RU2826219C2 - Novel aminoalkanoic acid derivative containing biphenyl group, and antifungal pharmaceutical composition containing it - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1, where R¹-R³, n and m are defined in the claim, a stereoisomer or a pharmaceutically acceptable salt thereof. Compound according to the invention exhibits excellent antifungal and fungicidal effects.

EFFECT: compound according to the invention exhibits a synergistic effect when used in combination with a common antifungal agent, has a wide spectrum of antifungal activity against a large number of fungal pathogens and can be widely used in fields, where it is necessary to use antifungal or fungicidal agents against human pathogenic fungi and animal pathogenic fungi, as well as phytopathogenic fungi.

19 cl, 3 dwg, 9 tbl, 94 ex

Description

Field of technology to which the invention relates

The present invention relates to a derivative compound in which a biphenyl group is introduced into an aminoalkanoic acid, its stereoisomer or its pharmaceutically acceptable salt, and to a pharmaceutical composition for the prevention and/or treatment of an infectious fungal disease, which includes this compound as an active ingredient.

Prerequisites creations inventions

As modern humans live longer, opportunistic fungal infections are increasing, especially among the elderly, due to their declining immune functions. In addition, opportunistic fungal infections are increasing worldwide, particularly among immunocompromised patients who are treated with immunosuppressants to reduce transplant rejection, or among organ transplant patients with compromised immune functions, or among patients with weakened immune systems due to chemotherapy or acquired immunodeficiency syndrome (AIDS). In the past, fungal infections were usually local fungal infections such as athlete's foot, tinea versicolor, and thrush, but recently, systemic fungal infections have become so common that they rank fourth among all types of infections in hospitals. Representative opportunistic fungi have been reported to includeCandida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformansetc. Pathogenic fungusCryptococcus neoformans,causing systemic infections, is commonly found in soil throughout the world, and its basidiospores can be inhaled from the environment into the lungs. In immunocompromised patients, such as organ transplant patients or AIDS patients, fungi in the lungs can cause pulmonary infections and enter the central nervous system through the blood-brain barrier (BBB), causing life-threatening meningitis. In particular, meningitis caused byCryptococcus,leads to the most high mortality rate among meningitis, with more than 600,000 deaths worldwide each year. However, because fungi are composed of eukaryotic cells like animal cells, the biochemical metabolic pathways of fungi and mammals are so similar that it is difficult to find a fungal-specific drug target. Thus, conventional antifungal agents for the treatment of cryptococcosis have several limitations in their clinical use. Antifungal agents developed to date for the treatment of fungiCryptococcus,include the polyene class, which includes amphotericin B; the azole class, which includes ketoconazole, fluconazole, itraconazole, and voriconazole; and the non-azole class, such as terbinafine and flucytosine; the echinocandin class, such as caspofungin. Amphotericin B, one of the polyene antifungals, binds to ergosterol in the cell membraneCryptococcus,causing oxidative damage, leading to the death of fungal cells. However, amphotericin B causes side effects due to its strong toxicity to the human body. Azole antifungals are known to inhibit the biosynthesis of ergosterol, one of the main elements of the fungal cell membrane, by inhibiting 14-α-demethylase, which is involved in the conversion of lanosterol to ergosterol, thereby weakening the cell membrane and causing fungal cell death. However, increasing fungal resistance to azole has been reported. Terbinafine inhibits ergosterol synthesis by inhibiting the conversion of squalene to epoxide squalene. Flucytosine, which is a metabolic antagonist that inhibits nucleic acid synthesis, exhibits antifungal effects by causing abnormal coding of fungal RNA and counteracting fungal DNA synthesis. Echinocandin class antifungals exhibit antifungal effects by inhibiting the synthesis of fungal cell wall, while other antifungals mentioned above act on fungal cell membranes. As mentioned above, conventional antifungals, like other drugs, have a number of problems related to side effects, such as severe toxicity, development of drug resistance, etc. Therefore, it is urgently needed to develop a new class of antifungal agent that can exhibit enhanced antifungal effects while minimizing side effects.

Disclosure of invention

Technical problem

The present invention provides a novel aminoalkanoic acid derivative containing a biphenyl group, a salt and/or solvate thereof.

Furthermore, the present invention provides an antifungal pharmaceutical composition containing the said aminoalkanoic acid derivative, its salt and/or solvate as an active ingredient.

Furthermore, the present invention provides an agricultural antifungal agent containing the said aminoalkanoic acid derivative, a salt thereof and/or a solvate thereof as an active ingredient.

In addition, the present invention provides an antifungal agent for animals containing the said aminoalkanoic acid derivative, a salt thereof and/or a solvate thereof as an active ingredient.

Furthermore, the present invention provides an antifungal composition comprising said aminoalkanoic acid derivative, a salt thereof and/or a solvate thereof as an active ingredient.

In addition, the present invention provides a cleansing composition for the human body, a cosmetic composition or a shampoo composition containing the said aminoalkanoic acid derivative, a salt thereof and/or a solvate thereof as an active ingredient.

Furthermore, the aim of the present invention is to provide a method for producing a benzyloxybenzylaminyl amino acid derivative according to the invention.

Technical solution

As one aspect for achieving the above objects, the present invention provides a compound represented by formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Formula 1

where in the given formula 1:

n is 0, 1, 2, 3, 4 or 5,

R ₁ , R ₂ and R ₃ are independently the same or different from each other and are each independently selected from hydrogen, C _1-7 alkyl, hydroxyl, halogen, halogenated C _1-7 alkyl, C _1-7 alkyloxy and halogenated C _1-7 alkyloxy, and

X represents m substituents (where m is an integer from 1 to 5), which are identical to or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group.

In addition, the compound represented by formula 1 is a compound having no limitation on the three-dimensional structure of the arrangement of the substituent attached to the chiral carbon, and it may include all structurally accessible enantiomers or optical isomers. In particular, the compound represented by formula 1 may be provided, but not limited thereto, in the form of one (R) or (S) isomer, or a mixture thereof, such as a racemic mixture or a racemate thereof.

In the present invention, the halogen may be selected from the group consisting of fluorine, chlorine, bromine and iodine.

C _1-7 alkyl may be linear, branched or cyclic alkyl and may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

The C _1-7 alkyloxy group may be selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy and octyloxy.

The halogenated C _1-7 alkyl may be selected from the group consisting of difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, trifluoropentyl, trifluoroheptyl and trifluoroheptyl.

The halogenated C _1-7 alkyloxy may be selected from the group consisting of difluoromethyloxy, trifluoromethyloxy, difluoroethyloxy, trifluoroethyloxy, trifluoropropyloxy, trifluoropentyloxy, trifluoroheptyloxy and trifluoroheptyloxy.

The present invention may include not only the compound of formula 1 or a pharmaceutically acceptable salt thereof, but also a solvate or hydrate having the same action effects that can be obtained by using them according to the present invention.

The compound of the invention is based on an aminoalkanoic acid and it may be a derivative in which a biphenyl group is introduced into the aminoalkanoic acid.

In particular, the aminoalkanoic acid may be a derivative of an α-amino acid containing a straight C _2-4 hydrocarbon chain in the side chain, such as α-aminobutyric acid, norvaline or norleucine.

As used herein, the term "α-aminobutyric acid (AABA)" refers to the compound represented by Formula 6 below, which has the IUPAC name 2-aminobutyric acid, which is a non-proteinogenic α-amino acid of formula C ₄ H ₉ NO ₂ , also known in biochemistry as homoalanine. This α-aminobutyric acid includes a straight C ₂ hydrocarbon chain in the side chain, which contains an additional C ₁ compared to alanine.

Formula 6

As used herein, the term "norvaline (Nva)" refers to the compound represented by formula 7, which has the IUPAC name 2-aminopentanoic acid, which is a water-soluble amino acid that is an isomer of valine, and is a branched chain amino acid (BCAA) of the formula _CH3 ( _CH2 ) _2CH ( _NH2 ) _CO2H .

Formula 7

As used herein, the term "norleucine (Nle)" refers to the compound represented by the following formula 8, which has the IUPAC name 2-aminohexanoic acid, and is an amino acid having the formula CH ₃ (CH ₂ ) ₃ CH(NH ₂ )CO ₂ H.

Formula 8

For example, a compound of the invention may be a compound in which each R ₁ and R ₂ is independently H or methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl, and R ₃ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In addition, the compound of the invention may be a compound in which each of R ₁ and R ₂ independently represents H or methyl, and R ₃ represents methyl, ethyl or n-propyl, but is not limited thereto.

For example, in a compound of the invention, X may be one or two identical or different substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl and trifluoromethoxy. For example, X may be one, two or more substituents that are identical to each other, or be different.

For example, X in a compound of the invention may be fluorine, chlorine, trifluoromethyl or trifluoromethoxy, and in particular X may be p-fluorine, m-fluorine, p, m-difluoro, p-chloro, m-chloro, p, m-dichloro, p-trifluoromethyl or p-trifluoromethoxy, but is not limited thereto.

In particular, the compound of the invention may be the following compounds:

1) 2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)butanamide;

2) 2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)pentanamide;

3) 2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)hexanamide;

4) 2-amino-N-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)pentanamide;

5) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)butanamide;

6) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)pentanamide;

7) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)hexanamide;

8) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(dimethylamino)pentanamide;

9) 2-amino-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)pentanamide;

10) 2-amino-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)hexanamide;

11) 2-amino-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)pentanamide;

12) 2-amino-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)hexanamide;

13) 2-amino-N-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)pentanamide;

14) 2-amino-N-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)hexanamide;

15) N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(methylamino)pentanamide;

16) 2-(methylamino)-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)pentanamide;

17) N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide;

18) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)butanamide;

19) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

20) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)hexanamide;

21) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide;

22) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

23) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide;

24) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide;

25) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

26) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide;

27) 2-amino-N-(2-(3’,4’-difluoro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

28) N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(methylamino)butanamide;

29) N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)pentanamide;

30) N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)hexanamide;

31) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide;

32) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

33) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide;

34) 2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide;

35) 2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide;

36) 2-(methylamino)-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide; or

37) N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide;

but not limited to those specified.

The compound of the invention may be in the form of a pharmaceutically acceptable salt. The salt may be an acid addition salt formed from a pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" as used herein refers to an organic or inorganic addition salt of a compound represented by formula 1 that is tolerated by patients and that is non-toxic to a degree sufficient to allow its use at a concentration that exhibits the pharmacological effects of the compound.

The acid addition salt is prepared by conventional methods, such as dissolving the compound in an excess of an aqueous acid solution, and precipitating the resulting salt using a water-miscible organic solvent, such as methanol, ethanol, acetone, or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water are heated, and then the resulting mixture can be evaporated and dried, or the precipitated salt can be filtered off by suction.

In this case, organic acids and inorganic acids can be used as free acids. As inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used, and as organic acids, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used, and the free acid is not limited to those specified.

In addition, a pharmaceutically acceptable metal salt can be obtained using a base. An alkali metal salt or an alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide solution or an alkaline earth metal hydroxide, followed by filtering the undissolved salt of the compound, evaporating and drying the filtrate. In this case, it is preferable to obtain, in particular, sodium, potassium or calcium salts as a pharmaceutically acceptable metal salt, while the metal salt is not limited to the listed ones. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, with silver nitrate).

A pharmaceutically acceptable salt of a compound of the invention includes a salt formed with an acidic or basic group that may be present in the compound of formula 1, unless otherwise specified. For example, a pharmaceutically acceptable salt may comprise sodium, calcium, potassium, and the like salts of a hydroxyl group. Examples of other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), and the like, and they can be prepared by a method for preparing salts known in the art.

The salt of the compound of formula 1 according to the invention is a pharmaceutically acceptable salt, although any salt can be used without limitation, provided that the salt has a pharmacological activity equivalent to that of the compound of formula 1. For example, when the salt of the compound of formula 1 exhibits antifungal activity.

As another aspect, the present invention provides a method for producing a derivative of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in which a biphenyl group is introduced into an aminoalkanoic acid, the method comprising a first step of forming a peptide bond by reacting an aminoalkanoic acid derivative protected with a butoxycarbonyl (Boc) protecting group, represented by formula 2, with a biphenyl derivative comprising a primary amino group, represented by the following formula 3; and a second step of removing the Boc protecting group by reacting the compound obtained in the first step with an acid:

Formula 1

Formula 2

Formula 3

where in formula 1:

n is 0, 1, 2, 3, 4 or 5,

R ₁ , R ₂ and R ₃ are independently the same or different from each other and are each independently selected from the group consisting of hydrogen, C _1-7 alkyl, hydroxyl, halogen, halogenated C _1-7 alkyl, C _1-7 alkyloxy and halogenated C _1-7 alkyloxy, and

X represents m substituents (where m is an integer from 1 to 5), which are identical to or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group.

In the production method of the invention, an aminoalkanoic acid derivative protected with a Boc protecting group, which is represented by formula 2, can be obtained by reacting an amino acid derivative represented by formula 4 with di-tert-butyl dicarbonate (also known as Boc anhydride):

Formula 4

where in formula 4:

R ₁ ', R ₂ and R ₃ are independently the same or different from each other and are each independently selected from the group consisting of hydrogen, C _1-7 alkyl, hydroxyl, halogen, halogenated C _1-7 alkyl, C _1-7 alkyloxy and halogenated C _1-7 alkyloxy.

In this case, when R ₂ of the obtained compound is alkyl, after the above reaction, an additional step of alkylating the compound by reacting the compound with a haloalkane in the presence of a base can be carried out. For example, the alkylation can be carried out by dissolving the compound represented by the formula 4 and a haloalkane compound corresponding to 5 to 20 equivalents of a compound such as an alkane iodide in an organic solvent such as tetrahydrofuran, adding sodium hydride as a base at a low temperature such as 0°C, and then reacting the reactants at a temperature of 15 to 30°C for 12 to 48 hours, but not limited thereto. An alkylation reaction of amines known in the art can be used without limitation, or it can be carried out with modifications.

In addition, the biphenyl derivative containing a primary amino group represented by formula 3 used in the production method of the invention can be obtained by reacting a C _0-2 alkylamine derivative in which a halophenyl group at one end is substituted, represented by formula 5, with di-tert-butyl dicarbonate to introduce a Boc protecting group into the amino group, followed by reacting the obtained alkylamine derivative with a phenylboronic acid derivative represented by formula 6, and then reacting the reactants with an acid to remove the Boc protecting group:

Formula 5

Formula 6

where in the given formulas:

X’ is a halogen, and

X represents m substituents (where m is an integer from 1 to 5), which are identical to or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group.

In this case, the reaction with the phenylboronic acid derivative can be carried out by a cross-coupling reaction using a metal catalyst in the presence of a base. For example, the reaction can be carried out under basic conditions using a metal catalyst such as palladium or nickel. The metal catalyst may be a catalyst in which a phosphine ligand is bonded to a metal. For example, the reaction may be a Suzuki-Miyaura cross-coupling reaction using Pd( _PPh3 ) ₄ in the presence _{of Na2CO3} , but not limited to.

For example, in the production method according to the invention, the first stage can be carried out by an anhydride coupling reaction carried out in an organic solvent in the presence of N-methylmorpholine (NMM) or isobutyl chloroformate (IBCF). Tetrahydrofuran can be used as an organic solvent, but is not limited to the said organic solvent.

For example, in the production method of the invention, the second step of removing the Boc protecting group can be carried out by reacting with hydrochloric acid, but is not limited thereto.

In addition, the production method of the invention may further comprise a third step of forming a secondary amine by alkylating the amine after the second step, when each of R ₁ and R ₂ of the obtained compound is alkyl. The amination can be performed by reacting with formaldehyde while feeding hydrogen gas as a reducing agent in the presence of Pd/C. For example, the reaction can be carried out at a temperature of 15 to 30°C for 6 to 24 hours, but is not limited thereto, and an alkylation reaction of amines known in the art can be used as is or with modifications.

As another aspect, the present invention provides an antifungal composition comprising, as an active ingredient, a derivative compound in which a biphenyl group is introduced into an aminoalkanoic acid, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

As another aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of a fungal infectious disease, wherein the composition comprises as an active ingredient an aminoalkanoic acid derivative into which a biphenyl group is introduced, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

For example, a novel aminoalkanoic acid derivative into which a biphenyl group is introduced, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to the invention can exhibit antifungal activity against opportunistic infectious fungi, and thus it can be used as an active ingredient in an antifungal composition, and furthermore, it can be used for preventing or treating a fungal infectious disease.

As used herein, the term "prophylaxis" (or "prevention") refers to any action that suppresses, inhibits or delays the onset, progression or recurrence of any disease in question upon administration of the said pharmaceutical composition. The term "treatment" refers to any action in which the symptoms of any disease in question are alleviated or favorably improved upon administration of the said pharmaceutical composition.

For example, a fungal infectious disease that can be prevented or treated by the pharmaceutical composition of the invention may include, for example, infectious diseases caused by Cryptococcus neoformans, Candida albicans, Candida auris, Candida glabrata and Aspergillus fumigatus . The infectious fungal disease may also be meningitis caused by Cryptococcus, but is not limited to the above.

The pharmaceutical composition of the invention may contain a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and may further include a pharmaceutically acceptable carrier, diluent, or excipient. For example, the pharmaceutical composition of the invention can be prepared and used in various forms such as an oral dosage form such as powder, granules, tablet, capsule, suspension, emulsion, syrup, or aerosol, or a sterile injection solution, wherein the administration of the dosage form is carried out in a conventional manner according to each intended use, and the dosage form can be administered orally or by various other routes including intravenous, intraperitoneal, subcutaneous, rectal, local administration, etc. Examples of a suitable carrier, diluent or excipient that can be included in such a composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the composition of the invention may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.

The solid preparation for oral administration includes a tablet, a pill, a powder, a granule, a capsule, etc., and the solid preparation is prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. with the composition. In addition, in addition to the simple excipient, magnesium stearate and talc can be used as a lubricant.

As the liquid preparation for oral administration, a suspension, an oral liquid, an emulsion, a syrup, etc. can be used, and in addition to water and liquid paraffin, which are simple and commonly used diluents, various auxiliary substances can be used, for example, a wetting agent, a sweetener, a flavoring agent, a preservative, or the like can be used.

Examples of the preparation for parenteral administration include an aqueous sterile solution, a solution in a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository. As a non-aqueous solvent for the solution and the suspension, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an ester used for injection such as ethyl oleate, and the like can be used. As a suppository base, witepsol®, macrogol, tween 61, cocoa butter, lauric fat, glycerogelatin, and the like can be used. Among other things, the injection preparations may include additives known in the art such as a solubilizer, an isotonic agent, a suspending agent, an emulsifier, a stabilizer, and a preservative.

The composition of the invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein refers to an amount that is sufficient to treat diseases with a reasonable benefit/risk ratio applicable to medical treatment without causing side effects, and the effective dosage level can be determined according to various factors including the health condition of the patient, the type of disease, the severity of the disease, the activity of the drug, the sensitivity to drugs, the route of administration, the time of administration, the route of administration, the rate of excretion, the duration of treatment, as well as taking into account the drugs used in combination or simultaneously, and taking into account other factors known in the art of medicine. The composition of the invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and it can be administered sequentially or simultaneously with some conventional therapeutic agents, and it can be administered as a single dose or multiple doses. It is important to administer the composition in a minimum amount so that maximum effects can be obtained without any side effects, taking into account all the above factors, and this amount can be easily determined by those skilled in the art.

For example, since the amount may be increased or decreased depending on the route of administration, severity of the disease, gender, body weight, age, etc., a specific dosage is in no way intended to limit the scope of the present invention.

Furthermore, the present invention provides a method of treating a fungal infectious disease, wherein the method comprises administering the pharmaceutical composition to an individual in need thereof.

The term "individual" used herein refers to animals including a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit and a guinea pig, and also includes a human who has developed a fungal infectious disease or who is likely to develop a fungal infectious disease, and such a disease can be effectively prevented or treated by administering the pharmaceutical composition of the invention to the individual. In addition, the pharmaceutical composition of the invention exhibits a therapeutic effect on a disease caused by a fungal infection due to its antifungal activity, and it can exhibit a synergistic effect when administered in combination with a known therapeutic agent.

The term "administration" as used herein refers to providing a predetermined material to a patient by any suitable route. With regard to the route of administration of the composition of the invention, the composition of the invention can be administered by any known route that can ensure that the target tissue is reached. The route of administration can be intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration and rectal administration, but is not limited to these. In addition, the pharmaceutical composition of the invention can also be administered by any device that can allow the active material or ingredient to move to the target cell. Preferred routes of administration and preparations are intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection and the like. The injection preparation can be prepared using an aqueous solvent such as physiological saline and Ringer's solution, a non-aqueous solvent such as vegetable oil, higher fatty acid ester (e.g. ethyl oleate, etc.) and alcohol (e.g. ethanol, benzyl alcohol, propylene glycol, glycerin, etc.), and such a preparation may include a pharmaceutical carrier, a stabilizer for preventing deterioration of the product (e.g. ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), an emulsifier, a buffer for maintaining pH and a preservative for inhibiting microbial growth (e.g. phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The term "therapeutically effective amount" as used in the present invention with respect to an active ingredient refers to an amount of an aminoalkanoic acid derivative compound wherein a biphenyl group is introduced into the aminoalkanoic acid, wherein such derivative is effective for preventing or treating a target disease, or an amount of a stereoisomer of the compound or a pharmaceutically acceptable salt thereof.

Technical results and effects

According to various exemplary embodiments of the invention, the disadvantages of conventional drugs used as antifungal agents can be overcome by using an aminoalkanoic acid-based compound comprising a biphenyl group, for example, a compound comprising alpha-aminobutyric acid, norvaline or norleucine as a main skeleton. In particular, the present invention provides antifungal compounds having improved safety and efficacy, for alleviating or eliminating the side effects of conventional antifungal agents and for enhancing the therapeutic effects of action. Accordingly, the present invention provides a pharmaceutical composition for the treatment and/or prevention of various fungal infectious diseases. In addition, the compound of the invention can be used to prepare an antibacterial composition against gram-positive, gram-negative and MRSA-resistant bacteria. In addition, the compound of the invention can also be used to manufacture an anti-inflammatory therapeutic agent.

Description of figures

FIG. 1 shows the results of a comparison of the antifungal activity of compound 74 of the invention with the activity of commercially available comparative drugs.

FIG. 2 shows the results of a comparison of the fungicidal activity of compound 74 according to the invention with the activity of commercially available comparative drugs.

FIG. 3 shows the results of comparison of the biofilm removal effects of compound 74 of the invention with those of commercially available comparative drugs.

The best option for implementing the invention

The present invention will now be described in more detail with reference to specific examples of the preparation of compounds and examples of the invention. It should be borne in mind that these examples are given only to illustrate the present invention, and the scope of the invention is not limited to these examples.

First, the reactions used in the synthesis of the compound of the invention can be summarized and presented in general as follows.

Reaction scheme a - Introduction of the Boc protecting group

Norleucine (1.0 equiv.), Boc anhydride (1.5 equiv.) and sodium bicarbonate (1.5 equiv.) were dissolved in a mixed solvent of distilled water and methanol at a ratio of 1:1, and the reaction was carried out at room temperature for 36-48 hours. After concentrating the mixture in vacuo, the aqueous layer was adjusted to pH 2 with 1.0 M hydrochloric acid. Then, moisture was removed from the organic layer obtained by extraction with ethyl acetate with sodium sulfate, and the solvent was evaporated in vacuo to give the title compound.

Reaction scheme b - Methylation of the amino group

The compound (1.0 equiv.) obtained according to reaction scheme a) and iodomethane (10 equiv.) were dissolved in tetrahydrofuran solvent, and sodium hydride (10 equiv.) was added dropwise very slowly at 0°C. The reactants were reacted at room temperature for 24 hours. After completion of the reaction, the obtained product was diluted with ether solvent and distilled water was added thereto. The pH of the aqueous layer was adjusted to 2 with 20% citric acid solution. Then, moisture was removed from the organic layer obtained by extraction with ethyl acetate with sodium sulfate, and the solvent was evaporated in vacuo. The resulting residue was separated and purified by silica gel chromatography to give the title compound.

Reaction Scheme c - Introduction of a Boc protecting group into a primary amine group

After dissolving 4-bromophenethylamine (1.0 equiv.) in methylene chloride solvent, potassium carbonate (1.5 equiv.) and Boc anhydride (1.05 equiv.) were added to the resulting solution. The resulting mixture was reacted at room temperature for about 12-18 hours. The reaction mixture was diluted with methylene chloride and washed twice with distilled water. The organic layer was dried over sodium sulfate and then concentrated in vacuo. The resulting residue was washed with hexane and then evaporated in vacuo to give the title compound.

Reaction scheme d - Synthesis of hydrochloride of biphenylamine derivative

The compound obtained according to the reaction scheme c, tert-butyl (4-bromobenzyl)carbamate or tert-butyl (4-bromophenyl)carbamate (1.0 equiv.), benzeneboronic acid (1.5 equiv.), sodium carbonate (5.0 equiv.) and tetrakis(triphenylphosphine)palladium (0.04 equiv.) were dissolved in a mixed solvent of degassed toluene and distilled water in a ratio of 2:1 to 2.5:1, and the reaction was carried out under reflux at a temperature of 140°C for 12-18 hours. After completion of the reaction, the catalyst was removed by filtration through celite, and the solvent was evaporated from the filtered organic layer under vacuum. The resulting residue was separated and purified by silica gel chromatography. After dissolving the purified product in ethyl acetate solvent, the resulting solution was stirred at room temperature, adding 4.0 M hydrochloric acid (6.0-10.0 equiv.) to it. The resulting white solid in the form of a salt was washed with ethyl acetate and then completely dried in vacuo to give the title compound.

Reaction Scheme e - Mixed anhydride coupling (MAC) reaction

The compound prepared according to the reaction scheme a or the compound prepared according to the reaction scheme b (1.0 equiv.) and N-methylmorpholine (NMM, 2.5-2.8 equiv.) were placed in distilled tetrahydrofuran solvent, and the resulting mixture was stirred for 15 minutes. Then, isobutyl chloroformate (IBCF, 1.3 equiv.) was added thereto, and the resulting mixture was further stirred for 15 minutes. Then, the compound prepared according to the reaction scheme d (1.05 equiv.) was added thereto. The reaction mixture was allowed to react at room temperature for about 3-5 hours. The mixture was filtered, and the solvent was evaporated in vacuo. The resulting residue was separated and purified by silica gel chromatography to give the title compound.

Reaction scheme f - Removal of the Boc protecting group

After dissolving the derivative compound (1.0 equiv.) obtained according to reaction scheme e in ethyl acetate solvent, the resulting solution was stirred at room temperature, adding 4.0 M hydrochloric acid (6.0-10.0 equiv.) to it. The resulting white solid in the form of a salt was washed with ethyl acetate and then completely dried in vacuo to give the title compound.

Reaction scheme g - Dimethylation of the amino group

The compound (1.0 equiv.) obtained according to reaction scheme f was dissolved in methanol and triethylamine (6.0 equiv.) was added thereto. Then, formaldehyde (37 wt.% solution, 1.0 to 2.5 equiv.) and 10% palladium catalyst (0.1 to 0.5 equiv.) were added successively. The reactants were reacted at room temperature for 18 hours. After completion of the reaction, the catalyst was removed by filtration through celite and the filtered organic layer was evaporated in vacuo to give a white solid. The resulting product was recrystallized from methanol and diethyl ether to give the title compound.

The following Examples of Preparation for the Synthesis of the Compound of the Invention are presented below.

Examples of receipt

Preparation Example 1: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)amino)butanoic acid (4)

Compound 1 (2-aminobutanoic acid, 5.00 g, 48.5 mmol), Boc anhydride (19.9 mL, 72.7 mmol), and _NaHCO3 (6.11 g, 72.7 mmol) were reacted according to reaction scheme a to synthesize compound 4, (R)/(S)-2-((tert-butoxycarbonyl)amino)butanoic acid (8.25 g, 83%), obtained as a white powder.

R _f = 0.00 (DCM:methanol 9.5:0.5, and a few drops of acetic acid);

¹ H NMR (DMSO _- d6 , 300 MHz) 12.40 (C(O)OH), 7.02 (d, J= 7.9 Hz, Boc-NH), 3.69-3.82 (m , chiral-H), 1.48-1.72 (m, CH ₂ CH ₃ ), 1.38 (s, Boc), 0.87 (t, J=7.3 Hz, CH ₂ CH ₃ ).

Preparation Example 2: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)amino)pentanoic acid (5)

Compound 2 (2-aminopentanoic acid, 10.00 g, 25.6 mmol), Boc anhydride (35.1 mL, 128.0 mmol), and _NaHCO3 (10.8 g, 128.0 mmol) were reacted according to reaction scheme a to synthesize compound 5, (R)/(S)-2-((tert-butoxycarbonyl)amino)pentanoic acid (13.40 g, 83%), obtained as a white powder.

R _f = 0.85 (DCM:methanol 3:17);

¹ H NMR (DMSO _- d6 , 400 MHz) 12.40 (C(O)OH), 7.03 (d, J= 8.0 Hz, Boc-NH), 3.75-3.89 (m , chiral-H), 1.50-1.65 (m, CH ₂ CH ₂ CH ₃ ), 1.20-1.38 (m, CH ₂ CH ₂ CH ₃ , Boc), 0.85 (t, J= 7.4 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 3: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)amino)hexanoic acid (6)

Compound 3 (2-aminohexanoic acid, 5.00 g, 38.1 mmol), Boc anhydride (15.7 mL, 57.2 mmol), and _NaHCO3 (4.80 g, 57.2 mmol) were reacted according to reaction scheme a to synthesize compound 6, (R)/(S)-2-((tert-butoxycarbonyl)amino)hexanoic acid (7.14 g, 81%), obtained as a white powder.

R _f = 0.40 (DCM:methanol 9:1);

¹ H NMR (CDCl ₃ , 400 MHz) 10.26 (C(O)OH), 5.00 (d, J= 7.6 Hz, Boc-NH), 4.32-4.33 (m, chiral -H), 1.63-1.87 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.47 (s, Boc), 1.31-1.38 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.93 (t, J= 7.0 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 4: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)methylamino)butanoic acid (7)

Compound 4 (3.00 g, 14.8 mmol), CH ₃ I (9.2 mL, 147.6 mmol), and NaH (3.54 g, 147.6 mmol) were reacted according to reaction scheme b to synthesize compound 7, (R)/(S)-2-((tert-butoxycarbonyl)methylamino)butanoic acid (2.84 g, 88%), obtained as a yellow oil.

R _f = 0.45 (DCM:methanol 9:1, and a few drops of acetic acid);

^1H NMR (DMSO _- d6 , 300 MHz) 12.7 (C(O)OH), 4.14-4.43 (m, chiral-H), 2.71 (s, _NCH3 ), 1, 50-1.73 (m, CH ₂ CH ₃₎ , Boc), 0.79-0.87 (m, CH ₂ CH ₃ ).

Preparation Example 5: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)methylamino)pentanoic acid (8)

Compound 5 (1.50 g, 6.90 mmol), CH ₃ I (4.3 mL, 69.0 mmol), and NaH (1.66 g, 69.0 mmol) were reacted with each other according to reaction scheme b to synthesize compound 8, (R)/(S)-2-((tert-butoxycarbonyl)methylamino)pentanoic acid (1.34 g, 83%), obtained as a yellow oil.

R _f = 0.45 (DCM:methanol 9:1, and a few drops of acetic acid);

^1H NMR (DMSO _- d6 , 300 MHz) 12.7 (C(O)OH), 4.54-4.28 (m, chiral-H), 2.70 (s, _NCH3 ), 1, 79-1.64 (m, CH ₂ CH ₂ CH ₃ ), 1.41-1.37 (m, CH ₂ CH ₂ CH ₃ , Boc), 1.37-1.29 (m, CH ₂ CH _{2 CH3} ).

Preparation Example 6: Preparation of (R)/(S)-2-((tert-butoxycarbonyl)methylamino)hexanoic acid (9)

Compound 6 (3.00 g, 13.0 mmol), CH ₃ I (8.1 mL, 129.7 mmol), and NaH (5.19 g, 129.7 mmol) were reacted with each other according to reaction scheme b to synthesize compound 9, (R)/(S)-2-((tert-butoxycarbonyl)methylamino)hexanoic acid (3.18 g, 100%), obtained as a yellow oil.

R _f = 0.38 (DCM:methanol 9:1);

^1H NMR ( _CDCl3 , 400 MHz) 12.6 (C(O)OH), 4.25-4.52 (m, chiral-H), 2.70 (s, _NCH3 ), 1.66- 1.79 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.18-1.40 (m, CH ₂ CH ₂ CH ₂ CH ₃ , Boc), 0.86-0.89 (m, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 7: Preparation of tert-butyl (4-bromophenethyl)carbamate (12)

4-Bromophenethylamine (3.9 mL, 25.1 mmol), K ₂ CO ₃ (5.21 g, 37.7 mmol), and Boc anhydride (7.2 mL, 26.4 mmol) were reacted according to reaction scheme c to synthesize compound 12, tert-butyl (4-bromophenethyl)carbamate (6.23 g, 83%), obtained as a white powder.

R _f =0.36 (EtOAc:n-hexane 1:5);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.46 (d, J = 8.6 Hz, ArH), 7.15 (d, J = 8.2 Hz, ArH), 6.87 (s, NH), 3.09-3.14 (m, NHCH ₂ CH ₂ ), 2.64-2.67 (m, NHCH ₂ CH ₂ ), 1.35 (s, Boc).

Preparation Example 8: Preparation of 3’,4’-dichloro-[1,1’-biphenyl]-4-amine hydrochloride (13)

After preparation of the compound by reaction of compound 10 (tert-butyl 4-bromophenylcarbamate, 4.00 g, 14.7 mmol), 3,4-dichlorophenylboronic acid (3.37 g, 17.6 mmol), tetrakis(triphenylphosphine)palladium (0.68 g, 0.59 mmol) and _Na2CO3 ( _7.80 g, 73.5 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (7.9 mL, 31.5 mmol in dioxane) to synthesize compound 13, 3',4'-dichloro-[1,1'-biphenyl]-4-amine hydrochloride (1.27 g, 34%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.94 (s, NH ₃ ), 7.95 (d, J = 2.0 Hz, ArH), 7.40-7.80 (m, ArH), 7.39 (d, J = 8.5 Hz, ArH).

Preparation Example 9: Preparation of 4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-amine hydrochloride (14)

After preparation of the compound by reaction of compound 10 (3.99 g, 14.7 mmol), 4-(trifluoromethoxy)phenylboronic acid (7.77 g, 22.0 mmol), tetrakis(triphenylphosphine)palladium (0.68 g, 0.59 mmol) and _Na2CO3 ( _7.77 g, 73.3 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (12.8 mL, 51.1 mmol in dioxane) to synthesize compound 14, 4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine hydrochloride (1.99 g, 48%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.45 (br s, NH ₃ ), 7.77 (d, J = 8.7 Hz, ArH), 7.71 (d, J = 8.4 Hz, ArH), 7.45 (d, J = 8.4 Hz, ArH), 7.28 (d, J = 8.2 Hz, ArH).

Preparation Example 10: Preparation of 2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methane-1-amine hydrochloride (15)

After preparation of the compound by reaction of compound 11 (tert-butyl 4-bromobenzylcarbamate, 6.00 g, 21.0 mmol), 3,4-dichlorophenylboronic acid (4.80 g, 25.2 _mmol ), tetrakis(triphenylphosphine)palladium (0.97 g, 0.84 mmol) and _Na2CO3 (111.1 g, 104.8 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (3.1 mL, 12.3 mmol in dioxane) to synthesize compound 15, 2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)methane-1-amine hydrochloride (1.08 g, 17%) obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.71 (s, NH ₃ ), 7.97 (s, ArH), 7.63-7.83 (m, ArH), 4.07 (s, NH ₃ CH ₂ ).

Preparation Example 11: Preparation of (4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methanamine hydrochloride (16)

After preparation of _the compound by reaction of compound 11 (6.00 g, 21.0 mmol), 4-(trifluoromethyl)phenylboronic acid (5.97 g, 31.5 mmol), tetrakis(triphenylphosphine)palladium (0.97 g, 0.84 mmol) and _Na2CO3 (11.1 g, 104.8 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (17.9 mL, 71.7 mmol in dioxane) to synthesize compound 16, (4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methanamine hydrochloride (1.08 g, 66%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.49 (s, NH ₃ ), 7.93 (d, J = 8.2 Hz, ArH), 7.83 (t, J = 9.0 Hz, ArH), 7.64 (d, J = 8.2 Hz, ArH), 4.09 (s, NH ₃ CH ₂ ).

Preparation Example 12: Preparation of (4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methanamine hydrochloride (17)

After preparation of the compound by reaction of compound 11 (4.00 g, 14.0 mmol), 4-(trifluoromethoxy)phenylboronic acid (4.32 g, 21.0 mmol), tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol) and _Na2CO3 ( _7.41 g, 69.9 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (13.9 mL, 55.6 mmol in dioxane) to synthesize compound 17, (4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methanamine hydrochloride (2.73 g, 65%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.33 (s, NH ₃ ), 7.81-7.83 (m, ArH), 7.75 (d, J = 8.2 Hz, ArH), 7.59 (d, J = 8.2 Hz, ArH), 7.48 (d, J = 8.3 Hz, ArH), 4.08 (s, NH ₃ CH ₂ ).

Preparation Example 13: Preparation of 2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethan-1-amine hydrochloride (18)

After preparation of the compound by reaction of compound 12 (tert-butyl (4-bromophenethyl)carbamate, 1.00 g, 3.33 mmol), 3,4-dichlorophenylboronic acid (0.76 g, 4.00 mmol), tetrakis(triphenylphosphine)palladium (0.15 g, 0.15 _mmol ) and _Na2CO3 (1.77 g, 16.7 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (2.50 mL, 10.0 mmol in dioxane) to synthesize compound 18, 2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethan-1-amine hydrochloride (2.73 g, 65%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.33 (s, NH ₃ ), 7.93 (d, J = 1.9 Hz, ArH), 7.66-7.72 (m, ArH), 7.39 (d, J = 8.2 Hz, ArH), 2.98-3.07 (m, NH ₃ CH ₂ CH ₂ ).

Preparation Example 14: Preparation of 2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethan-1-amine hydrochloride (19)

After preparation of the compound by reaction of compound 12 (0.50 g, 1.67 mmol), 4-(trifluoromethyl)phenylboronic acid (0.38 g, 2.00 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.07 mmol) and _Na2CO3 ( _0.88 g, 8.33 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (1.25 mL, 5.00 mmol in dioxane) to synthesize compound 19, 2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-amine hydrochloride (0.28 g, 56%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.37 (s, NH ₃ ), 7.71-7.91 (m, ArH), 7.44 (d, J= 8.1 Hz, ArH), 3.01-3.11 (m, NH ₃ CH ₂ CH ₂ ).

Preparation Example 15: Preparation of 2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethan-1-amine hydrochloride (20)

After preparation of the compound by reaction of compound 12 (1.50 g, 5.00 mmol), 4-(trifluoromethoxy)phenylboronic acid (1.23 g, 6.00 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol) and _Na2CO3 ( _2.65 g, 25.0 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (3.75 mL, 15.0 mmol in dioxane) to synthesize compound 20, 2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-amine hydrochloride (0.88 g, 55%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.31 (s, NH ₃ ), 7.79 (d, J = 8.7 Hz, ArH), 7.66 (d, J = 8.1 Hz, ArH), 7.45 (d, J = 8.2 Hz, ArH), 7.40 (d, J = 8.1 Hz, ArH), 2.97-3.10 (m, NH ₃ CH ₂ CH ₂ ).

Preparation Example 16: Preparation of 2-(3’,4’-difluoro[1,1’-biphenyl]-4-yl)ethan-1-amine hydrochloride (21)

After preparation of the compound by reaction of compound 12 (1.00 g, 3.33 mmol), 3,4-dichlorophenylboronic acid (0.76 g, 4.00 _mmol ), tetrakis(triphenylphosphine)palladium (0.15 g, 0.15 mmol) and _Na2CO3 (1.77 g, 16.7 mmol) according to Reaction Scheme d, the Boc group was removed using 4.0 M HCl (2.50 mL, 10.0 mmol in dioxane) to synthesize compound 21, 2-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)ethan-1-amine hydrochloride (2.73 g, 65%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.95 (s, NH ₃ ), 7.74-7.79 (m, ArH), 7.67 (d, J = 8.1 Hz, ArH), 7.48-7.54 (m, ArH), 7.37 (d, J = 8.1 Hz, ArH), 2.90-3.09 (m, NH ₃ CH ₂ CH ₂ ).

Preparation Example 17: Preparation of (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxobutan-2-yl)carbamate (22)

Compound 4 (0.63 g, 3.12 mmol), NMM (0.96 mL, 8.74 mmol), IBCF (0.53 mL, 4.06 mmol), and compound 13 (0.90 g, 3.28 mmol) were reacted with each other according to reaction scheme e to synthesize compound 22, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxobutan-2-yl)carbamate (1.09 g, 82%), obtained as a pale yellow powder.

R _f =0.33 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 8.55 (s, C(O)NH), 7.58 (d, J= 7.3 Hz, ArH), 7.44-7.47 (m, ArH ), 7.34 (dd, J= 1.8 Hz, 8.3 Hz, ArH), 5.12 (s, Boc-NH), 4.18 (s, chiral-H), 1.67-2 .05 (m, CH ₂ CH ₃ ), 1.47 (s, Boc), 1.03 (t, J = 7.4 Hz, CH ₂ CH ₃ ).

Preparation Example 18: Preparation of (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxopentan-2-yl)carbamate (23)

Compound 5 (0.30 g, 1.52 mmol), NMM (0.42 mL, 3.80 mmol), IBCF (0.26 mL, 1.98 mmol), and compound 13 (0.44 g, 1.60 mmol) were reacted with each other according to reaction scheme e to synthesize compound 23, (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxopentan-2-yl)carbamate (0.61 g, 92%), obtained as a white powder.

R _f =0.37 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 8.53 (s, C(O)NH), 7.62 (d, J= 8.6 Hz, ArH), 7.48-7.50 (m, ArH ), 7.38 (dd, J= 2.0 Hz, 8.3 Hz, ArH), 5.08 (s, Boc-NH), 4.24 (s, chiral-H), 1.63-1 .99 (m, CH ₂ CH ₂ CH ₃ ), 1.47-1.50 (m, Boc, CH ₂ CH ₂ CH ₃ ), 0.99 (t, J= 7.3 Hz, CH ₂ CH _{2 CH3} ).

Preparation Example 19: Preparation of (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxohexan-2-yl)carbamate (24)

Compound 6 (0.80 g, 3.46 mmol), NMM (0.95 mL, 8.69 mmol), IBCF (0.58 mL, 4.50 mmol), and compound 13 (1.00 g, 3.64 mmol) were reacted with each other according to reaction scheme e to synthesize compound 24, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxohexan-2-yl)carbamate (1.11 g, 71%), obtained as a white powder.

R _f =0.50 (EtOAc:n-hexane 1:3);

^1H NMR (DMSO _- d6 , 400 MHz) 10.10 (s, NH), 7.91 (d, J= 1.9 Hz, ArH), 7.64-7.74 (m, ArH), 7.04 (d, J= 7.8 Hz, NH), 4.02-4.07 (m, NHCHCH ₂ ), 1.57-1.64 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.39 (s, Boc), 1.26-1.32 (m, CH ₂ CH ₂ CH ₂ CH ₃ )0.86 (t, J= 6.8 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ) .

Preparation Example 20: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)amino)pentan-2-yl)carbamate (25)

Compound 5 (0.43 g, 1.97 mmol), NMM (0.61 mL, 5.52 mmol), IBCF (0.33 mL, 2.56 mmol), and compound 14 (0.60 g, 2.07 mmol) were reacted with each other according to reaction scheme e to synthesize compound 25, (R)/(S)-tert-butyl (1-oxo-1-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)amino)pentan-2-yl)carbamate (0.66 g, 73%), obtained as a white powder.

R _f =0.30 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 8.62 (s, C(O)NH), 7.61 (d, J= 7.3 Hz, ArH), 7.54 (d, J= 7.6 Hz, ArH), 7.49 (d, J= 7.9 Hz, ArH), 7.26-7.29 (m, ArH), 5.19 (d, J= 7.4 Hz, Boc-NH ), 4.29 (s, chiral-H), 1.65-1.98 (m _{, CH2CH2CH3 )} , 1.43-1.56 (m, Boc _{, CH2CH2CH3 )} , 0.99 (t, J= 7.1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 21: Preparation of (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxobutan-2-yl)methylcarbamate (26)

Compound 7 (0.68 g, 3.12 mmol), NMM (0.96 mL, 8.74 mmol), IBCF (0.53 mL, 4.06 mmol), and compound 13 (0.90 g, 3.28 mmol) were reacted with each other according to reaction scheme e to synthesize compound 26, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxobutan-2-yl)methylcarbamate (0.74 g, 54%), obtained as an oil.

R _f =0.50 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 8.50 (s, C(O)NH), 7.58-7.63 (m, ArH), 7.46-7.50 (m, ArH), 7 .38 (dd, J= 1.8 Hz, 8.2 Hz, ArH), 4.57 (s, chiral-H), 2.83 (s, NCH ₃ ), 1.71-2.04 (m , CH ₂ CH ₃ ), 1.51 (d, J= 6.8 Hz, Boc), 0.97 (t, J= 7.3 Hz, CH ₂ CH ₃ ).

Preparation Example 22: Preparation of (R)/(S)-tert-butyl(1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxopentan-2-yl)methylcarbamate (27)

Compound 8 (0.86 g, 3.72 mmol), NMM (1.14 mL, 10.4 mmol), IBCF (0.63 mL, 4.83 mmol), and compound 13 (1.07 g, 3.90 mmol) were reacted with each other according to reaction scheme e to synthesize compound 27, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxopentan-2-yl)methylcarbamate (0.79 g, 47%), obtained as a yellow powder.

R _f =0.48 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 8.49 (s, C(O)NH), 7.58-7.64 (m, ArH), 7.47-7.51 (m, ArH), 7 .38 (d, J= 8.3 Hz, ArH), 4.66 (s, chiral-H), 2.82 (s, NCH ₃ ), 1.67-2.04 (m, CH ₂ CH ₂ CH ₃ ), 1.51 (s, Boc), 1.33-1.39 (m, CH ₂ CH ₂ CH ₃ ), 0.99 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 23: Preparation of (R)/(S)-tert-butyl (1-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)amino)-1-oxohexan-2-yl)methylcarbamate (28)

Compound 9, (R)/(S)-2-((tert-butoxycarbonyl)methylamino)hexanoic acid (0.84 g, 3.47 mmol), NMM (1.10 mL, 9.71 mmol), IBCF (0.58 mL, 4.51 mmol), and compound 13 (1.00 g, 3.64 mmol) were reacted with each other according to Reaction Scheme e to synthesize compound 28, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxohexan-2-yl)methylcarbamate (0.86 g, 53%), obtained as an oil.

R _f =0.55 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 8.49 (s, C(O)NH), 7.58-7.64 (m, ArH), 7.47-7.51 (m, ArH), 7 .38 (dd, J= 2.1 Hz, 8.4 Hz, ArH), 4.64 (s, chiral-H), 2.82 (s, NCH ₃ ), 1.67-2.01 (m , CH ₂ CH ₂ CH ₂ CH ₃ ), 1.52 (s, Boc), 1.24-1.44 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.93 (t, J = 7, 1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 24: Preparation of (R)/(S)-2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)butanamide hydrochloride (29)

Compound 22 (1.06 g, 2.50 mmol) and 4.0 M HCl (3.80 mL, 15.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 29, (R)/(S)-2-amino-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)butanamide hydrochloride (0.87 g, 97%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR ( _CDCl3 , 400 MHz) 11.05 (s, C(O)NH), 8.38 (s, _NH3 ), 7.93 (d, J= 1.9 Hz, ArH), 7 .66-7.79 (m, ArH), 4.01-4.04 (m, chiral-H), 1.86-1.91 (m, CH ₂ CH ₃ ), 0.96 (t, J = 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 25: Preparation of (R)/(S)-2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)pentanamide hydrochloride (30)

Compound 23 (0.58 g, 1.33 mmol) and 4.0 M HCl (2.00 mL, 7.95 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 30, (R)/(S)-2-amino-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)pentanamide hydrochloride (0.40 g, 81%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 11.05 (s, C(O)NH), 8.40 (s, NH ₃ ), 7.93 (d, J= 1.5 Hz, ArH), 7.66-7.79 (m, ArH), 4.06 (s, chiral-H), 1.79-1.85 (m, CH ₂ CH ₂ CH ₃ ), 1.36-1.43 (m, CH ₂ CH ₂ CH ₃ ), 0.91 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 26: Preparation of (R)/(S)-2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)hexanamide hydrochloride (31)

Compound 24 (1.10 g, 2.44 mmol) and 4.0 M HCl (3.66 mL, 14.6 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 31, (R)/(S)-2-amino-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)hexanamide hydrochloride (0.81 g, 86%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 10.97 (s, C(O)NH), 8.38 (s, NH ₃ ), 7.93 (d, J= 2.0 Hz, ArH), 7.66-7.78 (m, ArH), 4.03 (s, chiral-H), 1.81-1.87 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.33-1.39 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.87 (t, J= 6.9 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 27: Preparation of (R)/(S)-2-amino-N-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)pentanamide hydrochloride (32)

Compound 25 (0.64 g, 1.41 mmol) and 4.0 M HCl (2.12 mL, 8.46 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 32, (R)/(S)-2-amino-N-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)pentanamide hydrochloride (0.51 g, 93%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 10.90 (s, C(O)NH), 8.35 (s, NH ₃ ), 7.76-7.79 (m, ArH), 7.70 (d, J = 8.8 Hz, ArH), 7.45 (d, J = 8.2 Hz, ArH), 4.03 (s, chiral-H), 1.82 (q, J = 6.9 Hz, 7.9 Hz, CH ₂ CH ₂ CH ₃ ), 1.34-1.47 (m, CH ₂ CH ₂ CH ₃ ), 0.92 (t, J = 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 28: Preparation of (R)/(S)-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)butanamide hydrochloride (33)

Compound 26 (0.69 g, 1.58 mmol) and 4.0 M HCl (2.40 mL, 9.50 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 33, (R)/(S)-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-2-(methylamino)butanamide hydrochloride (0.55 g, 93%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 11.00 (s, C(O)NH), 9.13 (s, NH ₂ ), 7.94 (d, J = 1.7 Hz, ArH), 7.66-7.78 (m, ArH), 3.96 (t, J = 5.5 Hz, chiral-H), 2.57 (s, NCH ₃ ), 1.87-2.05 (m, CH ₂ CH ₃ ), 0.94 (t, J = 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 29: Preparation of (R)/(S)-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)pentanamide hydrochloride (34)

Compound 27 (0.38 g, 0.83 mmol) and 4.0 M HCl (1.25 mL, 4.98 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 34, (R)/(S)-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-2-(methylamino)pentanamide hydrochloride (0.23 g, 71%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 10.98 (s, C(O)NH), 9.09 (s, NH ₂ ), 7.94 (s, ArH), 7.66-7.76 (m, ArH), 3.96 (t, J= 6.1 Hz, chiral-H), 2.57 (s, NCH ₃ ), 1.80-1.93 (m, CH ₂ CH ₂ CH ₃ ), 1.31-1.39 (m, CH ₂ CH ₂ CH ₃ ), 0.91 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 30: Preparation of (R)/(S)-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)hexanamide hydrochloride (35)

Compound 28 (0.82 g, 1.77 mmol) and 4.0 M HCl (2.65 mL, 10.6 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 35, (R)/(S)-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-2-(methylamino)hexanamide hydrochloride (0.60 g, 84%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 10.81 (s, C(O)NH), 9.05 (s, NH ₂ ), 7.94 (d, J = 2.0 Hz, ArH), 7.66-7.77 (m, ArH), 3.92 (s, chiral-H), 2.57 (s, NCH ₃ ), 1.87-1.99 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.29-1.33 (m, CH ₂ CH ₂ CH ₂ CH ₃ )0.86 (t, J = 6.8 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 31: Preparation of (R)/(S)-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(dimethylamino)pentanamide (36)

Compound 30 (1.0 equiv), triethylamine (6.0 equiv), formaldehyde (2.0 equiv), and palladium catalyst (0.4 equiv) were reacted according to reaction scheme g to synthesize compound 36, (R)/(S)-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-2-(dimethylamino)pentanamide.

¹ H NMR (DMSO- d ₆ , 400 MHz) 10.98 (s, C(O)NH), 7.94 (s, ArH), 7.66-7.76 (m, ArH), 3.96 (t, J= 6.1 Hz, chiral-H), 2.57 (s, N(CH ₃ ) ₂ ), 1.80-1.93 (m, CH ₂ CH ₂ CH ₃ ), 1.31-1.39 (m, CH ₂ CH ₂ CH ₃ ), 0.91 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 32: Preparation of (R)/(S)-tert-butyl (1-(((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)amino)-1-oxopentan-2-yl)carbamate (37)

Compound 5 (0.57 g, 2.64 mmol), NMM (0.73 mL, 6.60 mmol), IBCF (0.45 mL, 3.43 mmol), and compound 15 (0.80 g, 2.77 mmol) were reacted with each other according to reaction scheme e to synthesize compound 37, (R)/(S)-tert-butyl (1-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)amino)-1-oxopentan-2-yl)carbamate (1.20 g, 100%), obtained as a white powder.

R _f =0.04 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.64 (d, J= 2.0 Hz, ArH), 7.49 (dd, J= 2.6 Hz, 8.5 Hz, ArH), 7.33 -7.40 (m, ArH), 6.48 (s, C(O)NH), 4.93 (s, Boc-NH), 4.49 (d, J= 4.2 Hz, NHCH ₂ ) , 4.07-4.09 (m, chiral-H), 1.36-1.43 (m, CH ₂ CH ₂ CH ₃ , Boc), 0.95 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 33: Preparation of (R)/(S)-tert-butyl (1-(((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)amino)-1-oxohexan-2-yl)carbamate (38)

Compound 6 (0.38 g, 1.65 mmol), NMM (0.45 mL, 4.13 mmol), IBCF (0.28 mL, 2.15 mmol), and compound 15 (0.50 g, 1.74 mmol) were reacted with each other according to reaction scheme e to synthesize compound 38, (R)/(S)-tert-butyl (1-((((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)amino)-1-oxohexan-2-yl)carbamate (0.46 g, 60%), obtained as a white powder.

R _f =0.19 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.63 (d, J= 2.0 Hz, ArH), 7.49 (dd, J= 4.3 Hz, 8.2 Hz, ArH), 7.33 -7.39 (m, ArH), 6.55 (s, C(O)NH), 4.98 (d, J= 3.8 Hz, Boc-NH), 4.49 (d, J= 5 .5 Hz, NHCH ₂ ), 4.07-4.11 (m, chiral-H), 1.58-1.90 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc ), 1.34 (d, J= 2.2 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.88-0.94 (m, CH ₂ CH _{2 CH2CH3 )} .

Preparation Example 34: Preparation of (R)/(S)-tert-butyl (1-oxo-1(((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (39)

Compound 5 (0.36 g, 1.66 mmol), NMM (0.46 mL, 4.14 mmol), IBCF (0.28 mL, 2.15 mmol), and compound 16 (0.50 g, 1.74 mmol) were reacted with each other according to reaction scheme e to synthesize compound 39, (R)/(S)-tert-butyl (1-oxo-1-((((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (0.72 g, 96%), obtained as a white powder.

R _f =0.17 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 300 MHz) 7.62-7.70 (m, ArH), 7.44 (dd, J= 8.1 Hz, 44.7 Hz, ArH), 6.85 (s, C(O)NH), 5.16-5.18 (m, Boc-NH), 4.47-4.49 (m, ArCH ₂ ), 4.11-4.15 (m, chiral-H) , 1.54-1.89 (m, CH ₂ CH ₂ CH ₃ ), 1.41 (s, Boc, CH ₂ CH ₂ CH ₃ ), 0.93 (t, J= 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 35: Preparation of (R)/(S)-tert-butyl (1-oxo-1(((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)hexan-2-yl)carbamate (40)

Compound 6 (0.54 g, 2.32 mmol), NMM (0.71 mL, 6.49 mmol), IBCF (0.39 mL, 3.01 mmol), and compound 16 (0.70 g, 2.43 mmol) were reacted with each other according to reaction scheme e to synthesize compound 40, (R)/(S)-tert-butyl (1-oxo-1-((((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)hexan-2-yl)carbamate (0.87 g, 81%), obtained as a white powder.

R _f =0.16 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.70 (q, J= 4.6 Hz, 8.6 Hz, ArH), 7.57 (d, J= 8.2 Hz, ArH), 7.39 (d, J= 8.2 Hz, ArH), 6.50 (s, C(O)NH), 4.96 (s, Boc-NH), 4.53 (d, J= 4.7 Hz, NHCH ₂ ), 4.09-4.10 (m, chiral-H), 1.59-1.94 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.45 (s, Boc), 1, 37-1.38 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.93 (t, J= 7.0 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 36: Preparation of (R)/(S)-tert-butyl (1-oxo-1(((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (41)

Compound 5 (0.55 g, 2.51 mmol), NMM (0.77 mL, 7.02 mmol), IBCF (0.42 mL, 3.26 mmol), and compound 17 (0.80 g, 2.63 mmol) were reacted with each other according to reaction scheme e to synthesize compound 41, (R)/(S)-tert-butyl (1-oxo-1-((((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (1.05 g, 90%), obtained as a white powder.

R _f =0.09 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.57-7.61 (m, ArH), 7.53 (d, J= 8.2 Hz, ArH), 7.37 (d, J= 8.2 Hz, ArH), 7.30 (d, J= 8.2 Hz, ArH), 6.47 (s, C(O)NH), 4.96 (s, Boc-NH), 4.52 (s , NHCH ₂ ), 4.10-4.11 (m, chiral-H), 1.59-1.94 (m, CH ₂ CH ₂ CH ₃ ), 1.37-1.45 (m, CH ₂ CH ₂ CH ₃ , Boc), 0.97 (t, J = 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 37: Preparation of (R)/(S)-tert-butyl (1-oxo-1(((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)amino)hexan-2-yl)carbamate (42)

Compound 6 (0.58 g, 2.51 mmol), NMM (0.77 mL, 7.02 mmol), IBCF (0.42 mL, 3.26 mmol), and compound 17 (0.80 g, 2.63 mmol) were reacted with each other according to reaction scheme e to synthesize compound 42, (R)/(S)-tert-butyl (1-oxo-1-((((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)amino)hexan-2-yl)carbamate (1.06 g, 88%), obtained as a white powder.

R _f =0.18 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.58-7.61 (m, ArH), 7.53 (d, J= 8.1 Hz, ArH), 7.37 (d, J= 8.1 Hz, ArH), 7.30 (d, J= 8.5 Hz, ArH), 6.52 (s, C(O)NH), 4.99 (s, Boc-NH), 4.53 (d , J= 5.1 Hz, NHCH ₂ ), 4.09-4.11 (m, chiral-H), 1.62-1.94 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.45 (s, Boc), 1.36-1.37 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.92 (t, J= 6.9 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 38: Preparation of (R)/(S)-tert-butyl (1-((((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)amino)-1-oxopentan-2-yl)methylcarbamate (43)

Compound 8 (0.38 g, 1.65 mmol), NMM (0.46 mL, 4.13 mmol), IBCF (0.28 mL, 2.15 mmol), and compound 15 (0.50 g, 1.73 mmol) were reacted with each other according to reaction scheme e to synthesize compound 43, (R)/(S)-tert-butyl (1-(((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)amino)-1-oxopentan-2-yl)methylcarbamate (0.57 g, 73%), obtained as an oil.

R _f =0.18 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 300 MHz) 7.30-7.68 (m, ArH), 6.27-6.64 (m, C(O)NH), 4.41-4.59 (m, NHCH ₂ , chiral-H), 2.78 (s, NCH ₃ ), 2.04-1.63 (m, CH ₂ CH ₂ CH ₃ ), 1.44 (s, Boc), 1.32-1 .26 (m, CH ₂ CH ₂ CH ₃ ), 0.96 (t, J = 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 39: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1(((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (44)

Compound 8 (0.38 g, 1.66 mmol), NMM (0.46 mL, 4.14 mmol), IBCF (0.28 mL, 2.15 mmol), and compound 16 (0.50 g, 1.74 mmol) were reacted with each other according to reaction scheme e to synthesize compound 44, (R)/(S)-tert-butylmethyl (1-oxo-1-(((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (0.49 g, 64%), obtained as an oil.

R _f =0.22 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 300 MHz) 7.64-7.71 (m, ArH), 7.44 (dd, J= 7.9 Hz, 53.4 Hz, ArH), 6.28-6, 64 (m, C(O)NH), 4.43-4.61 (m, NHCH ₂ , chiral-H), 2.78 (s, NCH ₃ ), 1.63-2.04 (m, CH ₂ CH ₂ CH ₃ ), 1.44 (s, Boc), 1.26-1.35 (m, CH ₂ CH ₂ CH ₃ ), 0.96 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 40: Preparation of (R)/(S)-2-amino-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)pentanamide hydrochloride (45)

Compound 37 (1.19 g, 2.64 mmol) and 4.0 M HCl (3.95 mL, 15.8 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 45, (R)/(S)-2-amino-N-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)pentanamide hydrochloride (0.73 g, 71%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 300 MHz) 9.04 (s, C(O)NH), 8.21 (s, NH ₃ ), 7.94 (s, ArH), 7.66-7.73 (m, ArH), 7.40 (d, J = 8.1 Hz, ArH), 4.39-4.41 (m, NHCH ₂ ), 3.78-3.82 (t, J = 6.3 Hz, chiral-H), 1.68-1.76 (m, CH ₂ CH ₂ CH ₃ ), 1.29-1.39 (m, CH ₂ CH ₂ CH ₃ ), 0.89 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 41: Preparation of (R)/(S)-2-amino-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)hexanamide hydrochloride (46)

Compound 38 (0.46 g, 0.99 mmol) and 4.0 M HCl (1.48 mL, 1.48 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 46, (R)/(S)-2-amino-N-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)hexanamide hydrochloride (0.27 g, 85%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.17 (m, C(O)NH), 8.32 (s, NH ₃ ), 7.94 (d, J = 2.0 Hz, ArH), 7.66-7.73 (m, ArH), 7.41 (d, J = 8.2 Hz, ArH), 4.34-4.45 (m, NHCH ₂ ), 3.81 (t, J = 6.1 Hz, chiral-H), 1.75-1.76 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.27-1.28 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.85 (t, J = 6.6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 42: Preparation of (R)/(S)-2-amino-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)pentanamide hydrochloride (47)

Compound 39 (0.70 g, 1.55 mmol) and 4.0 M HCl (2.33 mL, 9.32 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 47, (R)/(S)-2-amino-N-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide hydrochloride (0.60 g, 99%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 300 MHz) 9.37 (t, J = 5.7 Hz, C(O)NH), 8.46 (s, NH ₃ ), 7.71-7.92 (m, ArH), 7.45-7.51 (m, ArH), 4.40-4.43 (m, NHCH ₂ ), 3.89 (s, chiral-H), 1.74-1.82 (m, CH ₂ CH ₂ CH ₃ ), 1.16-1.42 (m, CH ₂ CH ₂ CH ₃ )0.89 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 43: Preparation of (R)/(S)-2-amino-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)hexanamide hydrochloride (48)

Compound 40 (0.85 g, 1.83 mmol) and 4.0 M HCl (2.75 mL, 11.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 48, (R)/(S)-2-amino-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)hexanamide hydrochloride (0.72 g, 98%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.09 (s, C(O)NH), 8.23 (s, NH ₃ ), 7.89 (d, J= 8.2 Hz, ArH), 7.82 (d, J= 8.4 Hz, ArH), 7.73 (d, J= 8.1 Hz, ArH), 7.44 (d, J= 8.1 Hz, ArH), 4.36-4.46 (m, NHCH ₂ ), 3.80 (t, J= 6.4 Hz, chiral-H), 1.74-1.76 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.27-1.29 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.85 (t, J= 6.5 Hz, CH ₂ CH _{2 CH2CH3 )} .

Preparation Example 44: Preparation of (R)/(S)-2-amino-N-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)pentanamide hydrochloride (49)

Compound 41 (1.04 g, 2.22 mmol) and 4.0 M HCl (3.34 mL, 13.3 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 49, (R)/(S)-2-amino-N-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)pentanamide hydrochloride (0.82 g, 92%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.14 (t, J = 5.7 Hz, C(O)NH), 8.30 (s, NH ₃ ), 7.77-7.81 (m, ArH), 7.67 (d, J = 8.2 Hz, ArH), 7.46 (d, J = 8.1 Hz, ArH), 7.41 (d, J = 8.2 Hz, ArH), 4.40 (d, J = 5.8 Hz, NHCH ₂ ), 3.82 (t, J = 6.5 Hz, chiral-H), 1.71-1.76 (m, CH ₂ CH ₂ CH ₃ ), 1.28-1.38 (m, CH ₂ CH ₂ CH ₃ ), 0.89 (t, J = 7.3 Hz, CH _{2 CH2CH3 )} .

Preparation Example 45: Preparation of (R)/(S)-2-amino-N-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)hexanamide hydrochloride (50)

Compound 42 (1.04 g, 2.17 mmol) and 4.0 M HCl (3.26 mL, 13.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 50, (R)/(S)-2-amino-N-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)hexanamide hydrochloride (0.88 g, 97%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.09 (t, J = 5.8 Hz, C(O)NH), 8.25 (s, NH ₃ ), 7.78 (d, J = 8.7 Hz, ArH), 7.66 (d, J = 8.2 Hz, ArH), 7.45 (d, J = 8.3 Hz, ArH), 7.41 (d, J = 8.2 Hz, ArH), 4.35-4.44 (m, NHCH ₂ ), 3.80 (t, J = 6.4 Hz, chiral-H), 1.72-1.75 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.27-1.28 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.85 (t, J = 6.5 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 46: Preparation of (R)/(S)-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(methylamino)pentanamide hydrochloride (51)

Compound 43 (0.84 g, 1.81 mmol) and 4.0 M HCl (2.80 mL, 10.9 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 51, (R)/(S)-N-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)-2-(methylamino)pentanamide hydrochloride (0.64 g, 88%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 300 MHz) 9.10-9.78 (m, NH ₂ ), 9.57 (t, J = 5.5 Hz, C(O)NH), 7.96 (s, ArH), 7.69-7.72 (m, ArH), 7.43 (d, J = 10.7 Hz, ArH), 4.42-4.44 (m, NHCH ₂ ), 3.85-3.90 (m, chiral-H), 2.48 (s, NCH ₃ ), 1.76-1.90 (m, CH ₂ CH ₂ CH ₃ ), 1.26-1.38 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J = 7.1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 47: Preparation of (R)/(S)-2-(methylamino)-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)pentanamide hydrochloride (52)

Compound 44 (0.45 g, 0.97 mmol) and 4.0 M HCl (1.45 mL, 5.81 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 52, (R)/(S)-2-(methylamino)-N-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide hydrochloride (0.32 g, 82%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 300 MHz) 9.03-9.81 (m, NH ₂ ), 9.52 (t, J = 5.5 Hz, C(O)NH), 7.72-7.92 (m, ArH), 7.46 (d, J = 8.2 Hz, ArH), 4.43-4.45 (m, NHCH ₂ ), 3.86 (s, chiral-H), 2.48 (s, NCH ₃ ), 1.77-1.89 (m, CH ₂ CH ₂ CH ₃ ), 1.25-1.38 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 48: Preparation of (R)/(S)-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide (53)

Compound 45 (1.0 equiv), triethylamine (6.0 equiv), formaldehyde (1.05 equiv), and palladium catalyst (0.2 equiv) were reacted according to reaction scheme g to synthesize compound 53, (R)/(S)-N-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide.

¹ H NMR (DMSO- d ₆ , 300 MHz) 9.57 (t, J = 5.5 Hz, C(O)NH), 7.96 (s, ArH), 7.69-7.72 (m, ArH), 7.43 (d, J = 10.7 Hz, ArH), 4.42-4.44 (m, NHCH ₂ ), 3.85-3.90 (m, chiral-H), 2.48 (s, N (CH ₃ ) ₂ ), 1.76-1.90 (m, CH ₂ CH ₂ CH ₃ ), 1.26-1.38 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J = 7.1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 49: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxobutan-2-yl)carbamate (54)

Compound 4 (0.32 g, 1.57 mmol), NMM (0.43 mL, 3.93 mmol), IBCF (0.27 mL, 2.05 mmol), and compound 18 (0.50 g, 1.65 mmol) were reacted with each other according to reaction scheme e to synthesize compound 54, (R)/(S)-tert-butyl (1-((2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxobutan-2-yl)carbamate (0.66 g, 93%), obtained as a white powder.

R _f =0.05 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.65 (s, ArH), 7.47-7.50 (m, ArH), 7.39 (d, J= 8.2 Hz, ArH), 7, 26-7.28 (m, ArH), 6.07 (s, C(O)NH), 4.94 (s, Boc-NH), 3.93 (d, J= 6.6 Hz, chiral- H), 3.50-3.94 (m, NHCH ₂ CH ₂ ), 2.86 (t, J = 6.9 Hz, NHCH ₂ CH ₂ ), 1.55-2.88 (m, CH ₂ CH ₃ ), 1.43 (s, Boc), 0.91 (t, J= 7.4 Hz, CH ₂ CH ₃ ).

Preparation Example 50: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)carbamate (55)

Compound 5 (0.50 g, 2.30 mmol), NMM (0.51 mL, 4.60 mmol), IBCF (0.39 mL, 2.99 mmol), and compound 18 (0.73 g, 2.42 mmol) were reacted with each other according to reaction scheme e to synthesize compound 55, (R)/(S)-tert-butyl (1-((2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)carbamate (0.96 g, 89%), obtained as a white powder.

R _f =0.26 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.46-7.64 (m, ArH), 7.26-7.40 (m, ArH), 6.36 (s, C(O)NH), 5 .07 (s, Boc-NH), 4.01-4.03 (m, chiral-H), 3.47-3.61 (m, NHCH ₂ CH ₂ ), 2.85 (t, J= 7 .0 Hz, NHCH ₂ CH ₂ ), 2.67 (s, NCH ₃ ), 1.48-1.80 (m, CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1.26 -1.36 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J= 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 51: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxohexan-2-yl)carbamate (56)

Compound 6 (0.36 g, 1.57 mmol), NMM (0.43 mL, 3.93 mmol), IBCF (0.27 g, 2.05 mmol), and compound 18 (0.50 g, 16.5 mmol) were reacted with each other according to reaction scheme e to synthesize compound 56, (R)/(S)-tert-butyl (1-((2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxohexan-2-yl)carbamate (0.76 g, 100%), obtained as a white powder.

R _f =0.07 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.65 (s, ArH), 7.48 (d, J= 6.3 Hz, ArH), 7.39 (d, J= 8.0 Hz, ArH) , 7.26-7.28 (m, ArH), 6.07 (s, C(O)NH), 4.91 (s, Boc-NH), 3.97 (d, J= 5.6 Hz , chiral-H), 3.51-3.62 (m, NHCH ₂ CH ₂ ), 2.86 (t, J= 6.1 Hz, NHCH ₂ CH ₂ ), 1.51-1.81 (m , CH ₂ CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1.27 (d, J= 6.7 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.87 (d, J = 5.5 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 52: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (57)

Compound 4 (0.42 g, 2.08 mmol), NMM (0.57 mL, 5.21 mmol), IBCF (0.35 mL, 2.71 mmol), and compound 19 (0.66 g, 2.19 mmol) were reacted with each other according to reaction scheme e to synthesize compound 57, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (0.92 g, 98%), obtained as a white powder.

R _f =0.16 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.70 (s, ArH), 7.57 (d, J= 8.0 Hz, ArH), 7.29-7.33 (m, ArH), 6, 15 (s, C(O)NH), 5.00 (s, Boc-NH), 3.94-3.99 (m, chiral-H), 3.53-3.66 (m, NHCH ₂ CH ₂ ), 2.90 (t, J= 7.0 Hz, NHCH ₂ CH ₂ ), 1.58-1.90 (m, CH ₂ CH ₃ ), 1.45 (s, Boc), 0.93 (t, J= 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 53: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (58)

Compound 5 (0.55 g, 2.53 mmol), NMM (0.69 mL, 6.31 mmol), IBCF (0.43 mL, 3.28 mmol), and compound 19 (0.80 g, 2.65 mmol) were reacted with each other according to reaction scheme e to synthesize compound 58, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (1.05 g, 89%), obtained as a white powder.

R _f =0.20 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 300 MHz) 7.67 (s, ArH), 7.41 (dd, J= 8.1 Hz, 63.6 Hz, ArH), 6.36 (s, C(O) NH), 5.05-5.07 (m, Boc-NH), 4.00-4.05 (m, chiral-H), 3.45-3.66 (m, NHCH ₂ CH ₂ ), 2 .87 (t, J= 7.1 Hz, NHCH ₂ CH ₂ ), 1.50-1.83 (m, CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1.28-1 .39 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 54: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)carbamate (59)

Compound 6 (0.76 g, 3.16 mmol), NMM (0.87 mL, 7.89 mmol), IBCF (0.53 mL, 4.10 mmol), and compound 19 (1.00 g, 3.31 mmol) were reacted with each other according to reaction scheme e to synthesize compound 59, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)carbamate (1.34 g, 89%), obtained as a white powder.

R _f =0.13 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.87 (d, J = 8.2 Hz, ArH, C(O)NH), 7.80 (d, J = 8.5 Hz, ArH), 7.66 (d, J = 8.1 Hz, ArH), 7.35 (d, J = 8.1 Hz, ArH), 6.73 (d, J = 8.2 Hz, Boc-NH), 3.83 (q, J = 5.6 Hz, 8.4 Hz, chiral-H), 3.24-3.43 (m, NHCH ₂ CH ₂ ), 2.77 (t, J = 7.0 Hz, NHCH ₂ CH ₂ ), 1.37-1.52 (m, CH ₂ CH ₂ CH ₂ CH ₃ , Boc), 1.15-1.20 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.80 (t, J = 6.8 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 55: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (60)

Compound 4 (0.49 g, 2.40 mmol), NMM (0.66 mL, 6.00 mmol), IBCF (0.41 mL, 3.12 mmol), and compound 20 (0.80 g, 2.52 mmol) were reacted with each other according to Reaction Scheme e to synthesize compound 60, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (0.94 g, 84%), obtained as a white powder.

R _f =0.14 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.68-7.73 (m, ArH), 7.51-7.62 (m, ArH), 7.29-7.33 (m, ArH), 6 .17 (d, J= 5.6 Hz, C(O)NH), 5.01 (s, NH), 3.95-3.98 (m, chiral-H), 3.51-3.67 (m, NHCH ₂ CH ₂ ), 2.87-2.92 (m, NHCH ₂ CH ₂ ), 1.56-1.92 (m, CH ₂ CH ₃ ), 1.45 (s, Boc), 0.93 (t, J= 7.4 Hz, CH ₂ CH ₃ ).

Preparation Example 56: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl))amino)pentan-2-yl)carbamate (61)

Compound 5 (0.33 g, 1.50 mmol), NMM (0.41 mL, 3.75 mmol), IBCF (0.25 mL, 1.95 mmol), and compound 20 (0.50 g, 1.57 mmol) were reacted with each other according to reaction scheme e to synthesize compound 61, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (0.70 g, 98%), obtained as a white powder.

R _f =0.12 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.88 (t, J = 5.6 Hz, C(O)NH), 7.74-7.77 (m, ArH), 7.59 (d, J = 8.2 Hz, ArH), 7.44 (d, J = 8.1 Hz, ArH), 7.32 (d, J = 8.2 Hz, ArH), 6.74 (d, J = 8.2 Hz, Boc-NH), 4.86 (q, J = 5.6 Hz, 8.2 Hz, chiral-H), 3.26-3.40 (m, NHCH ₂ CH ₂ ), 2.76 (t, J = 7.0 Hz, NHCH ₂ CH ₂ ), 1.37-1.52 (m, CH ₂ CH ₂ CH ₃ , Boc), 1.17-1.25 (m, CH ₂ CH ₂ CH ₃ ), 0.81 (t, J=7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 57: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl))amino)hexan-2-yl)carbamate (62)

Compound 6 (0.50 g, 2.18 mmol), NMM (0.60 mL, 5.45 mmol), IBCF (0.37 mL, 2.83 mmol), and compound 20 (0.72 g, 2.29 mmol) were reacted with each other according to reaction scheme e to synthesize compound 62, (R)/(S)-tert-butyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (0.95 g, 88%), obtained as a white powder.

R _f =0.13 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.70-7.73 (m, ArH), 7.57 (d, J= 8.1 Hz, ArH), 7.32 (d, J= 8.1 Hz, ArH), 6.15 (s, C(O)NH), 4.95 (s, Boc-NH), 4.00 (q, J= 6.4 Hz, 7.2 Hz, chiral-H ), 3.53-3.65 (m, NHCH ₂ CH ₂ ), 2.90 (t, J = 7.0 Hz, NHCH ₂ CH ₂ ), 1.52-1.85 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.45 (s, Boc), 1.31-1.34 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.90 (t, J= 6.9 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 58: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-difluoro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)carbamate (63)

Compound 5 (0.50 g, 2.29 mmol), NMM (0.70 mL, 6.40 mmol), IBCF (0.39 mL, 2.97 mmol), and compound 21 (0.80 g, 2.40 mmol) were reacted with each other according to reaction scheme e to synthesize compound 63, (R)/(S)-tert-butyl (1-((2-(3’,4’-difluoro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)carbamate (0.97 g, 98%), obtained as a white powder.

R _f =0.10 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.46 (d, J= 7.9 Hz, ArH), 7.33-7.38 (m, ArH), 7.17-7.27 (m, ArH ), 6.11 (s, C(O)NH), 4.92 (s, Boc-NH), 3.96-4.01 (m, chiral-H), 3.47-3.63 (m , NHCH ₂ CH ₂ ), 2.85 (t, J = 7.0 Hz, NHCH ₂ CH ₂ ), 1.48-1.82 (m, CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1.26-1.36 (m, CH ₂ CH ₂ CH ₃ ), 0.90 (t, J = 7.3 Hz, CH _{2 CH2CH3 )} .

Preparation Example 59: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxobutan-2-yl)methylcarbamate (64)

Compound 7 (0.82 g, 3.78 mmol), NMM (1.04 mL, 9.44 mmol), IBCF (0.64 mL, 4.91 mmol), and compound 18 (1.20 g, 3.97 mmol) were reacted with each other according to reaction scheme e to synthesize compound 64, (R)/(S)-tert-butyl (1-((2-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxobutan-2-yl)methylcarbamate (1.38 g, 79%), obtained as an oil.

R _f =0.22 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.66 (d, J= 2.0 Hz, ArH), 7.49-7.53 (m, ArH), 7.41 (dd, J= 2.1 Hz, 6.3 Hz, ArH), 7.27-7.29 (m ArH), 6.26 (s, C(O)NH), 4.44 (s, chiral-H), 3.55- 3.64 (m, NHCH ₂ CH ₂ ), 2.87 (t, J= 6.7 Hz, NHCH ₂ CH ₂ ), 2.70 (s, NCH ₃ ), 1.61-1.98 (m , CH ₂ CH ₃ ), 1.45 (s, Boc), 0.88 (t, J= 7.4 Hz, CH ₂ CH ₃ ).

Preparation Example 60: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)methylcarbamate (65)

Compound 8 (0.35 g, 1.51 mmol), NMM (0.33 mL, 3.03 mmol), IBCF (0.26 mL, 1.97 mmol), and compound 18 (0.48 g, 1.59 mmol) were reacted with each other according to reaction scheme e to synthesize compound 65, (R)/(S)-tert-butyl (1-((2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxopentan-2-yl)methylcarbamate (0.69 g, 95%), obtained as an oil.

R _f =0.33 (EtOAc:n-hexane 1:3);

^1H NMR ( _CDCl3 , 400 MHz) 7.46-7.64 (m, ArH), 7.35-7.40 (m, ArH), 7.25-7.27 (m, ArH), 5 .95-6.25 (m, C(O)NH), 4.51 (s, chiral-H), 3.53-3.60 (m, NHCH ₂ CH ₂ ), 2.84 (t, J = 6.6 Hz, NHCH ₂ CH ₂ ), 2.67 (s, NCH ₃ ), 1.57-1.90 (m, CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1 .22-1.32 (m, CH ₂ CH ₂ CH ₃ ), 0.95 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 61: Preparation of (R)/(S)-tert-butyl (1-((2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)amino)-1-oxohexan-2-yl)methylcarbamate (66)

Compound 9 (0.29 g, 1.20 mmol), NMM (0.33 mL, 2.99 mmol), IBCF (0.20 mL, 0.16 mmol), and compound 18 (0.38 g, 1.26 mmol) were reacted with each other according to reaction scheme e to synthesize compound 66, (R)/(S)-tert-butyl (1-((2-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-1-oxohexan-2-yl)methylcarbamate (0.60 g, 97%), obtained as an oil.

R _f =0.30 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.89 (d, J = 1.9 Hz, ArH, C(O)NH), 7.62-7.71 (m, ArH), 7.30 (d, J = 8.1 Hz, ArH), 4.27-4.47 (m, chiral-H), 3.32-3.35 (m, NHCH ₂ CH ₂ ), 2.77 (t, J = 6.5 Hz, NHCH ₂ CH ₂ ), 2.67 (s, NCH ₃ ), 1.53-1.71 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.39 (s, Boc), 1.12-1.28 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.84 (s, CH ₂ CH _{2 CH2CH3 )} .

Preparation Example 62: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (67)

Compound 7 (0.62 g, 2.84 mmol), NMM (0.87 mL, 7.95 mmol), IBCF (0.48 mL, 3.69 mmol), and compound 19 (0.90 g, 2.98 mmol) were reacted with each other according to reaction scheme e to synthesize compound 67, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (0.89 g, 67%), obtained as a white powder.

R _f =0.15 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.70 (t, J= 9.7 Hz, ArH), 7.56 (d, J= 7.9 Hz, ArH), 7.28-7.32 ( m, ArH), 5.94-6.22 (m, C(O)NH), 4.45 (s, chiral-H), 3.57-3.64 (m, NHCH ₂ CH ₂ ), 2 .89 (d, J= 6.1 Hz, NHCH ₂ CH ₂ ), 2.70 (s, NCH ₃ ), 1.61-1.99 (m, CH ₂ CH ₃ ), 1.45 (s, Boc), 0.89 (t, J= 7.3 Hz, CH ₂ CH ₃ ).

Preparation Example 63: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (68)

Compound 8 (0.58 g, 2.53 mmol), NMM (0.69 mL, 6.31 mmol), IBCF (0.43 mL, 3.28 mmol), and compound 19 (0.80 g, 2.65 mmol) were reacted with each other according to Reaction Scheme e to synthesize compound 68, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (1.19 g, 98%), obtained as an oil.

R _f =0.26 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 300 MHz) 7.64-7.70 (m, ArH), 7.41 (dd, J= 8.1 Hz, 67.4 Hz, ArH), 5.95-6, 21 (s, C(O)NH), 4.52 (s, chiral-H), 3.54-3.63 (m, NHCH ₂ CH ₂ ), 2.86 (t, J= 6.8 Hz , NHCH ₂ CH ₂ ), 2.67 (s, NCH ₃ ), 1.55-1.91 (m, CH ₂ CH ₂ CH ₃ ), 1.42 (s, Boc), 1.23-1, 27 (m, CH ₂ CH ₂ CH ₃ ), 0.88-0.95 (m, CH ₂ CH ₂ CH ₃ ).

Preparation Example 64: Preparation of (R)/(S)-tert-butylmethyl ((1-oxo-1((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (69)

Compound 9 (0.70 g, 2.84 mmol), NMM (0.87 mL, 7.95 mmol), IBCF (0.48 mL, 3.69 mmol), and compound 19 (0.90 g, 2.98 mmol) were reacted with each other according to reaction scheme e to synthesize compound 69, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (0.88 g, 63%), obtained as a yellow powder.

R _f =0.32 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.87 (d, J = 8.3 Hz, ArH, C(O)NH), 7.80 (d, J = 8.4 Hz, ArH), 7.66 (d, J = 8.2 Hz, ArH), 7.33 (d, J = 8.1 Hz, ArH), 4.27-4.47 (m, chiral-H), 3.32-3.33 (m, NHCH ₂ CH ₂ ), 2.78 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.66 (s, NCH ₃ ), 1.53-1.71 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.39 (s, Boc), 1.12-1.28 (m, CH ₂ CH ₂ CH ₂ CH ₃ )0.84-0.89 (m, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 65: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (70)

Compound 7 (0.65 g, 3.00 mmol), NMM (0.92 mL, 8.99 mmol), IBCF (0.51 mL, 3.90 mmol), and compound 20 (1.00 g, 3.15 mmol) were reacted with each other according to Reaction Scheme e to synthesize compound 70, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (1.00 g, 69%), obtained as an oil.

R _f =0.19 (EtOAc:n-hexane 1:3);

¹ H NMR (CDCl ₃ , 400 MHz) 7.51-7.70 (m, ArH), 7.29 (t, J= 3.7 Hz, ArH), 5.98-6.26 (m, C (O)NH), 4.45 (s, chiral-H), 3.59-3.60 (m, NHCH ₂ CH ₂ ), 2.87 (s, NHCH ₂ CH ₂ ), 2.70 (d , J= 3.2 Hz, NCH ₃ ), 1.62-2.07 (m, CH ₂ CH ₃ ), 1.45 (s, Boc), 0.90 (m, CH ₂ CH ₃ ).

Preparation Example 66: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl))amino)pentan-2-yl)carbamate (71)

Compound 8 (0.25 g, 1.08 mmol), NMM (0.30 mL, 2.69 mmol), IBCF (0.18 mL, 1.40 mmol), and compound 20 (0.36 g, 1.13 mmol) were reacted with each other according to reaction scheme e to synthesize compound 71, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (0.32 g, 60%), obtained as a white powder.

R _f =0.18 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.89 (s, C(O)NH), 7.76 (d, J= 8.4 Hz, ArH), 7.59 (d, J= 7.8 Hz, ArH), 7.44 (d, J= 8.2 Hz, ArH), 7.30 (d, J= 7.8 Hz, ArH), 4.30-4.49 (m, chiral-H), 3.28-3.40 (m, NHCH ₂ CH ₂ ), 2.77 (s, NHCH ₂ CH ₂ ), 2.66 (s, NCH ₃ ), 1.53-1.90 (m, CH ₂ CH ₂ CH ₃ ), 1.39 (s, Boc), 1.16-1.23 (m, CH ₂ CH ₂ CH ₃ ), 0.88-0.89 (m, CH ₂ CH ₂ CH ₃ ).

Preparation Example 67: Preparation of (R)/(S)-tert-butylmethyl (1-oxo-1((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl))amino)hexan-2-yl)carbamate (72)

Compound 9 (0.74 g, 3.00 mmol), NMM (0.92 mL, 8.99 mmol), IBCF (0.51 mL, 3.90 mmol), and compound 20 (1.00 g, 3.15 mmol) were reacted with each other according to Reaction Scheme e to synthesize compound 72, (R)/(S)-tert-butylmethyl (1-oxo-1-((2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (0.92 g, 60%), obtained as an oil.

R _f =0.29 (EtOAc:n-hexane 1:3);

¹ H NMR (DMSO- d ₆ , 400 MHz) 7.88 (s, C(O)NH), 7.74-7.77 (m, ArH), 7.59 (d, J= 8.2 Hz, ArH), 7.44 (d, J= 8.0 Hz, ArH), 7.30 (d, J= 8.1 Hz, ArH), 4.28-4.47 (m, chiral-H), 3.30-3.34 (m, NHCH ₂ CH ₂ ), 2.77 (t, J= 6.7 Hz, NHCH ₂ CH ₂ ), 2.66 (s, NCH ₃ ), 1.53-1.72 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.39 (s, Boc), 1.12-1.29 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.84-0.90 (m, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 68: Preparation of (R)/(S)-2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)butanamide hydrochloride (73)

Compound 54 (0.66 g, 1.47 mmol) and 4.0 M HCl (2.20 mL, 8.81 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 73, (R)/(S)-2-amino-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)butanamide hydrochloride (0.52 g, 91%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.66 (t, J = 5.3 Hz, C(O)NH), 8.23 (s, NH ₃ ), 7.92 (d, J = 1.9 Hz, ArH), 7.65- 7.72 (m, ArH), 7.35 (d, J = 8.1 Hz, ArH), 3.67 (t, J = 6.0 Hz, chiral-H), 3.31-3.55 (m, NHCH ₂ CH ₂ ), 2.79-2.83 (m, NHCH ₂ CH ₂ ), 1.67-1.74 (m, CH ₂ CH ₃ ), 0.79 (t, J = 7.4 Hz, CH ₂ CH ₃ ).

Preparation Example 69: Preparation of (R)/(S)-2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (74)

Compound 55 (0.95 g, 2.04 mmol) and 4.0 M HCl (3.06 mL, 12.2 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 74, (R)/(S)-2-amino-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (0.66 g, 80%), obtained as a yellow powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.82 (t, J = 5.3 Hz, C(O)NH), 8.34 (s, NH ₃ ), 7.64-7.90 (m, ArH), 7.35-7.38 (d, J = 8.1 Hz, ArH), 3.73 (t, J = 6.3 Hz, chiral-H), 3.29-3.57 (m, NHCH ₂ CH ₂ ), 2.82-2.85 (m, NHCH ₂ CH ₂ ), 1.60-1.67 (m, CH ₂ CH ₂ CH ₃ ), 1.14-1.22 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J = 7.1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 70: Preparation of (R)/(S)-2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (75)

Compound 56 (0.75 g, 1.56 mmol) and 4.0 M HCl (2.35 mL, 9.39 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 75, (R)/(S)-2-amino-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (0.60 g, 92%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.60 (t, J = 5.5 Hz, C(O)NH), 8.18 (s, NH ₃ ), 7.91 (d, J = 2.0 Hz, ArH), 7.65- 7.72 (m, ArH), 7.35 (d, J = 8.2 Hz, ArH), 3.66 (t, J = 6.2 Hz, chiral-H), 3.28-3.58 (m, NHCH ₂ CH ₂ ), 2.81-2.85 (m, NHCH ₂ CH ₂ ), 1.59-1.64 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.14-1.23 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.79 (t, J= 6.8 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 71: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide hydrochloride (76)

Compound 57 (0.90 g, 2.00 mmol) and 4.0 M HCl (3.00 mL, 12.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 76, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)butanamide hydrochloride (0.75 g, 96%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.62 (s, C(O)NH), 8.17 (s, NH ₃ ), 7.88 (d, J = 8.2 Hz, ArH), 7.81 (d, J = 8.4 Hz, ArH), 7.68 (d, J = 8.3 Hz, ArH), 7.38 (d, J = 8.1 Hz, ArH), 3.66 (t, J = 6.1 Hz, chiral-H), 3.30-3.57 (m, NHCH ₂ CH ₂ ), 2.82 (t, J = 7.0 Hz, NHCH ₂ CH ₂ ), 1.67-1.74 (m, CH ₂ CH ₃ ), 0.79 (t, J = 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 72: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (77)

Compound 58 (1.03 g, 2.22 mmol) and 4.0 M HCl (5.56 mL, 22.2 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 77, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (0.75 g, 85%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 300 MHz) 8.81 (t, J = 5.3 Hz, C(O)NH), 8.35 (s, NH ₃ ), 7.84 (dd, J = 8.2 Hz, 15.7 Hz, ArH), 7.54 (dd, J = 8.1 Hz, 73.4 Hz, ArH), 3.71-3.75 (t, J = 6.3 Hz, chiral-H), 3.30-3.60 (m, NH ₂ CH ₂ CH ₂ ), 2.85 (t, J = 6.3 Hz, NHCH ₂ CH ₂ ), 1.61-1.68 (m, CH ₂ CH ₂ CH ₃ ), 1.15-1.22 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J= 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 73: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (78)

Compound 59 (1.32 g, 2.76 mmol) and 4.0 M HCl (4.14 mL, 16.6 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 78, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (0.82 g, 72%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.69 (t, J = 4.9 Hz, C(O)NH), 8.26 (s, NH ₃ ), 7.88 (d, J = 8.2 Hz, ArH), 7.81 (d, J = 8.3 Hz, ArH), 7.68 (d, J = 8.1 Hz, ArH), 7.39 (d, J = 8.0 Hz, ArH), 3.69 (t, J = 6.2 Hz, chiral-H), 3.29-3.59 (m, NHCH ₂ CH ₂ ), 2.80-2.89 (m, NHCH ₂ CH ₂ ), 1.61-1.67 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.14-1.23 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.79 (t, J= 6.8 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 74: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide hydrochloride (79)

Compound 60 (0.91 g, 1.95 mmol) and 4.0 M HCl (2.92 mL, 11.7 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 79, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)butanamide hydrochloride (0.43 g, 54%), obtained as a yellow powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.67 (s, C(O)NH), 8.24 (s, NH ₃ ), 7.35-7.89 (m, ArH), 3.67 (d, J= 4.3 Hz, chiral-H), 3.30-3.55 (m, NHCH ₂ CH ₂ ), 2.80-2.85 (m, NHCH ₂ CH ₂ ), 1.68-1.75 (m, CH ₂ CH ₃ ), 0.80 (t, J= 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 75: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (80)

Compound 61 (0.70 g, 1.45 mmol) and 4.0 M HCl (2.18 mL, 8.70 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 80, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (0.55 g, 91%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.71 (t, J = 5.4 Hz, C(O)NH), 8.28 (s, NH ₃ ), 7.77 (d, J = 8.8 Hz, ArH), 7.62 (d, J = 8.2 Hz, ArH), 7.35-7.45 (m, ArH), 3.70 (t, J = 6.4 Hz, chiral-H), 3.28-3.57 (m, NHCH ₂ CH ₂ ), 2.80-2.86 (m, NHCH ₂ CH ₂ ), 1.61-1.65 (m, CH ₂ CH ₂ CH ₃ ), 1.13-1.24 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J = 7.4 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 76: Preparation of (R)/(S)-2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (81)

Compound 62 (0.79 g, 1.59 mmol) and 4.0 M HCl (2.38 mL, 9.54 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 81, (R)/(S)-2-amino-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (0.62 g, 91%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.66 (t, J = 5.4 Hz, C(O)NH), 8.23 (s, NH ₃ ), 7.88 (d, J = 8.2 Hz, ArH), 7.81 (d, J = 8.4 Hz, ArH), 7.68 (d, J = 8.2 Hz, ArH), 7.39 (d, J = 8.2 Hz, ArH), 3.68 (t, J = 6.4 Hz, chiral-H), 3.29- 3.59 (m, NHCH ₂ CH ₂ ), 2.81-2.87 (m, NHCH ₂ CH ₂ ), 1.60-1.66 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.13-1.23 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.79 (t, J= 7.0 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 77: Preparation of (R)/(S)-2-amino-N-(2-(3’,4’-difluoro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (82)

Compound 62 (0.94 g, 2.17 mmol) and 4.0 M HCl (3.26 mL, 13.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 82, (R)/(S)-2-amino-N-(2-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (0.68 g, 85%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.55 (s, C(O)NH), 8.10 (s, NH ₃ ), 7.72-7.77 (m, ArH), 7.62 (d, J= 8.1 Hz, ArH), 7.50-7.53 (m, ArH), 7.33 (d, J= 8.1 Hz, ArH), 3.65 (t, J= 5.9 Hz, chiral-H), 3.29-3.57 (m, NHCH ₂ CH ₂ ), 2.78-2.84 (m, NHCH ₂ CH ₂ ), 1.58 (q, J= 6.9 Hz, 8.8 Hz, CH ₂ CH ₂ CH ₃ ), 1.14-1.20 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J= 7.3 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 78: Preparation of (R)/(S)-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)butanamide hydrochloride (83)

Compound 64 (1.31 g, 2.81 mmol) and 4.0 M HCl (4.20 mL, 16.9 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 83, (R)/(S)-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(methylamino)butanamide hydrochloride (1.07 g, 94%), obtained as a yellow powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.79 (s, C(O)NH, NH ₂ ), 7.92 (d, J = 2.0 Hz, ArH), 7.65-7.72 (m, ArH), 7.36 (d, J = 8.1 Hz, ArH), 3.59 (t, J = 6.4 Hz, chiral-H), 3.39-3.53 (m, NHCH ₂ CH ₂ ), 2.83 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.38 (t, J = 6.1 Hz, NCH ₃ ), 1.68-1.80 (m, CH ₂ CH ₃ ), 0.77 (t, J = 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 79: Preparation of (R)/(S)-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)pentanamide hydrochloride (84)

Compound 65 (0.65 g, 1.36 mmol) and 4.0 M HCl (2.03 mL, 8.13 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 84, (R)/(S)-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(methylamino)pentanamide hydrochloride (0.33 g, 57%), obtained as a yellow powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.26 (s, NH ₂ ), 8.96 (t, J = 5.3 Hz, C(O)NH), 7.90-7.91 (m, ArH), 7.64-7.71 (m, ArH), 7.36 (d, J = 8.1 Hz, ArH), 3.64-3.68 (m, chiral-H), 3.42-3.56 (m, NHCH ₂ CH ₂ ), 2.84 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.35 (s, NCH ₃ ), 1.60-1.77 (m, CH ₂ CH ₂ CH ₃ ), 1.09-1.16 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J= 7.2 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 80: Preparation of (R)/(S)-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)hexanamide hydrochloride (85)

Compound 66 (0.57 g, 1.16 mmol) and 4.0 M HCl (1.74 mL, 6.95 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 85, (R)/(S)-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(methylamino)hexanamide hydrochloride (0.38 g, 75%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.70-9.36 (s, NH ₂ ), 8.80 (t, J = 5.4 Hz, C(O)NH), 7.91 (d, J = 2.0 Hz, ArH), 7.65-7.72 (m, ArH), 7.35 (d, J = 8.2 Hz, ArH), 3.55 (t, J = 6.6 Hz, chiral-H), 3.38-3.52 (m, NHCH ₂ CH ₂ ), 2.83 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.35 (s, NCH ₃ ), 1.60-1.76 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.05-1.23 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.78 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 81: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide hydrochloride (86)

Compound 67 (0.86 g, 1.84 mmol) and 4.0 M HCl (2.77 mL, 11.1 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 86, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)butanamide hydrochloride (0.65 g, 88%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.04 (s, NH ₂ ), 8.79 (s, C(O)NH), 7.87 (d, J = 8.3 Hz, ArH), 7.80 (d, J = 8.4 Hz, ArH), 7.68 (d, J = 8.2 Hz, ArH), 7.39 (d, J = 8.2 Hz, ArH), 3.59 (t, J = 2.5 Hz, 4.9 Hz, chiral-H), 3.40-3.56 (m, NHCH ₂ CH ₂ ), 2.84 (t, J = 6.9 Hz, NHCH ₂ CH ₂ ), 2.37 (s, NCH ₃ ), 1.67-1.85 (m, CH ₂ CH ₃ ), 0.77 (t, J= 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 82: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (87)

Compound 68 (1.17 g, 2.45 mmol) and 4.0 M HCl (3.67 mL, 14.7 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 87, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (81%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.93-9.79 (m, NH ₂ ), 9.04 (t, J = 5.2 Hz, C(O)NH), 7.84 (dd, J = 8.3 Hz, 15.1 Hz, ArH), 7.54 (dd, J = 8.0 Hz, 73.4 Hz, ArH), 3.68-3.72 (m, chiral-H), 3.42-3.58 (m, NHCH ₂ CH ₂ ), 2.87 (t, J = 6.7 Hz, NHCH ₂ CH ₂ ), 2.36 (s, NCH ₃ ), 1.64-1.82 (m, CH ₂ CH ₂ CH ₃ ), 1.09-1.22 (m, CH ₂ CH ₂ CH ₃ ), 0.81 (t, J=7.1 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 83: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (88)

Compound 69 (0.85 g, 1.72 mmol) and 4.0 M HCl (2.60 mL, 10.3 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 88, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (0.53 g, 71%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.00 (s, NH ₂ ), 8.75 (t, J = 5.4 Hz, C(O)NH), 7.87 (d, J = 8.3 Hz, ArH), 7.81 (d, J = 8.4 Hz, ArH), 7.68 (d, J = 8.2 Hz, ArH), 7.38 (d, J = 8.2 Hz, ArH), 3.57-3.61 (m, chiral-H), 3.40-3.55 (m, NHCH ₂ CH ₂ ), 2.84 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.36 (s, NCH ₃ ), 1.60-1.75 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.06-1.24 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.78 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 84: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide hydrochloride (89)

Compound 70 (0.97 g, 2.01 mmol) and 4.0 M HCl (3.00 mL, 12.1 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 89, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)butanamide hydrochloride (0.73 g, 88%), obtained as a yellow powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 9.00 (s, NH ₂ ), 8.77 (s, C(O)NH), 7.77 (d, J = 8.7 Hz, ArH), 7.61 (d, J = 8.2 Hz, ArH), 7.44 (d, J = 8.2 Hz, ArH), 7.35 (d, J = 8.1 Hz, ArH), 3.57-3.60 (m, chiral-H), 3.39-3.55 (m, NHCH ₂ CH ₂ ), 2.82 (t, J = 6.9 Hz, NHCH ₂ CH ₂ ), 2.37 (s, NCH ₃ ), 1.67-1.83 (m, CH ₂ CH ₃ ), 0.77 (t, J = 7.5 Hz, CH ₂ CH ₃ ).

Preparation Example 85: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (90)

Compound 71 (0.83 g, 1.67 mmol) and 4.0 M HCl (2.51 mL, 10.0 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 90, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (0.40 g, 61%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.85-9.19 (m, NH ₂ ), 8.75 (s, C(O)NH), 7.76 (d, J = 7.7 Hz, ArH), 7.61 (d, J = 7.5 Hz, ArH), 7.44 (d, J = 8.0 Hz, ArH), 7.35 (d, J = 7.4 Hz, ArH), 3.60 (s, chiral-H), 3.40-3.56 (m, NHCH ₂ CH ₂ ), 2.83 (t, J = 6.5 Hz, NHCH ₂ CH ₂ ), 2.36 (s, NCH ₃ ), 1.60-1.66 (m, CH ₂ CH ₂ CH ₃ ), 1.09-1.17 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J = 7.0 Hz, CH ₂ CH ₂ CH ₃ ).

Preparation Example 86: Preparation of (R)/(S)-2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (91)

Compound 72 (0.89 g, 1.74 mmol) and 4.0 M HCl (2.61 mL, 10.4 mmol in dioxane) were reacted according to reaction scheme f to synthesize compound 91, (R)/(S)-2-(methylamino)-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide hydrochloride (0.66 g, 86%), obtained as a white powder.

R _f =0.00 (EtOAc:acetone 9:1);

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.95 (s, NH ₂ ), 8.72 (s, C(O)NH), 7.76 (d, J = 8.7 Hz, ArH), 7.61 (d, J = 8.1 Hz, ArH), 7.44 (d, J = 8.4 Hz, ArH), 7.35 (d, J = 8.1 Hz, ArH), 3.57-3.60 (m, chiral-H), 3.29-3.56 (m, NHCH ₂ CH ₂ ), 2.83 (t, J = 6.8 Hz, NHCH ₂ CH ₂ ), 2.37 (s, NCH ₃ ), 1.59-1.74 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.08-1.24 (m, CH ₂ CH ₂ CH ₂ CH ₃ ), 0.78 (t, J = 7.2 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ).

Preparation Example 87: Preparation of (R)/(S)-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide (92)

Compound 74 (1.0 equiv), triethylamine (6.0 equiv), formaldehyde (1.05 equiv), and palladium catalyst (0.2 equiv) were reacted according to reaction scheme g to synthesize compound 92, (R)/(S)-N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide.

¹ H NMR (DMSO- d ₆ , 400 MHz) 8.96 (t, J = 5.3 Hz, C(O)NH), 7.90-7.91 (m, ArH), 7.64-7.71 (m, ArH), 7.36 (d, J = 8.1 Hz, ArH), 3.64-3.68 (m, chiral-H), 3.42-3.56 (m, NHCH ₂ CH ₂ ), 2.82-2.85 (m, NHCH ₂ CH ₂ ), 2.35 (s, N (CH ₃ ) ₂ ), 1.60-1.77 (m, CH ₂ CH ₂ CH ₃ ), 1.09-1.16 (m, CH ₂ CH ₂ CH ₃ ), 0.80 (t, J = 7.2 Hz, _{CH2CH2CH3 ) .}

Variants of implementation of the invention

Examples

Example 1: Analysis of antifungal activity against fungi pathogenic to humans

In vitro antifungal susceptibility testing was performed according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) to measure the degree of antifungal activity of the compounds synthesized in the Preparation Examples against opportunistic fungi. In this Example, the minimum inhibitory concentrations (MICs) at which the compounds could inhibit the growth of pathogenic fungi Cryptococcus neoformans, Candida albicans, Candida glabrata , and Aspergillus fumigatus were determined as shown in Table 1. The MIC value (μg/mL) was expressed as a range. Specifically, Candida species and Cryptococcus neoformans were incubated on Sabouraud dextrose agar (SDA) solid medium (Sigma-Aldrich) for 24 and 48 hours, respectively, to obtain single colonies. The obtained single colonies were suspended in 0.85% saline to obtain a fungal cell suspension (1 to 5 x 10 ⁶ cells/L). Fungal cells diluted 2000-fold in RPMI1640 broth (Sigma-Aldrich) were seeded in 96-well plates (5 x 10 ² to 2.5 x 10 ³ cells/mL, at a rate of 195 μL per well). Serial dilutions of the compounds in two-fold steps (128, 64, 32, 16, 8, 4, 2, 1, and 0.5 μg/mL) were prepared by diluting the compounds synthesized according to the above Preparation Examples. Then, 5 μl of each dilution was added to a well of a 96-well plate containing the fungal cell suspension to obtain a final suspension of 200 μl per well. The compound-treated Candida species and C. neoformans were incubated at 35°C for 48 hours and 72 hours, respectively, and then the MIC was determined by visual inspection of the bottom of the 96-well plate to determine whether the fungi had developed and grown. Amphotericin B (AMB), which is very toxic to humans although it is considered a typical antifungal agent, was used as a positive control. The results are shown in Tables 1-3 below.

Table 1 Receiving example (connection #) R1 R2 R3 X MIC (µg/ml) C.neoformans C. albicans C.glabrata A. fumigatus 24 (29) H H CH ₃ 3,4-Cl 2~8 4~16 4~16 4~16 25 (30) H H _{CH2CH3 ​} 3,4-Cl 2~8 4~16 4~16 4~16 26 (31) H H _{CH2CH2CH3 ​ ​} 3,4-Cl 0.5~4 0.5~4 0.5~4 0.5~4 27 (32) H H _{CH2CH3 ​} 4-OCF ₃ 2~8 4~16 4~16 4~16 28 (33) H CH ₃ CH ₃ 3,4-Cl 4~16 8~32 8~32 8~32 29 (34) H CH _{3 CH2CH3 ​} 3,4-Cl 2~8 4~16 8~32 8~32 30 (35) H CH _{3 CH2CH2CH3 ​ ​} 3,4-Cl 0.5~4 0.5~4 0.5~4 0.5~4 31 (36) CH ₃ CH _{3 CH2CH3 ​} 3,4-Cl 2~8 4~16 4~16 4~16

Table 2 Receiving example (connection #) R1 R2 R3 X MIC (µg/ml) C.neoformans C. albicans C.glabrata A. fumigatus 40 (45) H H _{CH2CH3 ​} 3,4-Cl 2~8 8~32 8~32 8~32 41 (46) H H _{CH2CH2CH3 ​ ​} 3,4-Cl 0.5~4 2~8 2~8 2~8 42 (47) H H _{CH2CH3 ​} 4-CF ₃ 4~16 8~32 8~32 8~32 43 (48) H H _{CH2CH2CH3 ​ ​} 4-CF ₃ 4~16 4~16 4~16 4~16 44 (49) H H _{CH2CH3 ​} 4-OCF ₃ 4~16 8~32 8~32 8~32 45 (50) H H _{CH2CH2CH3 ​ ​} 4-OCF ₃ 4~16 4~16 4~16 4~16 46 (51) H CH _{3 CH2CH3 ​} 3,4-Cl 2~8 4~16 4~16 4~16 47 (52) H CH _{3 CH2CH3 ​} 4-CF ₃ 4~16 8~32 8~32 8~32 48 (53) CH ₃ CH _{3 CH2CH3 ​} 3,4-Cl 2~8 8~32 8~32 8~32

Table 3 Receiving example (connection #) R1 R2 R3 X MIC (µg/ml) C.neoformans C. albicans C.glabrata A. fumigatus 68 (73) H H CH ₃ 3,4-Cl 2~8 8~32 8~32 8~32 69 (74) H H _{CH2CH3 ​} 3,4-Cl 0.5~4 0.5~4 0.5~4 0.5~4 70 (75) H H _{CH2CH2CH3 ​ ​} 3,4-Cl 0.5~4 0.5~4 0.5~4 0.5~4 71 (76) H H CH ₃ 4-CF ₃ 8~32 16~64 8~32 8~32 72 (77) H H _{CH2CH3 ​} 4-CF ₃ 4~16 8~32 8~32 8~32 73 (78) H H _{CH2CH2CH3 ​ ​} 4-CF ₃ 2~8 4~16 4~16 4~16 74 (79) H H CH ₃ 4-OCF ₃ 8~32 8~32 8~32 8~32 75 (80) H H _{CH2CH3 ​} 4-OCF ₃ 2~8 4~16 4~16 4~16 76 (81) H H _{CH2CH2CH3 ​ ​} 4-OCF ₃ 2~8 2~8 2~8 2~8 77 (82) H H _{CH2CH3 ​} 3,4-F 4~16 4~16 4~16 4~16 78 (83) H CH ₃ CH ₃ 3,4-Cl 2~8 8~32 8~32 8~32 79 (84) H CH _{3 CH2CH3 ​} 3,4-Cl 2~8 4~1 4~1 4~1 80 (85) H CH _{3 CH2CH2CH3 ​ ​} 3,4-Cl 0.5~4 0.5~4 0.5~4 0.5~4 81 (86) H CH ₃ CH ₃ 4-CF ₃ 8~32 16~64 16~64 16~64 82 (87) H CH _{3 CH2CH3 ​} 4-CF ₃ 4~16 4~16 4~16 4~16 83 (88) H CH _{3 CH2CH2CH3 ​ ​} 4-CF ₃ 2~8 4~16 4~16 4~16 84 (89) H CH ₃ CH ₃ 4-OCF ₃ 8~32 8~32 8~32 8~32 85 (90) H CH _{3 CH2CH3 ​} 4-OCF ₃ 4~16 4~16 4~16 4~16 86 (91) H CH _{3 CH2CH2CH3 ​ ​} 4-OCF ₃ 2~8 4~16 4~16 4~16 87 (92) CH ₃ CH ₃ CH ₃ 3,4-Cl 4~16 8~32 8~32 8~32 ABM 0.25 0.25 0.5 1

Example 2: Analysis of antifungal activity of compound 74

To evaluate the antifungal activity of compound 74, the minimum inhibitory concentration (MIC) capable of inhibiting fungal growth was measured according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Fungal cells were spread on solid YPD medium (Sigma-Aldrich) and then aliquoted into wells of 96-well plates (2.5 x 10 ³ microconidia/mL for T. rubrum and T. mentagrophytes or 2.5 x 10 ³ CFU/mL for Candida albicans, Candida glabrata and Cryptococcus neoformans, at 195 μL per well). Serial dilutions of compound 74 were prepared in two-fold steps ranging from 128 to 0.5 μg/mL (128, 64, 32, 16, 8, 4, 2, 1, and 0.5 μg/mL). Five μL of each dilution of compound 74 was then added to the wells of a 96-well plate containing fungal cells to yield a final suspension of 200 μL per well. The compound-treated fungal cells were incubated at 35°C for 48 h ( Candida spp.) and 72 h ( Trichophyton spp. and C. neoformans) , respectively. After incubation, the MIC (μg/mL) was determined by visual inspection of the bottom of the 96-well plate to determine whether fungal growth had occurred. The results are presented in Table 4 below.

Table 4 Target mushroom MIC (µg/ml) T. rubrum (KCCM60443) 1~4 T. rubrum (KCCM60450) 2~4 T. mentagrophytes (KCCM60449) 2~8 C. albicans ATCC90028 (WT), n=30 2~4 C. albicans 12-99 (mutant) 2~8 C. glabrata , n=30 2~4 C. tropicalis 2~4 C. neoformans , n=10 2~4 A. fumigatus 2~8

Example 3: Comparison of the speed of action of compound 74 with commercially available comparators

In order to evaluate the rapidity of action of compound 74, the growth of Candida albicans fungi was studied when treated with compound 74 or commercially available antifungal drugs such as efinaconazole, tavaborole, terbinafine and ciclopirox at the same concentration and for the same period of time. Specifically, Candida albicans cells were prepared at a concentration of 2.5 x 10 ³ CFU/mL, and 195 μL aliquots per well were transferred to 96-well plates. Then, the Candida albicans cells in the 96-well plate were treated with compound 74 or each of the commercially available comparative drugs (50 μg/mL or 100 μg/mL) for 30 minutes, respectively. Then, the fungal cells treated with compound 74 were plated on YPD medium (Sigma-Aldrich), and the number of grown single colonies was counted. The results are shown in Fig. 1. As can be seen from Fig. 1, it was confirmed that compound 74 has excellent rapidity of action compared with commercially available comparative drugs.

Example 4: Comparison of the fungicidal activity of compound 74 with commercially available comparators

To evaluate the fungicidal activity of compound 74, the growth was studiedT. rubrumafter treatment with compound 74 or commercially available antifungal drugs such as efinaconazole, amorolfine, terbinafine, ciclopirox and amphotericin B (at 0.5-, 1-, 2-, 4-, 8- or 16-fold the respective MIC values of compound 74 or other commercially available antifungal drugs) for a given time. In particular, cellsT. rubrum(6 x 10³CFU/mL) and aliquots of 195 μL per well were transferred to 96-well plates. Then, 5 μL of compound 74 or each of the other commercially available drugs was added to the wells of the 96-well plate containing cellsT. rubrum,to obtain a final volume of 200 μl per well. At 0, 2, 4, 6, 12, 24, 48, 72 or 120 hours after the addition, fungal cells treated with compound 74 or other antifungal drugs were spotted on the solid YPD medium, and the number of single colonies grown was then counted. The results are shown in Fig. 2. As follows from Fig. 2, compound 74 exhibits fungicidal activity at a concentration corresponding to the MIC, suggesting that compound 74 has fungicidal activity at a lower concentration than other commercially available comparative drugs.

Example 5: Comparison of the biofilm disruption activity of compound 74 with commercially available comparators

The biofilm disruption activity of compound 74 was studied. For this purpose, a biofilm of Candida albicans was formed. Then, compound 74 or a commercially available antifungal drug such as caspofungin, amphotericin B or efinaconazole was added to the resulting biofilm at respective concentrations of 4, 8, 16 and 32 μg/mL, and the biofilm disruption was evaluated. Specifically, Candida albicans cells (2.5 x 10 ³ CFU/L) were seeded in a 96-well plate and incubated for 90 minutes to form a biofilm, and then the biofilm was treated with compound 74 or each of the above comparative drugs, and then the growth of Candida albicans was evaluated 24 hours after the treatment. The results are shown in Fig. 3. As shown in Fig. 3, it was found that the compound 74 of the invention exhibits excellent effects in inhibiting the growth of Candida albicans by breaking down the biofilm, especially compared with the commercially available comparative drugs.

Example 6: Analysis of antibacterial activity

The compounds of the invention were also evaluated for antibacterial activity against Gram-positive bacteria, Gram-negative bacteria or multidrug-resistant bacteria. The MIC assay was performed according to CLSI guidelines. E. coli (-), P. aeruginosa (-) and S. enterica (-) were used as typical Gram-negative bacteria, B. cereus (+), B. subtilis (+), B. coagulans (+), L. monocytogenes (+), M. luteus (+), P. acnes (+), S. epidermidis (+) and S. aureus (+) were used as typical Gram-positive bacteria. Methicillin-resistant Staphylococcus aureus (MRSA) was used as a typical multidrug-resistant bacterium. Bacterial cells were incubated until the OD ₆₀₀ value of individual colonies reached 0.1. The cells, diluted 100-fold in liquid MHB medium (Sigma-Aldrich), were seeded in 96-well plates to obtain a suspension (100 μl per well) with a concentration corresponding to an OD ₆₀₀ value of 0.001. Then, the compounds of the invention were serially diluted in two-fold steps (64, 32, 16, 8, 4, 2, 1 and 0.5 μg/ml) and added to the wells to obtain a final suspension of 200 μl per well. Then, the bacterial cells were incubated at 37°C for 24 hours, and the MIC (μg/ml) was determined by visual inspection and determining the optical density at 600 nm (OD ₆₀₀ ). Nofloxacin and vancomycin were used as positive controls. The results are shown in Tables 5-8 below.

Table 5 Compound B. cereus(+) B. subtilis(+) B. coagulans(+) 74 16 8 2 84 32 16 8 51 32 16 4 75 16 8 2, 4 46 16 8 4 85 32 16 4 30 32 16 8 78 16 <4 <4 76 64 16 <4 81 16 4 <4 79 64 16 <4 31 <4 <4 <4 73 32 8 <4 86 64 32 <4 89 >64 16 <4 88 >64 32 <4 91 16 16 <4 29 8 <4 <4 33 16 8 <4 35 <4 <4 <4 34 8 <4 <4 Nofloxacin 1 <0.125 <0.125 Vancomycin 0.5 0.25 0.25

Table 6 Compound E. coli(-) S. aureus enterica(-) 74 32 >32 84 >32 >32 51 >32 >32 75 32 >32 46 32 32 85 >32 >32 30 >32 >32 78 8 16 76 16 32 81 8 16 79 16 32 31 <4 8 73 8 16 86 32 64 89 16 32 88 8 >64 91 8 16 29 8 8 33 8 16 35 <4 64 34 8 32 Nofloxacin <0.125 <0.125 Vancomycin 64 >64

Table 7 Compound L. monocytogenes(+) M. luteus(+) P. acnes(+) 74 8 8 8 84 16 16 16 51 16 16 16 75 8 8 8 46 8 8 8 85 16 8 16 30 16 8, 16 16 78 <4 8 >64 76 16 16 16 81 <4 <4 8 79 16 16 16 31 <4 <4 <4 73 8 8 8 86 16 16 16 89 16 16 16 88 <4 >64 <4 91 <4 <4 <4 29 <4 <4 <4 33 <4 <4 <4 35 >64 <4 <4 34 <4 <4 <4 Nofloxacin <0.125 <0.125 <0.125 Vancomycin 0.25 0.25 <0.125

Table 8 Compound S. epidermidis(+) S. aureus(+) MRSA 74 8 8 8 84 16 16 16 51 16 16 16 75 8 8 8 46 8 8 8 85 16 16 16 30 16 16 16 78 8 8 8 76 16 32 32 81 8 8 8 79 8 16 16 31 <4 <4 <4 73 8 8 8 86 16 32 32 89 16 32 32 88 8 8 8 91 <4 8 8 29 <4 <4 <4 33 <4 8 <4 35 <4 8 <4 34 <4 <4 <4 Nofloxacin 0.5 Vancomycin 1

Example 7: Analysis of anti-inflammatory activity

The anti-inflammatory effect of the compounds of the invention was evaluated using RAW264.7 cells stimulated to secrete interleukin 6 (IL-6). Specifically, RAW264.7 mouse macrophage cells (obtained from the Korean Cell Line Bank) were added to a 12-well plate at a concentration of 5 x 10 ⁵ cells per well, and then incubated at 37°C for 16-24 hours. The compounds of the invention were added to the cell culture medium containing RAW264.7 cells and incubated as above at a final concentration of 0 or 8 μg/ml, and then incubated at 37°C for 1 hour. Thereafter, lipopolysaccharide (LPS, Sigma-Aldrich, USA) was further added to the medium at a final concentration of 1 μg/ml, and the medium was incubated at 37°C for 24 hours to induce the expression of IL-6. Then, the levels of IL-6 produced by RAW264.7 cells were measured using an ELISA kit (Komabiotech Inc., Korea) according to the manufacturer's instructions. The results are shown in Table 9. In Table 9, the IL-6 levels are expressed as a relative percentage (%) between the levels of LPS-induced IL-6 after treatment with the compound of the invention and the levels of LPS-induced IL-6 without treatment with the compound of the invention.

Table 9 Connection No. Relative IL-6 levels
(%) 76 9.58 47 12 48 67 49 50 50 68 52 13 32 16 53 5 77 5 45 3 80 6 82 3 83 9 36 9 87 24

Industrial applicability

The present invention relates to a new compound and its use, and this compound can be used to prepare antifungal and antibacterial compositions, and can also be used to obtain a pharmaceutical composition for the prevention and treatment of fungal infectious diseases.

Claims (80)

1. A compound represented by the following chemical formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof: Formula 1 where n is 0, 1, 2, 3, 4, or 5, m is an integer from 1 to 5; R ₁ , R ₂ and R ₃ are independently the same or different from each other and are each independently selected from the group consisting of hydrogen and C _1-7 alkyl, and X represents m substituents, which are identical to or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group; provided that when n is 0 or 1 and R ₁ and R ₂ are hydrogen, R ₃ is C _1-3 alkyl; and when n is 0, R ₃ is not hydrogen. 2. A compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ and R ₂ independently of one another are H or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl, and R ₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. 3. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein X is any one or two identical or different substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl and trifluoromethoxy. 4. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, wherein X is p-fluoro, m-fluoro, p,m-difluoro, p-chloro, m-chloro, p,m-dichloro, p-trifluoromethyl or p-trifluoromethoxy. 5. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 3) 2-amino-N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)hexanamide; 5) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)butanamide; 6) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)pentanamide; 7) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(methylamino)hexanamide; 8) N-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)-2-(dimethylamino)pentanamide; 10) 2-amino-N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)hexanamide; 12) 2-amino-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)hexanamide; 14) 2-amino-N-((4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)methyl)hexanamide; 15) N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(methylamino)pentanamide; 16) 2-(methylamino)-N-((4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)methyl)pentanamide; 17) N-((3’,4’-dichloro-[1,1’-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide; 18) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)butanamide; 19) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 20) 2-amino-N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)hexanamide; 21) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide; 22) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 23) 2-amino-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide; 24) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide; 25) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 26) 2-amino-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide; 27) 2-amino-N-(2-(3’,4’-difluoro-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 28) N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(methylamino)butanamide; 29) N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)pentanamide; 30) N-(2-(3’,4’-dichloro-[1,1’-biphenyl]-4-yl)ethyl)-2-(methylamino)hexanamide; 31) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)butanamide; 32) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 33) 2-(methylamino)-N-(2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)ethyl)hexanamide; 34) 2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)butanamide; 35) 2-(methylamino)-N-(2-(4’-(trifluoromethoxy)-[1,1’-biphenyl]-4-yl)ethyl)pentanamide; 36) 2-(methylamino)-N-(2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ethyl)hexanamide or 37) N-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide. 6. A method for producing a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5, comprising a first step of forming a peptide bond by reacting an aminoalkanoic acid derivative protected by a butoxycarbonyl (Boc) protecting group, which is represented by formula 2, with a biphenyl derivative containing a primary amino group, represented by formula 3; and the second stage of removing the Boc protecting group by reacting the compound obtained in the first stage with an acid: Formula 1 Formula 2 Formula 3 where n is 0, 1, 2, 3, 4, or 5, m is an integer from 1 to 5; R ₁ , R ₂ and R ₃ are independently the same or different from each other and are each independently selected from the group consisting of hydrogen and C _1-7 alkyl, and X represents m substituents, which are identical to or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group. 7. The method according to claim 6, wherein the aminoalkanoic acid derivative protected by a Boc-protecting group, which is represented by formula 2, is obtained by reacting the amino acid derivative represented by formula 4 with di-tert-butyl dicarbonate (Boc anhydride): Formula 4 where in the formula: R ₁ ' is hydrogen, and each R ₂ and R ₃ are independently the same or different from each other and are each independently selected from the group consisting of hydrogen and C _1-7 alkyl, wherein when R ₂ of the obtained compound of formula 2 is alkyl, then after the above-mentioned step of obtaining the compound of formula 2, a step of alkylation of the said compound is carried out by reacting the compound with a haloalkane in the presence of a base. 8. The method according to claim 6, wherein the biphenyl derivative compound containing a primary amine group, which is represented by formula 3, is obtained by reacting a C _0-2 alkylamine derivative in which a halophenyl group at one end is substituted, as represented by formula 5, with di-tert-butyl dicarbonate to introduce a Boc protecting group into the amino group, followed by reacting the obtained alkylamine derivative with a phenylboronic acid derivative represented by formula 6, and then reacting the reactants with an acid to remove the Boc protecting group: Formula 5 Formula 6 where in the formulas: X’ represents halogen and X represents m substituents, where m represents an integer from 1 to 5, which are the same as or different from each other, selected from the group consisting of a halogen group, a halogenated C _1-7 alkyl group and a halogenated C _1-7 alkoxy group. 9. The method according to claim 8, wherein the reaction with the phenylboronic acid derivative is carried out by means of a cross-coupling reaction in the presence of a base using a metal catalyst. 10. The method according to claim 6, wherein the first stage is carried out by means of an anhydride coupling reaction carried out in an organic solvent in the presence of N-methylmorpholine (NMM) and isobutyl chloroformate (IBCF). 11. The method of claim 6, further comprising after the second step a third step of alkylating the amine to obtain a compound represented by formula 1, in which R ₁ and R ₂ are both alkyl. 12. An antifungal composition comprising as an active ingredient a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient. 13. The antifungal composition of claim 12, wherein the antifungal composition has antifungal activity against Cryptococcus neoformans, Candida albicans, Candida glabrata or Aspergillus fumigatus . 14. A pharmaceutical composition for the treatment or prevention of a fungal infectious disease, containing as an active ingredient a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient. 15. The pharmaceutical composition according to claim 14, wherein the fungal infectious disease is caused by Cryptococcus neoformans, Candida albicans, Candida glabrata or Aspergillus fumigatus infections. 16. An antibacterial composition containing as an active ingredient a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient. 17. The antibacterial composition according to claim 16, wherein the antibacterial composition has antibacterial activity against gram-negative bacteria, gram-positive bacteria or multidrug-resistant bacteria. 18. A pharmaceutical composition for the treatment or prevention of a bacterial infectious disease, containing as an active ingredient a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient. 19. A pharmaceutical composition for the treatment or prevention of an inflammatory disease, comprising a compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient.

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