention can also rapidly kill the above drug-resistant strains.

[0228] Example 8: The compounds of the present invention affect the morphology of bacterial cell membranes

[0229] Experimental protocol: Collect the cells of Staphylococcus aureus in the logarithmic phase, and treat them with the PBS solution of the compounds of the present invention at a specified concentration and the PBS solution of an equal amount of DMSO respectively. After 12 h, stop the drug treatment, add 2.5% glutaraldehyde to fix for 2 h, wash three times with PBS for 10 min each time, fix with 1% osmium tetroxide for 1 h, and wash three times with PBS for 10 min each time. Dehydrate with 30%, 50%, 70%, 80%, 90% ethanol for 10 min each time, and dehydrate with absolute ethanol for 10 min. Dry by critical point drying method for 2 h. Stick the dried powder on the stage, sputter gold for 40 min, and observe and photograph on the scanning electron microscope.

[0230] Result analysis: As shown in Figure 5 Appendix A, after 12 h, the cell morphology of Staphylococcus aureus in the blank control group was normal, and the cell membrane surface was smooth; different degrees of cracks and depressions appeared on the cell membrane surface of the cells treated with the compounds of the present invention, indicating that the compounds of the present invention changed the morphology of the bacterial cell membrane.

[0231] Example 9: The compounds of the present invention disrupt the integrity of bacterial cell membranes

[0232] (1) Immunofluorescence detection of the integrity of bacterial cell membranes

[0233] Experimental protocol: Incubate Staphylococcus aureus and methicillin-resistant Staphylococcus aureus overnight at 37 °C, wash with PBS and resuspend them (OD6 00(= 0.2), DAPI, PI, and SYTOX Green dyes were added respectively, and then the compound of the present invention at a specified concentration was added. An equal amount of DMSO was added to the blank control group. After incubation for a period of time, immunofluorescence imaging was performed.

[0234] Result analysis: As shown in Appendix Figure 5 B, compared with the blank control group, in both the Staphylococcus aureus group and the methicillin-resistant Staphylococcus aureus group, there was obvious fluorescence in the PI channel and SYTOX Green channel of the compound treatment group of the invention, indicating that the compound of the present invention can damage the bacterial cell membrane.

[0235] (2) Detection of bacterial cell membrane integrity by flow cytometry

[0236] Experimental protocol: Logarithmic-phase Staphylococcus aureus and methicillin-resistant Staphylococcus aureus cells were collected, washed with PBS and resuspended to a final concentration of 10 8 CFU / ml, divided into two groups, and the compound of the present invention at a specified concentration and an equal amount of DMSO were added respectively. An appropriate amount of propidium iodide (PI dye) was added to both groups, and they were incubated in the dark at 37 °C in an incubator for 1 h. The cell suspension was immediately subjected to flow cytometry analysis.

[0237] Result analysis: As shown in Appendix Figure 5 C, compared with the blank control group, after treatment with the compound of the present invention, the peak shifted significantly to the right, indicating that the compound of the present invention can damage the bacterial cell membrane.

[0238] (3) Ethidium bromide (EB) uptake assay

[0239] Experimental protocol: Logarithmic-phase Staphylococcus aureus and methicillin-resistant Staphylococcus aureus cells were collected, washed with PBS and resuspended to a final concentration of 10 7 CFU / ml, divided into two groups, and then an appropriate concentration of EB was added. They were incubated in the dark at 37 °C in an incubator for 1 h. Different concentrations of the compound of the present invention were added respectively, and an equal amount of DMSO was added to the blank control group. Using light with a wavelength of 540 nm as the excitation light, the fluorescence values at 590 nm were measured at different time points after adding the drug.

[0240] Result analysis: As shown in Appendix Figure 5 D, as the concentration of the compound of the present invention increased, the fluorescence intensity gradually increased, indicating that the compound of the present invention can damage the bacterial cell membrane and bacterial DNA leaked out.

[0241] The above experimental results show that the compound of the present invention can damage the integrity of the bacterial cell membrane, causing it to be damaged and losing its barrier function.

[0242] Example 10: The compound of the present invention can inhibit the growth of methicillin-resistant Staphylococcus aureus in vivo and significantly prolong the survival period of mice.

[0243] (1) Method for the compound of the present invention to inhibit the growth of methicillin-resistant Staphylococcus aureus in vivo: 30 Balb / c mice were randomly divided into 5 groups with 6 mice in each group. A certain amount of methicillin-resistant Staphylococcus aureus in the logarithmic phase was injected into the abdominal cavity of the mice. One hour later, 0.5 ml of normal saline was intraperitoneally injected into the 5 infected groups as the blank, vancomycin (12.5 mg / kg) as the positive control group, the low-dose compound of the present invention (3.125 mg / kg), the medium-dose group (6.25 mg / kg), and the high-dose group (12.5 mg / kg). After 24 hours of administration, the mice were sacrificed by cervical dislocation. After separating the heart, liver, spleen, lungs, and kidneys of the mice, the bacteria in each tissue were extracted, and the abdominal cavity fluid was spotted on a TSA plate by serial dilution method and cultured in an inverted position at 37 °C for 18 - 24 h. The bacterial concentration in the main organs of each group of mice was counted and calculated.

[0244] Result analysis: As shown in Figure 6 Figure A, compared with the blank control group, the bacterial content in the main organs of the mice in the compound treatment group of the present invention was significantly reduced and showed a concentration-dependent manner, indicating that the compound of the present invention can significantly inhibit the growth of methicillin-resistant Staphylococcus aureus in mice. Compared with the positive control group, at the same concentration, the antibacterial effect of the compound of the present invention in mice was significantly better than that of the positive control group.

[0245] (2) The compound of the present invention can significantly prolong the survival period of mice infected with methicillin-resistant Staphylococcus aureus.

[0246] Experimental protocol: 30 Balb / c mice were randomly divided into 5 groups with 6 mice in each group. A lethal dose of methicillin-resistant Staphylococcus aureus in the logarithmic phase was injected into the abdominal cavity of the mice. One hour later, 0.5 ml of normal saline was intraperitoneally injected into the 5 infected groups as the blank, vancomycin (12.5 mg / kg) as the positive control group, the low-dose compound of the present invention (3.125 mg / kg), the medium-dose group (6.25 mg / kg), and the high-dose group (12.5 mg / kg). The death of the mice was counted every day for 7 consecutive days.

Claims

1. A class of small molecule organic compounds with double-substituted aromatic rings by nitrogen atoms, characterized in that, Its structure is as follows as shown in formula (III): Formula (III) wherein, n = 0 - 5; Selected from any one of a monocyclic aryl group, a polycyclic aryl group, and a polyheterocyclic aryl group; the monocyclic aryl group is selected from a phenyl group, a heteroaromatic nitrogen-containing ring group, a heteroaromatic sulfur-containing ring group, or a heteroaromatic oxygen-containing ring group; the polycyclic aryl group and the polyheterocyclic aryl group include two or more monocyclic aryl groups; R1 is a hydroxyl group; R3 is selected from any one of the following groups: C1-C 12 alkyl, C1-C 12 haloalkyl; X, Y, Z, and W are each independently selected from one or more of CH, CH=CH, CH=N, NH, N, O, or S; R4 is selected from one of the following groups: hydrogen, halogen, alkyl, trifluoromethyl, trifluoromethoxy, alkoxy.

2. The nitrogen atom double-substituted aromatic ring-based small molecule organic compound according to claim 1, wherein The structure is as shown in the following formula (IV): Formula (IV) wherein, n1 = 1 - 11.

3. The small molecule organic compound of the nitrogen atom double-substituted aromatic ring type according to claim 2, wherein n=1。 4. The small molecule organic compound of the nitrogen atom double-substituted aromatic ring according to claim 1, characterized in that, Comprising: N -(Benzo[b]thiophen-2-ylmethyl- N -(3-Hydroxy-[1,1'-biphenyl]-4-yl-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(3-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-[1,1'-biphenyl]-4-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4'-chloro-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4'-bromo-4-hydroxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -4,4,4-trifluoro-N-(4'-tert-butyl-4-hydroxy-[1,1'-biphenyl]-3-yl)butanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-2'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-3'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-2'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-3'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(4-hydroxy-4'-trifluoromethyl-[1,1'-biphenyl]-3-yl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-5-(4-pyridyl)phenyl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-5-(5-pyridyl)phenyl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-5-(2-thienyl)phenyl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-5-(2-furyl)phenyl)-4,4,4-trifluorobutanamide N -(benzo[b]thiophen-2-ylmethyl)- N -(2-hydroxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-4,4,4-trifluorobutanamide.

5. A pharmaceutically acceptable salt of a small molecule organic compound with a nitrogen atom double-substituted aromatic ring according to any one of claims 1-4, characterized in that, The pharmaceutically acceptable salts include acid addition salts formed with the following acids; wherein, the acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, pyruvic acid, maleic acid, succinic acid.

6. A pharmaceutical composition containing the nitrogen atom double-substituted aromatic ring small molecule organic compound according to any one of claims 1 - 4 or the pharmaceutically acceptable salt according to claim 5, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition according to claim 6, characterized in that, The dosage form of the pharmaceutical composition is an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch, or excipient.

8. Use of the small molecule organic compound of a nitrogen atom double-substituted aromatic ring according to any one of claims 1-4, or the pharmaceutically acceptable salt according to claim 5, or the pharmaceutical composition according to claim 6 in the preparation of an antibacterial agent for preventing and / or treating diseases related to pathogenic bacteria infection, characterized in that, The pathogenic bacteria are Gram-positive bacteria, Gram-negative bacteria, or their respective drug-resistant bacteria.

9. The application according to claim 8, characterized in that, The Gram-positive bacteria include Staphylococcus, Streptococcus, Erysipelothrix, Mycobacterium, Bacillus anthracis; the Gram-negative bacteria include Escherichia coli, Pasteurella, Riemerella, Salmonella, Haemophilus, Brucella, Pseudomonas aeruginosa, Neisseria gonorrhoeae; The drug-resistant bacteria include methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, norfloxacin-resistant Staphylococcus aureus, multi-drug resistant Staphylococcus aureus, multi-drug resistant Staphylococcus hominis.

10. The application according to claim 8, characterized in that The diseases include yellow and white diarrhea, asthma, erysipelas, edema disease, clostridial enteritis, proliferative enteritis, tuberculosis, pasteurellosis, anthrax, salmonellosis.

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