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METHOD FOR PREPARING AMINOALKANOIC ACID DERIVATIVE CONTAINING BIPHENYL GROUP

20230056812 · 2023-02-23

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a derivative compound in which a biphenyl group is introduced into an aminoalkanoic acid, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound of the present invention exhibits excellent antifungal and fungicidal effects. Furthermore, the compound of the present invention exhibits a synergistic effect when used in combination with a conventional antifungal agent. Furthermore, the compound of the present invention provides broad-spectrum antifungal activity against a wide range of fungal pathogens. Therefore, the compound of the present invention may be widely used in fields requiring treatment with antifungal or fungicidal agents against human pathogenic fungi and animal pathogenic fungi, and phytopathogenic fungi.

    Claims

    1. A method for preparing the compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, the method comprising a first step of forming a peptide bond by reacting an aminoalkanoic acid derivative compound protected by a butoxycarbonyl (Boc) protecting group, which is represented by the following Formula 2, with a biphenyl derivative compound containing a primary amine group, which is 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: ##STR00028## in the formulae, n is 0, 1, 2, 3, 4 or 5, R.sub.1, R.sub.2 and R.sub.3 are each independently the same as or different from each other, and are each independently selected from hydrogen, a C.sub.1-7 alkyl, hydroxyl, a halogen, a halogenated C.sub.1-7 alkyl, a C.sub.1-7 alkyloxy and a halogenated C.sub.1-7 alkyloxy, and X is m substituents (m is 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.sub.1-7 alkyl group and a halogenated C.sub.1-7 alkoxy group.

    2. The method of claim 1, wherein the aminoalkanoic acid derivative compound protected by the Boc protecting group, which is represented by Formula 2 is prepared by reacting an amino acid derivative represented by the following Formula 4 with di-tert-butyl dicarbonate (Boc anhydride): ##STR00029## in the formula, R.sub.1′, R.sub.2 and R.sub.3 are each independently the same as or different from each other, and are each independently selected from hydrogen, a C.sub.1-7 alkyl, hydroxyl, a halogen, a halogenated C.sub.1-7 alkyl, a C.sub.1-7 alkyloxy and a halogenated C.sub.1-7 alkyloxy.

    3. The method of claim 2, wherein when R.sub.2 of the finally prepared compound is an alkyl, a step of alkylating the compound by reacting the compound with a haloalkane in the presence of a base after the above reaction is further performed.

    4. The method of claim 1, wherein a biphenyl derivative compound comprising a primary amine group, which is represented by Formula 3 is prepared by reacting a C.sub.0-2 alkylamine derivative in which a halophenyl group at one end is substituted, which is represented by the following Formula 5, with di-tert-butyl dicarbonate to introduce a Boc protecting group into an amine group, then reacting the resulting alkylamine derivative with a phenylboronic acid derivative represented by the following Formula 6, and then reacting the reactants with an acid to remove the Boc protecting group: ##STR00030## in the formulae, X′ is a halogen, and X is m substituents (m is 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.sub.1-7 alkyl group and a halogenated C.sub.1-7 alkoxy group.

    5. The method of claim 4, wherein the reaction with the phenylboronic acid derivative is achieved by a cross-coupling reaction using a metal catalyst in the presence of a base.

    6. The method of claim 1, wherein the first step is achieved by an anhydride coupling reaction performed in an organic solvent in the presence of N-methylmorpholine (NMM) and isobutyl chloroformate (IBCF).

    7. The method of claim 1, further comprising a third step of forming a secondary amine by alkylating amine after the second step when both R.sub.1 and R.sub.2 of the compound finally prepared are an alkyl.

    Description

    BRIEF DESCRIPTION OF DRAWINGS

    [0108] FIG. 1 compares the antifungal activity of Compound 74 of the present invention with those of commercially available comparative drugs.

    [0109] FIG. 2 compares the fungicidal activity of Compound 74 of the present invention with those of commercially available comparative drugs.

    [0110] FIG. 3 compares the effect of removing a biofilm of Compound 74 of the present invention with those of commercially available comparative drugs.

    DETAILED DESCRIPTION

    [0111] Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for exemplifying the present invention, and the scope of the present invention is not limited thereto.

    [0112] First, reactions used in the synthesis of the compound of the present invention were generalized and summarized as follows.

    [0113] Reaction Scheme a—Introduction of Boc Protecting Group

    ##STR00008##

    [0114] Norleucine (1.0 eq), Boc anhydride (1.5 eq), and sodium bicarbonate (1.5 eq) were dissolved in a 1:1 mixed solvent of distilled water and methanol and reacted at room temperature for 36 to 48 hours. After the mixture was concentrated in a vacuum state, the pH of an aqueous layer was adjusted to 2 with 1.0 M hydrochloric acid. Then, the moisture of an organic layer obtained by extraction with ethyl acetate was removed with sodium sulfate, and the solvent was evaporated in vacuum to obtain the title compound.

    [0115] Reaction Scheme b—Methylation of Amine Group

    ##STR00009##

    [0116] The compound (1.0 eq) obtained from Reaction Scheme a and iodomethane (10 eq) were dissolved in a tetrahydrofuran solvent, and sodium hydride (10 eq) was very slowly added dropwise thereto at 0° C. The reactants were reacted at room temperature for 24 hours. After the reaction was completed, the resulting product was diluted with an ether solvent, and distilled water was added thereto. The pH of an aqueous layer was adjusted to 2 with a 20% citric acid solution. Then, the moisture of an organic layer obtained by extraction with ethyl acetate was removed with sodium sulfate, and the solvent was evaporated in vacuum. The obtained residue was separated and purified by chromatography using silica gel to obtain the title compound.

    [0117] Reaction Scheme C—Introduction of Boc Protecting Group on Primary Amine Group

    ##STR00010##

    [0118] After 4-bromophenetylamine (1.0 eq) was dissolved in a methylene chloride solvent, potassium carbonate (1.5 eq) and Boc anhydride (1.05 eq) were added thereto, and the resulting mixture was reacted at room temperature for about 12 to 18 hours. The reaction mixture was diluted with methylene chloride and washed twice with distilled water. The organic layer was dried with sodium sulfate and then concentrated in vacuum. The obtained residue was washed with hexane and then evaporated in a vacuum state to obtain the title compound.

    [0119] Reaction Scheme d—Synthesis of Biphenylamine Hydrochloride Derivative

    ##STR00011##

    [0120] The compound obtained from Reaction Scheme c, tert-butyl (4-bromobenzyl)carbamate or tert-butyl (4-bromophenyl)carbamate (1.0 eq), benzene boronic acid (1.5 eq), sodium carbonate (5.0 eq), and tetrakis(triphenylphosphine)palladium (0.04 eq) were dissolved in a 2:1 to 2.5:1 mixed solvent of degassed toluene and distilled water, and reacted under reflux at a temperature of 140° C. for 12 to 18 hours. After the reaction, the catalyst was removed by filtration through Celite, and the solvent was evaporated from the filtered organic layer in a vacuum state. The obtained residue was separated and purified by chromatography using silica gel. After the purified product was dissolved in an ethyl acetate solvent, the resulting solution was stirred at room temperature while adding 4.0 M hydrochloric acid (6.0 to 10.0 eq) thereto. The obtained white solid in the form of a salt was washed with ethyl acetate, and then completely dried in a vacuum state to obtain the title compound.

    [0121] Reaction Scheme e—Mixed Anhydride Coupling (MAC) Reaction

    ##STR00012##

    [0122] The compound synthesized according to Reaction Scheme a or the compound synthesized according to Reaction Scheme b (1.0 eq), and N-methylmorpholine (NMM, 2.5 to 2.8 eq) were put into a distilled tetrahydrofuran solvent and the resulting mixture was stirred for 15 minutes. Then isobutyl chloroformate (IBCF, 1.3 eq) was added thereto, and the resulting mixture was further stirred for 15 minutes, and then the compound (1.05 eq) obtained from Reaction Scheme d was added thereto. The reaction mixture was allowed to react at room temperature for about 3 to 5 hours. The mixture was filtered to evaporate the solvent in a vacuum state. The obtained residue was separated and purified by chromatography using silica gel to obtain the title compound.

    [0123] Reaction Scheme f—Removal of Boc Protecting Group

    ##STR00013##

    [0124] After the compound derivative (1.0 eq) obtained from Reaction Scheme e was dissolved in an ethyl acetate solvent, the resulting solution was stirred at room temperature while adding 4.0 M hydrochloric acid (6.0 to 10.0 eq) thereto. The obtained white solid in the form of a salt was washed with ethyl acetate, and then completely dried in a vacuum state to obtain the title compound.

    [0125] Reaction Scheme g—Dimethylation of Amine Group

    ##STR00014##

    The compound (1.0 eq) obtained from Reaction Scheme f was dissolved in methanol, triethylamine (6.0 eq) was added thereto, and then formaldehyde (37% by weight solution, 1.0 to 2.5 eq) and a 10% palladium catalyst (0.1 to 0.5 eq) were sequentially added thereto. The reactants were reacted at room temperature for 18 hours. After the reaction, the catalyst was removed by filtration through Celite, and the filtered organic layer was evaporated in a vacuum state to obtain a white solid. The resulting product was recrystallized with methanol and diethyl ether to obtain the title compound.

    ##STR00015##

    [0126] Preparation Examples for synthesizing the compound of the present invention are as follows.

    Preparation Examples

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

    [0127] ##STR00016##

    [0128] Compound 1 (2-aminobutanoic acid, 5.00 g, 48.5 mmol), Boc anhydride (19.9 mL, 72.7 mmol), and NaHCO.sub.3 (6.11 g, 72.7 mmol) were reacted using Reaction Scheme a to synthesize Compound 4, (R)/(S)-2-((tert-butoxycarbonyl)amino)butanoic acid (8.25 g, 83%) in the form of a white powder.

    [0129] R.sub.f=0.00 (DCM 9.5: Methanol 0.5 and few drops of acetic acid);

    [0130] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 12.40 (C(0)OH), 7.02 (d, J=7.9 Hz, Boc-NH), 3.69-3.82 (m, Chiral-H), 1.48-1.72 (m, CH.sub.2CH.sub.3), 1.38 (s, Boc), 0.87 (t, J=7.3 Hz, CH.sub.2CH.sub.3).

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

    [0131] ##STR00017##

    [0132] Compound 2 (2-aminopentanoic acid, 10.00 g, 25.6 mmol), Boc anhydride (35.1 mL, 128.0 mmol), and NaHCO.sub.3 (10.8 g, 128.0 mmol) were reacted using Reaction Scheme a to synthesize Compound 5, (R)/(S)-2-((tert-butoxycarbonyl)amino)pentanoic acid (13.40 g, 83%) in the form of a white powder.

    [0133] R.sub.f=0.85 (DCM 3: Methanol 17);

    [0134] .sup.1-H NMR(DMSO-d.sub.6, 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.sub.2CH.sub.2CH.sub.3), 1.20-1.38 (m, CH.sub.2CH.sub.2CH.sub.3, Boc), 0.85 (t, J=7.4 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0135] ##STR00018##

    [0136] Compound 3 (2-aminohexanoic acid, 5.00 g, 38.1 mmol), Boc anhydride (15.7 mL, 57.2 mmol), and NaHCO.sub.3 (4.80 g, 57.2 mmol) were reacted using Reaction Scheme a to synthesize Compound 6, (R)/(S)-2-((tert-butoxycarbonyl)amino)hexanoic acid (7.14 g, 81%) in the form of a white powder.

    [0137] R.sub.f=0.40 (DCM 9: Methanol 1);

    [0138] .sup.1-H NMR (CDCl.sub.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.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.47 (s, Boc), 1.31-1.38 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.93 (t, J=7.0 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0139] ##STR00019##

    [0140] Compound 4 (3.00 g, 14.8 mmol), CH.sub.3I (9.2 ml, 147.6 mmol), and NaH (3.54 g, 147.6 mmol) were reacted using Reaction Scheme b to synthesize Compound 7, (R)/(S)-2-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (2.84 g, 88%) in the form of a yellow oil.

    [0141] R.sub.f=0.45 (DCM 9: Methanol 1 and few drops of acetic acid);

    [0142] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 12.7 (C(P)OH), 4.14-4.43 (m, Chiral-H), 2.71 (s, NCH.sub.3), 1.50-1.73 (m, CH.sub.2CH.sub.3, Boc), 0.79-0.87 (m, CH.sub.2CH.sub.3).

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

    [0143] Compound 5 (1.50 g, 6.90 mmol), CH.sub.3I (4.3 ml, 69.0 mmol), and NaH (1.66 g, 69.0 mmol) were reacted using Reaction Scheme b to synthesize Compound 8, (R)/(S)-2-((tert-butoxycarbonyl)(methyl)amino)pentanoic acid (1.34 g, 83%) in the form of a yellow oil.

    [0144] R.sub.f=0.45 (DCM 9: Methanol 1 and few drops of acetic acid);

    [0145] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 12.7 (C(O)OH), 4.54-4.28 (m, Chiral-H), 2.70 (s, NCH.sub.3), 1.79-1.64 (m, CH.sub.2CH.sub.2CH.sub.3), 1.41-1.37 (m, CH.sub.2CH.sub.2CH.sub.3, Boc), 1.37-1.29 (m, CH.sub.2CH.sub.2CH.sub.3).

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

    [0146] Compound 6 (3.00 g, 13.0 mmol), CH.sub.3I (8.1 ml, 129.7 mmol), and NaH (5.19 g, 129.7 mmol) were reacted using Reaction Scheme b to synthesize Compound 9, (R)/(S)-2-((tert-butoxycarbonyl)(methyl)amino)hexanoic acid (3.18 g, 100%) in the form of a yellow oil.

    [0147] R.sub.f=0.38 (DCM 9: Methanol 1);

    [0148] .sup.1H NMR (CDCl.sub.3, 400 MHz) 12.6 (C(O)OH), 4.25-4.52 (m, Chiral-H), 2.70 (s, NCH.sub.3), 1.66-1.79 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.18-1.40 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, Boc), 0.86-0.89 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0149] 4-bromophenethylamine (3.9 ml, 25.1 mmol), K.sub.2CO.sub.3 (5.21 g, 37.7 mmol), and Boc anhydride (7.2 ml, 26.4 mmol) were reacted using Reaction Scheme c to synthesize Compound 12, tert-butyl(4-bromophenethyl)carbamate (6.23 g, 83%) in the form of a white powder.

    [0150] R.sub.f=0.36 (EtOAc 1: n-hexane 5);

    [0151] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.64-2.67 (m, NHCH.sub.2CH.sub.2), 1.35 (s, Boc).

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

    [0152] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (7.80 g, 73.5 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0153] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0154] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.94 (s, NH.sub.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)

    [0155] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (7.77 g, 73.3 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0156] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0157] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.45 (bRs, NH.sub.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)methan-1-amine hydrochloride (15)

    [0158] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (111.1 g, 104.8 mmol) using Reaction Scheme d, a 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)methan-1-amine hydrochloride (1.08 g, 17%) in the form of a white powder.

    [0159] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0160] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.71 (s, NH.sub.3), 7.97 (s, ArH), 7.63-7.83 (m, ArH), 4.07 (s, NH.sub.3CH.sub.2).

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

    [0161] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (11.1 g, 104.8 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0162] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0163] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.49 (s, NH.sub.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.sub.3CH.sub.2).

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

    [0164] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (7.41 g, 69.9 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0165] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0166] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.33 (s, NH.sub.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.sub.3CH.sub.2).

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

    [0167] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (1.77 g, 16.7 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0168] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0169] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.33 (s, NH.sub.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.sub.3CH.sub.2CH.sub.2).

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

    [0170] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (0.88 g, 8.33 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0171] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0172] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.37 (s, NH.sub.3), 7.71-7.91 (m, ArH), 7.44 (d, J=8.1 Hz, ArH), 3.01-3.11 (m, NH.sub.3CH.sub.2CH.sub.2).

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

    [0173] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (2.65 g, 25.0 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0174] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0175] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.31 (s, NH.sub.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.sub.3CH.sub.2CH.sub.2).

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

    [0176] After a compound was obtained by reacting 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 Na.sub.2CO.sub.3 (1.77 g, 16.7 mmol) using Reaction Scheme d, a 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%) in the form of a white powder.

    [0177] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0178] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 7.95 (s, NH.sub.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.sub.3CH.sub.2CH.sub.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)

    [0179] 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 using 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%) in the form of a pale yellow powder.

    [0180] R.sub.f=0.33 (EtOAc 1: n-hexane 3);

    [0181] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.3), 1.47 (s, Boc), 1.03 (t, J=7.4 Hz, CH.sub.2CH.sub.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)

    [0182] 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 using 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%) in the form of a white powder.

    [0183] R.sub.f=0.37 (EtOAc 1: n-hexane 3);

    [0184] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2CH.sub.3), 1.47-1.50 (m, Boc, CH.sub.2CH.sub.2CH.sub.3), 0.99 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

    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)

    [0185] 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 using 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%) in the form of a white powder.

    [0186] R.sub.f=0.50 (EtOAc 1: n-hexane 3);

    [0187] .sup.1H NMR (DMSO-d.sub.6, 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.sub.2), 1.57-1.64 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (s, Boc), 1.26-1.32 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.86 (t, J=6.8 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.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)

    [0188] 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 using 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%) in the form of a white powder.

    [0189] R.sub.f=0.30 (EtOAc 1: n-hexane 3);

    [0190] .sup.1H NMR (CDCl.sub.3, 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, CH.sub.2CH.sub.2CH.sub.3), 1.43-1.56 (m, Boc, CH.sub.2CH.sub.2CH.sub.3), 0.99 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0191] 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 using 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)(methyl)carbamate (0.74 g, 54%) in the form of an oil.

    [0192] R.sub.f=0.50 (EtOAc 1: n-hexane 3);

    [0193] .sup.1H NMR (CDCl.sub.3, 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.sub.3), 1.71-2.04 (m, CH.sub.2CH.sub.3), 1.51 (d, J=6.8 Hz, Boc), 0.97 (t, J=7.3 Hz, CH.sub.2CH.sub.3).

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

    [0194] 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 using 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)(methyl)carbamate (0.79 g, 47%) in the form of a yellow powder.

    [0195] R.sub.f=0.48 (EtOAc 1: n-hexane 3);

    [0196] .sup.1H NMR (CDCl.sub.3, 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.sub.3), 1.67-2.04 (m, CH.sub.2CH.sub.2CH.sub.3), 1.51 (s, Boc), 1.33-1.39 (m, CH.sub.2CH.sub.2CH.sub.3), 0.99 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0197] Compound 9 (R)/(S)-2-((tert-butoxycarbonyl)(methyl)amino)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 using 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)(methyl)carbamate (0.86 g, 53%) in the form of an oil.

    [0198] R.sub.f=0.55 (EtOAc 1: n-hexane 3);

    [0199] .sup.1H NMR (CDCl.sub.3, 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.sub.3), 1.67-2.01 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.52 (s, Boc), 1.24-1.44 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.93 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0200] Compound 22 (1.06 g, 2.50 mmol) and 4.0 M HCl (3.80 ml, 15.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0201] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0202] .sup.1H NMR (CDCl.sub.3, 400 MHz) 11.05 (s, C(O)NH), 8.38 (s, NH.sub.3), 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.sub.2CH.sub.3), 0.96 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0203] Compound 23 (0.58 g, 1.33 mmol) and 4.0 M HCl (2.00 ml, 7.95 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0204] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0205] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.05 (s, C(O)NH), 8.40 (s, NH.sub.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.sub.2CH.sub.2CH.sub.3), 1.36-1.43 (m, CH.sub.2CH.sub.2CH.sub.3), 0.91 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0206] Compound 24 (1.10 g, 2.44 mmol) and 4.0 M HCl (3.66 ml, 14.6 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0207] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0208] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 10.97 (s, C(O)NH), 8.38 (s, NH.sub.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.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.33-1.39 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.87 (t, J=6.9 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0209] Compound 25 (0.64 g, 1.41 mmol) and 4.0 M HCl (2.12 ml, 8.46 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0210] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0211] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 10.90 (s, C(O)NH), 8.35 (s, NH.sub.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.sub.2CH.sub.2CH.sub.3), 1.34-1.47 (m, CH.sub.2CH.sub.2CH.sub.3), 0.92 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0212] Compound 26 (0.69 g, 1.58 mmol) and 4.0 M HCl (2.40 ml, 9.50 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0213] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0214] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 11.00 (s, C(O)NH), 9.13 (s, NH.sub.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.sub.3), 1.87-2.05 (m, CH.sub.2CH.sub.3), 0.94 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0215] Compound 27 (0.38 g, 0.83 mmol) and 4.0 M HCl (1.25 ml, 4.98 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0216] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0217] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 10.98 (s, C(O)NH), 9.09 (s, NH.sub.2), 7.94 (s, ArH), 7.66-7.76 (m, ArH), 3.96 (t, J=6.1 Hz, Chiral-H), 2.57 (s, NCH.sub.3), 1.80-1.93 (m, CH.sub.2CH.sub.2CH.sub.3), 1.31-1.39 (m, CH.sub.2CH.sub.2CH.sub.3), 0.91 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0218] Compound 28 (0.82 g, 1.77 mmol) and 4.0 M HCl (2.65 ml, 10.6 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0219] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0220] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 10.81 (s, C(O)NH), 9.05 (s, NH.sub.2), 7.94 (d, J=2.0 Hz, ArH), 7.66-7.77 (m, ArH), 3.92 (s, Chiral-H), 2.57 (s, NCH .sub.3), 1.87-1.99 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.29-1.33 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.86 (t, J=6.8 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

    ##STR00020##

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

    [0221] Compound 30 (1.0 eq), triethylamine (6.0 eq), formaldehyde (2.0 eq), and a palladium catalyst (0.4 eq) were reacted using Reaction Scheme g to synthesize Compound 36, (R)/(S)-N-(3 ‘,4’-dichloro-[1,1′-biphenyl]-4-yl)-2-(dimethylamino)pentanamide.

    [0222] .sup.1H NMR (DMSO-d.sub.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.sub.3)2), 1.80-1.93 (m, CH.sub.2CH.sub.2CH.sub.3), 1.31-1.39 (m, CH.sub.2CH.sub.2CH.sub.3), 0.91 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

    ##STR00021##

    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)

    [0223] 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 using 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%) in the form of a white powder.

    [0224] R.sub.f=0.04 (EtOAc 1: n-hexane 3);

    [0225] .sup.1H NMR (CDCl.sub.3, 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.sub.2), 4.07-4.09 (m, Chiral-H), 1.36-1.43 (m, CH.sub.2CH.sub.2CH.sub.3, Boc), 0.95 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.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)

    [0226] 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 using 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%) in the form of a white powder.

    [0227] R.sub.f=0.19 (EtOAc 1: n-hexane 3);

    [0228] .sup.1H NMR (CDCl.sub.3, 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 .sub.2), 4.07-4.11 (m, Chiral-H), 1.58-1.90 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.34 (d, J=2.2 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.88-0.94 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

    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)

    [0229] 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 using 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%) in the form of a white powder.

    [0230] R.sub.f=0.17 (EtOAc 1: n-hexane 3);

    [0231] .sup.1H NMR (CDCl.sub.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.sub.2), 4.11-4.15 (m, Chiral-H), 1.54-1.89 (m, CH.sub.2CH.sub.2CH.sub.3), 1.41 (s, Boc, CH.sub.2CH.sub.2CH.sub.3), 0.93 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.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)

    [0232] 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 using 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%) in the form of a white powder.

    [0233] R.sub.f=0.16 (EtOAc 1: n-hexane 3);

    [0234] .sup.1H NMR (CDCl.sub.3, 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.sub.2), 4.09-4.10 (m, Chiral-H), 1.59-1.94 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.45 (s, Boc), 1.37-1.38 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.93 (t, J=7.0 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

    [0235] 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)

    [0236] 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 using Reaction Scheme e to synthesize Compound 41, (R)/(S)-tert-butyl (1-oxo-1-(((4′-(trifluoromethoxy)-[1, -biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (1.05 g, 90%) in the form of a white powder.

    [0237] R.sub.f=0.09 (EtOAc 1: n-hexane 3);

    [0238] .sup.1H NMR (CDCl.sub.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.sub.2), 4.10-4.11 (m, Chiral-H), 1.59-1.94 (m, CH.sub.2CH.sub.2CH.sub.3), 1.37-1.45 (m, CH.sub.2CH.sub.2CH.sub.3, Boc), 0.97 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.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)

    [0239] 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 using 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%) in the form of a white powder.

    [0240] R.sub.f=0.18 (EtOAc 1: n-hexane 3);

    [0241] .sup.1H NMR (CDCl.sub.3, 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.sub.2), 4.09-4.11 (m, Chiral-H), 1.62-1.94 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.45 (s, Boc), 1.36-1.37 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.92 (t, J=6.9 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.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)(methyl)carbamate (43)

    [0242] 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 using 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)(methyl)carbamate (0.57 g, 73%) in the form of an oil.

    [0243] R.sub.f=0.18 (EtOAc 1: n-hexane 3);

    [0244] .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.30-7.68 (m, ArH), 6.27-6.64 (m, C(O)NH), 4.41-4.59 (m, NHCH.sub.2, Chiral-H), 2.78 (s, NCH.sub.3), 2.04-1.63 (m, CH.sub.2CH.sub.2CH.sub.3), 1.44 (s, Boc), 1.32-1.26 (m, CH.sub.2CH.sub.2CH.sub.3), 0.96 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0245] 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 using Reaction Scheme e to synthesize Compound 44, (R)/(S)-tert-butyl methyl (1-oxo-1-(((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)amino)pentan-2-yl)carbamate (0.49 g, 64%) in the form of an oil.

    [0246] R.sub.f=0.22 (EtOAc 1: n-hexane 3);

    [0247] .sup.1H NMR (CDCl.sub.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.sub.2, Chiral-H), 2.78 (s, NCH.sub.3), 1.63-2.04 (m, CH.sub.2CH.sub.2CH.sub.3), 1.44 (s, Boc), 1.26-1.35 (m, CH.sub.2CH.sub.2CH.sub.3), 0.96 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0248] Compound 37 (1.19 g, 2.64 mmol) and 4.0 M HCl (3.95 ml, 15.8 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0249] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0250] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.04 (s, C(O)NH), 8.21 (s, NH.sub.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.sub.2), 3.78-3.82 (t, J=6.3 Hz, Chiral-H), 1.68-1.76 (m, CH.sub.2CH.sub.2CH.sub.3), 1.29-1.39 (m, CH.sub.2CH.sub.2CH.sub.3), 0.89 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0251] Compound 38 (0.46 g, 0.99 mmol) and 4.0 M HCl (1.48 ml, 1.48 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0252] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0253] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.17 (m, C(O)NH), 8.32 (s, NH.sub.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.sub.2), 3.81 (t, J=6.1 Hz, Chiral-H), 1.75-1.76 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.27-1.28 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.85 (t, J=6.6 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0254] Compound 39 (0.70 g, 1.55 mmol) and 4.0 M HCl (2.33 ml, 9.32 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0255] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0256] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.37 (t, J=5.7 Hz, C(O)NH), 8.46 (s, NH.sub.3), 7.71-7.92 (m, ArH), 7.45-7.51 (m, ArH), 4.40-4.43 (m, NHCH.sub.2), 3.89 (s, Chiral-H), 1.74-1.82 (m, CH.sub.2CH.sub.2CH.sub.3), 1.16-1.42 (m, CH.sub.2CH.sub.2CH.sub.3), 0.89 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0257] Compound 40 (0.85 g, 1.83 mmol) and 4.0 M HCl (2.75 ml, 11.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0258] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0259] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.09 (s, C(O)NH), 8.23 (s, NH.sub.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.sub.2), 3.80 (t, J=6.4 Hz, Chiral-H), 1.74-1.76 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.27-1.29 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.85 (t, J=6.5 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0260] Compound 41 (1.04 g, 2.22 mmol) and 4.0 M HCl (3.34 ml, 13.3 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0261] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0262] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.14 (t, J=5.7 Hz, C(O)NH), 8.30 (s, NH.sub.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.sub.2), 3.82 (t, J=6.5 Hz, Chiral-H), 1.71-1.76 (m, CH.sub.2CH.sub.2CH.sub.3), 1.28-1.38 (m, CH.sub.2CH.sub.2CH.sub.3), 0.89 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0263] Compound 42 (1.04 g, 2.17 mmol) and 4.0 M HCl (3.26 ml, 13.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0264] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0265] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.09 (t, J=5.8 Hz, C(O)NH), 8.25 (s, NH .sub.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.sub.2), 3.80 (t, J=6.4 Hz, Chiral-H), 1.72-1.75 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.27-1.28 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.85 (t, J=6.5 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0266] Compound 43 (0.84 g, 1.81 mmol) and 4.0 M HCl (2.80 ml, 10.9 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0267] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0268] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.10-9.78 (m, NH.sub.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.sub.2), 3.85-3.90 (m, Chiral-H), 2.48 (s, NCH.sub.3), 1.76-1.90 (m, CH.sub.2CH.sub.2CH.sub.3), 1.26-1.38 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0269] Compound 44 (0.45 g, 0.97 mmol) and 4.0 M HCl (1.45 ml, 5.81 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0270] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0271] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.03-9.81 (m, NH .sub.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 .sub.2), 3.86 (s, Chiral-H), 2.48 (s, NCH.sub.3), 1.77-1.89 (m, CH.sub.2CH.sub.2CH.sub.3), 1.25-1.38 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

    ##STR00022##

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

    [0272] Compound 45 (1.0 eq), triethylamine (6.0 eq), formaldehyde (1.05 eq), and a palladium catalyst (0.2 eq) were reacted using Reaction Scheme g to synthesize Compound 53, (R)/(S)-N-((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide.

    [0273] .sup.1H NMR (DMSO-d.sub.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.sub.2), 3.85-3.90 (m, Chiral-H), 2.48 (s, N(CH.sub.3)2), 1.76-1.90 (m, CH.sub.2CH.sub.2CH.sub.3), 1.26-1.38 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

    ##STR00023##

    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)

    [0274] 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 using 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%) in the form of a white powder.

    [0275] R.sub.f=0.05 (EtOAc 1: n-hexane 3);

    [0276] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.86 (t, J=6.9 Hz, NHCH.sub.2CH.sub.2), 1.55-2.88 (m, CH.sub.2CH.sub.3), 1.43 (s, Boc), 0.91 (t, J=7.4 Hz, CH.sub.2CH.sub.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)

    [0277] 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 using 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%) in the form of a white powder.

    [0278] R.sub.f=0.26 (EtOAc 1: n-hexane 3);

    [0279] .sup.1H NMR (CDCl.sub.3, 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.sub.2CH.sub.2), 2.85 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 2.67 (s, NCH.sub.3), 1.48-1.80 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.26-1.36 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.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)

    [0280] 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 using 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%) in the form of a white powder.

    [0281] R.sub.f=0.07 (EtOAc 1: n-hexane 3);

    [0282] .sup.1H NMR (CDCl.sub.3, 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.sub.2CH.sub.2), 2.86 (t, J=6.1 Hz, NHCH.sub.2CH.sub.2), 1.51-1.81 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.27 (d, J=6.7 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.87 (d, J=5.5 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

    [0283] 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)

    [0284] 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 using 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%) in the form of a white powder.

    [0285] R.sub.f=0.16 (EtOAc 1: n-hexane 3);

    [0286] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.90 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.58-1.90 (m, CH.sub.2CH.sub.3), 1.45 (s, Boc), 0.93 (t, J=7.5 Hz, CH.sub.2CH.sub.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)

    [0287] 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 using 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%) in the form of a white powder.

    [0288] R.sub.f=0.20 (EtOAc 1: n-hexane 3);

    [0289] .sup.1H NMR (CDCl.sub.3, 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.sub.2CH.sub.2), 2.87 (t, J=7.1 Hz, NHCH.sub.2CH.sub.2), 1.50-1.83 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.28-1.39 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

    [0290] Preparation Example 54: Preparation of (R)/(S)-tert-butyl (1-oxo-1-((2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)carbamate (59)

    [0291] 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 using 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%) in the form of a white powder.

    [0292] R.sub.f=0.13 (EtOAc 1: n-hexane 3);

    [0293] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.77 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.37-1.52 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, Boc), 1.15-1.20 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=6.8 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.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)

    [0294] 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 using 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%) in the form of a white powder.

    [0295] R.sub.f=0.14 (EtOAc 1: n-hexane 3);

    [0296] .sup.1H NMR (CDCl.sub.3, 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.sub.2CH.sub.2), 2.87-2.92 (m, NHCH.sub.2CH.sub.2), 1.56-1.92 (m, CH.sub.2CH.sub.3), 1.45 (s, Boc), 0.93 (t, J=7.4 Hz, CH.sub.2CH.sub.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)

    [0297] 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 using 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%) in the form of a white powder.

    [0298] R.sub.f=0.12 (EtOAc 1: n-hexane 3);

    [0299] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.76 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.37-1.52 (m, CH.sub.2CH.sub.2CH.sub.3, Boc), 1.17-1.25 (m, CH.sub.2CH.sub.2CH.sub.3), 0.81 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.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)

    [0300] 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 using 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%) in the form of a white powder.

    [0301] R.sub.f=0.13 (EtOAc 1: n-hexane 3);

    [0302] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.90 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.52-1.85 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.45 (s, Boc), 1.31-1.34 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=6.9 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.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)

    [0303] 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 using 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%) in the form of a white powder.

    [0304] R.sub.f=0.10 (EtOAc 1: n-hexane 3);

    [0305] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.85 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.48-1.82 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.26-1.36 (m, CH.sub.2CH.sub.2CH.sub.3), 0.90 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

    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)(methyl)carbamate (64)

    [0306] 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 using 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)(methyl)carbamate (1.38 g, 79%) in the form of an oil.

    [0307] R.sub.f=0.22 (EtOAc 1: n-hexane 3);

    [0308] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.87 (t, J=6.7 Hz, NHCH.sub.2CH.sub.2), 2.70 (s, NCH .sub.3), 1.61-1.98 (m, CH.sub.2CH.sub.3), 1.45 (s, Boc), 0.88 (t, J=7.4 Hz, CH.sub.2CH.sub.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)(methyl)carbamate (65)

    [0309] 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 using 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)(methyl)carbamate (0.69 g, 95%) in the form of an oil.

    [0310] R.sub.f=0.33 (EtOAc 1: n-hexane 3);

    [0311] .sup.1H NMR (CDCl.sub.3, 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.sub.2CH.sub.2), 2.84 (t, J=6.6 Hz, NHCH.sub.2CH.sub.2), 2.67 (s, NCH.sub.3), 1.57-1.90 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.22-1.32 (m, CH.sub.2CH.sub.2CH.sub.3), 0.95 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.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)(methyl)carbamate (66)

    [0312] 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 using 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)(methyl)carbamate (0.60 g, 97%) in the form of an oil.

    [0313] R.sub.f=0.30 (EtOAc 1: n-hexane 3);

    [0314] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.77 (t, J=6.5 Hz, NHCH.sub.2CH.sub.2), 2.67 (s, NCH.sub.3), 1.53-1.71 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (s, Boc), 1.12-1.28 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.84 (s, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0315] 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 using Reaction Scheme e to synthesize Compound 67, (R)/(S)-tert-butyl methyl(1-oxo-1-((2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (0.89 g, 67%) in the form of a white powder.

    [0316] R.sub.f=0.15 (EtOAc 1: n-hexane 3);

    [0317] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.89 (d, J=6.1 Hz, NHCH.sub.2CH.sub.2), 2.70 (s, NCH.sub.3), 1.61-1.99 (m, CH.sub.2CH.sub.3), 1.45 (s, Boc), 0.89 (t, J=7.3 Hz, CH.sub.2CH.sub.3).

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

    [0318] 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 using Reaction Scheme e to synthesize Compound 68, (R)/(S)-tert-butyl methyl (1-oxo-1((2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (1.19 g, 98%) in the form of an oil.

    [0319] R.sub.f=0.26 (EtOAc 1: n-hexane 3);

    [0320] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.86 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.67 (s, NCH.sub.3), 1.55-1.91 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 (s, Boc), 1.23-1.27 (m, CH.sub.2CH.sub.2CH.sub.3), 0.88-0.95 (m, CH.sub.2CH.sub.2CH.sub.3).

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

    [0321] 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 using Reaction Scheme e to synthesize Compound 69, (R)/(S)-tert-butyl methyl(1-oxo-1-((2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (0.88 g, 63%) in the form of a yellow powder.

    [0322] R.sub.f=0.32 (EtOAc 1: n-hexane 3);

    [0323] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.78 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.66 (s, NCH.sub.3), 1.53-1.71 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (s, Boc), 1.12-1.28 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.84-0.89 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0324] 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 using Reaction Scheme e to synthesize Compound 70, (R)/(S)-tert-butyl methyl (1-oxo-1-((2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)amino)butan-2-yl)carbamate (1.00 g, 69%) in the form of an oil.

    [0325] R.sub.f=0.19 (EtOAc 1: n-hexane 3);

    [0326] .sup.1H NMR (CDCl.sub.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.sub.2CH.sub.2), 2.87 (s, NHCH.sub.2CH.sub.2), 2.70 (d, J=3.2 Hz, NCH.sub.3), 1.62-2.07 (m, CH.sub.2CH.sub.3), 1.45 (s, Boc), 0.90 (m, CH.sub.2CH.sub.3).

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

    [0327] 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 using Reaction Scheme e to synthesize Compound 71, (R)/(S)-tert-butyl methyl(1-oxo-1-((2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)amino)pentan-2-yl)carbamate (0.32 g, 60%) in the form of a white powder.

    [0328] R.sub.f=0.18 (EtOAc 1: n-hexane 3);

    [0329] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.77 (s, NHCH.sub.2CH.sub.2), 2.66 (s, NCH.sub.3), 1.53-1.90 (m, CH.sub.2CH.sub.2CH.sub.3), 1.39 (s, Boc), 1.16-1.23 (m, CH.sub.2CH.sub.2CH.sub.3), 0.88-0.89 (m, CH.sub.2CH.sub.2CH.sub.3)

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

    [0330] 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 using Reaction Scheme e to synthesize Compound 72, (R)/(S)-tert-butyl methyl(1-oxo-1-((2-(4′-(trifluoromethoxy)-[1,1′ -biphenyl]-4-yl)ethyl)amino)hexan-2-yl)carbamate (0.92 g, 60%) in the form of an oil.

    [0331] R.sub.f=0.29 (EtOAc 1: n-hexane 3);

    [0332] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.77 (t, J=6.7 Hz, NHCH.sub.2CH.sub.2), 2.66 (s, NCH.sub.3), 1.53-1.72 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 (s, Boc), 1.12-1.29 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.84-0.90 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0333] Compound 54 (0.66 g, 1.47 mmol) and 4.0 M HCl (2.20 ml, 8.81 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0334] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0335] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.66 (t, J=5.3 Hz, C(O)NH), 8.23 (s, NH.sub.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.sub.2CH.sub.2), 2.79-2.83 (m, NHCH.sub.2CH.sub.2), 1.67-1.74 (m, CH.sub.2CH.sub.3), 0.79 (t, J=7.4 Hz, CH.sub.2CH.sub.3).

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

    [0336] Compound 55 (0.95 g, 2.04 mmol) and 4.0 M HCl (3.06 ml, 12.2 mmol in dioxane) were reacted using 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%) in the form of a yellow powder.

    [0337] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0338] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.82 (t, J=5.3 Hz, C(0)NH), 8.34 (s, NH.sub.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.sub.2CH.sub.2), 2.82-2.85 (m, NHCH.sub.2CH.sub.2), 1.60-1.67 (m, CH.sub.2CH.sub.2CH.sub.3), 1.14-1.22 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0339] Compound 56 (0.75 g, 1.56 mmol) and 4.0 M HCl (2.35 ml, 9.39 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0340] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0341] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.60 (t, J=5.5 Hz, C(O)NH), 8.18 (s, NH .sub.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.sub.2CH.sub.2), 2.81-2.85 (m, NHCH.sub.2CH.sub.2), 1.59-1.64 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.14-1.23 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.79 (t, J=6.8 Hz, CH.sub.2CH.sub.2CH.sub.2CH .sub.3).

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

    [0342] Compound 57 (0.90 g, 2.00 mmol) and 4.0 M HCl (3.00 ml, 12.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0343] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0344] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.62 (s, C(O)NH), 8.17 (s, NH .sub.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.sub.2CH.sub.2), 2.82 (t, J=7.0 Hz, NHCH.sub.2CH.sub.2), 1.67-1.74 (m, CH.sub.2CH.sub.3), 0.79 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0345] Compound 58 (1.03 g, 2.22 mmol) and 4.0 M HCl (5.56 ml, 22.2 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0346] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0347] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 8.81 (t, J=5.3 Hz, C(O)NH), 8.35 (s, NH.sub.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, NH2CH.sub.2CH.sub.2), 2.85 (t, J=6.3 Hz, NHCH.sub.2CH.sub.2), 1.61-1.68 (m, CH.sub.2CH.sub.2CH.sub.3), 1.15-1.22 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0348] Compound 59 (1.32 g, 2.76 mmol) and 4.0 M HCl (4.14 ml, 16.6 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0349] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0350] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.69 (t, J=4.9 Hz, C(O)NH), 8.26 (s, NH.sub.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.sub.2CH.sub.2), 2.80-2.89 (m, NHCH.sub.2CH.sub.2), 1.61-1.67 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.14-1.23 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.79 (t, J=6.8 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0351] Compound 60 (0.91 g, 1.95 mmol) and 4.0 M HCl (2.92 ml, 11.7 mmol in dioxane) were reacted using 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%) in the form of a yellow powder.

    [0352] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0353] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.67 (s, C(0)NH), 8.24 (s, NH .sub.3), 7.35-7.89 (m, ArH), 3.67 (d, J=4.3 Hz, Chiral-H), 3.30-3.55 (m, NHCH.sub.2CH.sub.2), 2.80-2.85 (m, NHCH.sub.2CH.sub.2), 1.68-1.75 (m, CH.sub.2CH.sub.3), 0.80 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0354] Compound 61 (0.70 g, 1.45 mmol) and 4.0 M HCl (2.18 ml, 8.70 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0355] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0356] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.71 (t, J=5.4 Hz, C(O)NH), 8.28 (s, NH .sub.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.sub.2CH.sub.2), 2.80-2.86 (m, NHCH.sub.2CH.sub.2), 1.61-1.65 (m, CH.sub.2CH.sub.2CH.sub.3), 1.13-1.24 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.4 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0357] Compound 62 (0.79 g, 1.59 mmol) and 4.0 M HCl (2.38 ml, 9.54 mmol in dioxane) were reacted using Reaction Scheme f to synthesize Compound 81, (R)/(S)-2-amino-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethy)phexanamide hydrochloride (0.62 g, 91%) in the form of a white powder.

    [0358] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0359] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.66 (t, J=5.4 Hz, C(O)NH), 8.23 (s, NH.sub.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.sub.2CH.sub.2), 2.81-2.87 (m, NHCH.sub.2CH.sub.2), 1.60-1.66 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.23 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.79 (t, J=7.0 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0360] Compound 62 (0.94 g, 2.17 mmol) and 4.0 M HCl (3.26 ml, 13.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0361] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0362] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.55 (s, C(O)NH), 8.10 (s, NH.sub.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.sub.2CH.sub.2), 2.78-2.84 (m, NHCH.sub.2CH.sub.2), 1.58 (q, J=6.9 Hz, 8.8 Hz, CH.sub.2CH.sub.2CH.sub.3), 1.14-1.20 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.3 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0363] Compound 64 (1.31 g, 2.81 mmol) and 4.0 M HCl (4.20 ml, 16.9 mmol in dioxane) were reacted using 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%) in the form of a yellow powder.

    [0364] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0365] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.79 (s, C(O)NH, NH.sub.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.sub.2CH.sub.2), 2.83 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.38 (t, J=6.1 Hz, NCH.sub.3), 1.68-1.80 (m, CH.sub.2CH.sub.3), 0.77 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0366] Compound 65 (0.65 g, 1.36 mmol) and 4.0 M HCl (2.03 ml, 8.13 mmol in dioxane) were reacted using 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%) in the form of a yellow powder.

    [0367] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0368] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.26 (s, NH.sub.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.sub.2CH.sub.2), 2.84 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.35 (s, NCH.sub.3), 1.60-1.77 (m, CH.sub.2CH.sub.2CH.sub.3), 1.09-1.16 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0369] Compound 66 (0.57 g, 1.16 mmol) and 4.0 M HCl (1.74 ml, 6.95 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0370] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0371] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.70-9.36 (s, NH.sub.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.sub.2CH.sub.2), 2.83 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.35 (s, NCH.sub.3), 1.60-1.76 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.05-1.23 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.78 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0372] Compound 67 (0.86 g, 1.84 mmol) and 4.0 M HCl (2.77 ml, 11.1 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0373] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0374] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.04 (s, NH.sub.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.sub.2CH.sub.2), 2.84 (t, J=6.9 Hz, NHCH.sub.2CH.sub.2), 2.37 (s, NCH.sub.3), 1.67-1.85 (m, CH.sub.2CH.sub.3), 0.77 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0375] Compound 68 (1.17 g, 2.45 mmol) and 4.0 M HCl (3.67 ml, 14.7 mmol in dioxane) were reacted using Reaction Scheme f to synthesize Compound 87, (R)/(S)-2-(methylamino)-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)pentanamide hydrochloride (81%) in the form of a white powder.

    [0376] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0377] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.93-9.79 (m, NH.sub.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.sub.2CH.sub.2), 2.87 (t, J=6.7 Hz, NHCH.sub.2CH.sub.2), 2.36 (s, NCH.sub.3), 1.64-1.82 (m, CH.sub.2CH.sub.2CH.sub.3), 1.09-1.22 (m, CH.sub.2CH.sub.2CH.sub.3), 0.81 (t, J=7.1 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0378] Compound 69 (0.85 g, 1.72 mmol) and 4.0 M HCl (2.60 ml, 10.3 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0379] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0380] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.00 (s, NH.sub.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.sub.2CH.sub.2), 2.84 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.36 (s, NCH.sub.3), 1.60-1.75 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.06-1.24 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.78 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

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

    [0381] Compound 70 (0.97 g, 2.01 mmol) and 4.0 M HCl (3.00 ml, 12.1 mmol in dioxane) were reacted using 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%) in the form of a yellow powder.

    [0382] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0383] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.00 (s, NH.sub.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.sub.2CH.sub.2), 2.82 (t, J=6.9 Hz, NHCH.sub.2CH.sub.2), 2.37 (s, NCH.sub.3), 1.67-1.83 (m, CH.sub.2CH.sub.3), 0.77 (t, J=7.5 Hz, CH.sub.2CH.sub.3).

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

    [0384] Compound 71 (0.83 g, 1.67 mmol) and 4.0 M HCl (2.51 ml, 10.0 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0385] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0386] .sup.1H NMR (DMSO-d6, 400 MHz) 8.85-9.19 (m, NH.sub.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.sub.2CH.sub.2), 2.83 (t, J=6.5 Hz, NHCH.sub.2CH.sub.2), 2.36 (s, NCH.sub.3), 1.60-1.66 (m, CH.sub.2CH.sub.2CH.sub.3), 1.09-1.17 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.0 Hz, CH.sub.2CH.sub.2CH.sub.3).

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

    [0387] Compound 72 (0.89 g, 1.74 mmol) and 4.0 M HCl (2.61 ml, 10.4 mmol in dioxane) were reacted using 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%) in the form of a white powder.

    [0388] R.sub.f=0.00 (EtOAc 9: acetone 1);

    [0389] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 8.95 (s, NH.sub.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.sub.2CH.sub.2), 2.83 (t, J=6.8 Hz, NHCH.sub.2CH.sub.2), 2.37 (s, NCH.sub.3), 1.59-1.74 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.08-1.24 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.78 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.2CH.sub.3).

    ##STR00024##

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

    [0390] Compound 74 (1.0 eq), triethylamine (6.0 eq), formaldehyde (1.05 eq), and a palladium catalyst (0.2 eq) were reacted using Reaction Scheme g to synthesize Compound 92, (R)/(S)-N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide.

    [0391] .sup.1H NMR (DMSO-d.sub.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.sub.2CH.sub.2), 2.82-2.85 (m, NHCH.sub.2CH.sub.2), 2.35 (s, N(CH.sub.3)2), 1.60-1.77 (m, CH.sub.2CH.sub.2CH.sub.3), 1.09-1.16 (m, CH.sub.2CH.sub.2CH.sub.3), 0.80 (t, J=7.2 Hz, CH.sub.2CH.sub.2CH.sub.3).

    EXAMPLES

    Example 1: Analysis of Antifungal Activity Against Human Pathogenic Fungi

    [0392] An in vitro antifungal susceptibility test was performed in accordance with the US Clinical and Laboratory Standards Institute (CLSI) guidelines to measure the degree of antifungal activity of the compounds synthesized in the Preparation Examples against opportunistic pathogenic fungi. In the present example, the minimum inhibitory concentrations (MICs) at which the compounds can inhibit the growth of fungi for pathogenic fungi Cryptococcus neoformans, Candida albicans, Candida glabrata, and Aspergillus fumigatus were determined, and are shown in Table 1. The MIC value (μg/custom-character) is expressed as a range value. Specifically, Candida species and Cryptococcus neoformans were incubated in a Sabouraud dextrose agar (SDA) (Sigma-Aldrich) solid medium for 24 and 48 hours, respectively to obtain single colonies. The obtained single colonies were suspended in 0.85% physiological saline to prepare fungal cell suspension (1 to 5×10.sup.6 cells/custom-character). Fungal cells 2000-fold diluted in RPMI1640 broth (Sigma-Aldrich) were seeded on 96-well plates (5×10.sup.2 to 2.5×10.sup.3 cells/custom-character, 195 custom-character/well). Serial two-fold dilutions (128, 64, 32, 16, 8, 4, 2, 1, and 0.5 μg/custom-character) of compounds were prepared by diluting the compounds synthesized according to the above preparation examples. Then, 5 custom-character from each dilution was added to the well of the 96-well plate containing fungal cell suspension to give a final suspension of 200 custom-character per well. The compound-treated Candida species and C. neoformans were incubated at 35° C. for 48 hours and for 72 hours, respectively, and then MICs were determined by visually observing the bottom of the 96-well plate to confirm whether the fungi were developed and grown. As a positive control, amphotericin B (AMB), which is highly toxic to the human body but is known as a representative antifungal agent, was used. The results are shown in Tables 1 to 3.

    TABLE-US-00001 TABLE 1 [00025]embedded image Preparation example # MIC (μg/mL) (compound #) R1 R2 R3 X C. neoformans C. albicans C. glabrata A. fumigatus 24 (29) H H CH.sub.3 3,4-Cl 2~8  4~16  4~16  4~16 25 (30) H H CH.sub.2CH.sub.3 3,4-Cl 2~8  4~16  4~16  4~16 26 (31) H H CH.sub.2CH.sub.2CH.sub.3 3,4-Cl 0.5~4   0.5~4   0.5~4   0.5~4   27 (32) H H CH.sub.2CH.sub.3 4-OCF.sub.3 2~8  4~16  4~16  4~16 28 (33) H CH.sub.3 CH.sub.3 3,4-Cl  4~16  8~32  8~32  8~32 29 (34) H CH.sub.3 CH.sub.2CH.sub.3 3,4-Cl 2~8  4~16  8~32  8~32 30 (35) H CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 3,4-Cl 0.5~4   0.5~4   0.5~4   0.5~4   31 (36) CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 3,4-Cl 2~8  4~16  4~16  4~16

    TABLE-US-00002 TABLE 2 [00026]embedded image Preparation example # MIC (μg/mL) (compound #) R1 R2 R3 X C. neoformans C. albicans C. glabrata A. fumigatus 40 (45) H H CH.sub.2CH.sub.3 3,4-Cl 2~8  8~32  8~32  8~32 41 (46) H H CH.sub.2CH.sub.2CH.sub.3 3,4-Cl 0.5~4   2~8 2~8 2~8 42 (47) H H CH.sub.2CH.sub.3 4-CF.sub.3  4~16  8~32  8~32  8~32 43 (48) H H CH.sub.2CH.sub.2CH.sub.3 4-CF.sub.3  4~16  4~16  4~16  4~16 44 (49) H H CH.sub.2CH.sub.3 4-OCF.sub.3  4~16  8~32  8~32  8~32 45 (50) H H CH.sub.2CH.sub.2CH.sub.3 4-OCF.sub.3  4~16  4~16  4~16  4~16 46 (51) H CH.sub.3 CH.sub.2CH.sub.3 3,4-Cl 2~8  4~16  4~16  4~16 47 (52) H CH.sub.3 CH.sub.2CH.sub.3 4-CF.sub.3  4~16  8~32  8~32  8~32 48 (53) CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 3,4-Cl 2~8  8~32  8~32  8~32

    TABLE-US-00003 TABLE 3 [00027]embedded image Preparation example # MIC (μg/mL) (compound #) R1 R2 R3 X C. neoformans C. albicans C. glabrata A. fumigatus 68 (73) H H CH.sub.3 3,4-Cl 2~8  8~32  8~32  8~32 69 (74) H H CH.sub.2CH.sub.3 3,4-Cl 0.5~4   0.5~4   0.5~4   0.5~4   70 (75) H H CH.sub.2CH.sub.2CH.sub.3 3,4-Cl 0.5~4   0.5~4   0.5~4   0.5~4   71 (76) H H CH.sub.3 4-CF.sub.3  8~32 16~64  8~32  8~32 72 (77) H H CH.sub.2CH.sub.3 4-CF.sub.3  4~16  8~32  8~32  8~32 73 (78) H H CH.sub.2CH.sub.2CH.sub.3 4-CF.sub.3 2~8  4~16  4~16  4~16 74 (79) H H CH.sub.3 4-OCF.sub.3  8~32  8~32  8~32  8~32 75 (80) H H CH.sub.2CH.sub.3 4-OCF.sub.3 2~8  4~16  4~16  4~16 76 (81) H H CH.sub.2CH.sub.2CH.sub.3 4-OCF.sub.3 2~8 2~8 2~8 2~8 77 (82) H H CH.sub.2CH.sub.3 3,4-F  4~16  4~16  4~16  4~16 78 (83) H CH.sub.3 CH.sub.3 3,4-Cl 2~8  8~32  8~32  8~32 79 (84) H CH.sub.3 CH.sub.2CH.sub.3 3,4-Cl 2~8 4~1 4~1 4~1 80 (85) H CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 3,4-Cl 0.5~4   0.5~4   0.5~4   0.5~4   81 (86) H CH.sub.3 CH.sub.3 4-CF.sub.3  8~32 16~64 16~64 16~64 82 (87) H CH.sub.3 CH.sub.2CH.sub.3 4-CF.sub.3  4~16  4~16  4~16  4~16 83 (88) H CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 4-CF.sub.3 2~8  4~16  4~16  4~16 84 (89) H CH.sub.3 CH.sub.3 4-OCF.sub.3  8~32  8~32  8~32  8~32 85 (90) H CH.sub.3 CH.sub.2CH.sub.3 4-OCF.sub.3  4~16  4~16  4~16  4~16 86 (91) H CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 4-OCF.sub.3 2~8  4~16  4~16  4~16 87 (92) CH.sub.3 CH.sub.3 CH.sub.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 for Compound 74

    [0393] To evaluate the antifungal activity of Compound 74, the minimum inhibitory concentration (MIC) capable of inhibiting the growth of fungi was measured in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. Fungal cells were spread on YPD solid media (Sigma-Aldrich) and then aliquoted into the wells of the 96-well plates (2.5×10.sup.3 microconidia/custom-character for T. rubrum and T. mentagrophytes species or was 2.5×10.sup.3 cfu/custom-character for Candida albicans, Candida glabrata and Cryptococcus neoformans species, 195 custom-character/well). Two-fold serial dilutions of the Compound 74, of which concentration are ranging from 128 to 0.5 μg/custom-character (128, 64, 32, 16, 8, 4, 2, 1 and 0.5 μg/custom-character), ware prepared. Next, 5 custom-character from each dilution of Compound 74 was added to the well of the 96-well plate including fungal cells to give a final suspension of 200 custom-character/well. The compound-treated fungal cells were incubated in a 35° C. incubator for 48 hours (Candida species) and for 72 hours (C. neoformans and Trichophyton species), respectively. After incubation, MICs (μg/custom-character) were determined by visually reading the bottom of the 96-well plate to detect fungal growth. The results are shown in Table 4.

    TABLE-US-00004 TABLE 4 Target Fungus 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 Fast-Acting Effects of Compound 74 with Commercially Available Comparators

    [0394] To evaluate fast-acting effects of Compound 74, the growth of Candida albicans was studied by treating Candida albicans with Compound 74 or commercially available drug of Efinaconazole, Tavaborole, Terbinafine, or Ciclopirox at the same concentration for the same period of time. Specifically, Candida albicans were prepared at a concentration of 2.5×10.sup.3 cfu/custom-character and aliquoted at 195 custom-character/well into 96-well plates. Subsequently, Candida albicans cells in 96-well plate were treated with Compound 74 or each of the commercially available comparative drugs (50 μg/custom-character or 100 μg/custom-character) for 30 minutes, respectively. Next, Compound 74 treated fungal cells were seeded on YPD media (Sigma-Aldrich), and the number of single colonies grown was counted. The results are shown in FIG. 1. As shown in FIG. 1, it was confirmed that Compound 74 has an excellent fast-acting effects comparing to the commercially available competitive drugs.

    Example 4: Comparison of Fungicidal Effects of Compound 74 with Commercially Available Competitive Drugs

    [0395] To evaluate fungicidal effects of Compound 74, the growth of T. rubrum was studied after treating T. rubrum with Compound 74 or commercially available antifungal drug of Efinaconazole, Amorolfine, Terbinafine, Ciclopirox, or Amphotericin B (0.5, 1-, 2-, 4-, 8-or 16-fold of the respective MICs of Compound 74 or the other commercially available antifungal drugs) for a predetermined time. Specifically, T. rubrum cells (6×10.sup.3 cfu/custom-character) were prepared and aliquoted at 195 custom-character/well into 96-well plates. Next, 5 custom-character of Compound 74 or each of the other commercially available drugs was added the well of the 96-well plate containing T. rubrum cells to give a final suspension of 200 custom-character/well. 0, 2, 4, 6, 12, 24, 48, 72 or 120 hours after the addition, fungal cells treated with the Compound 74 or other antifungal drugs were spread on YPD solid media, and then the number of single colonies grown was counted. The results are illustrated in FIG. 2. As shown in FIG. 2, Compound 74 exhibited fungicidal effects at the MIC concentration, which suggests that Compound 74 has fungicidal effects at a lower concentration than other comparators.

    Example 5: Comparison of Biofilm Disruption Activities of Compound 74 with Commercially Available Drugs

    [0396] The biofilm disruption activities of Compound 74 were studied. Candida albicans was allowed to form a biofilm. Next, Compound 74 or commercially available drug of Caspofungin, Amphotericin B or Efinaconazole was added to the obtained biofilm at respective concentrations of 4, 8, 16 and 32 μg/custom-character to evaluate the disruption of the biofilm.

    [0397] Specifically, Candida albicans cells (2.5×10 3 cfu/custom-character) were seeded on 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 comparative drugs above, and then the growth of Candida albicans was studied 24 hours after the treatment. The results are presented in FIG. 3. As shown in FIG. 3, it was suggested that Compound 74 of the present invention exhibited remarkably excellent growth inhibitory effects on Candida albicans through biofilm disruption especially in comparison to those of the commercially available comparative drugs.

    Example 6: Analysis of Antibacterial Activities

    [0398] The antibacterial activities against Gram-positive bacteria, Gram-negative bacteria or multi-drug resistant bacteria were evaluated for the compounds of the present invention. The MIC test was conducted in accordance CLSI guidelines. E. coli(−), P. aeruginosa(−), and S. enterica(−) were used as Gram-negative bacteria, B. cereus(+), B. subtilis(+), B. coagulans(+), L. monocytogenes(+), M. luteus(+), P. acnes(+), S. epidermidis(+), and S. aureus(+) were used as Gram-positive bacteria. Methicillin-resistant Staphylococcus aureus (MRSA) was used as multi-drug resistant bacteria. The bacterial cells were incubated until the OD.sub.600 of the single colonies reached 0.1. Cells diluted in 100-fold in a MHB liquid medium (Sigma-Aldrich) were seeded on 96-well plates to give a suspension of 100 custom-character per well with 0.001 OD.sub.600. Next, two-fold serially diluted compounds of the present invention (64, 32, 16, 8, 4, 2, 1, and 0.5 μg/custom-character) were added to the wells to provide a final suspension of 200 custom-character/well. Subsequently, bacterial cells were incubated at 37° C. for 24 hours, and then the MICs (μg/custom-character) were determined by visual reading and optical density detection at 600 nm (OD.sub.600). As a positive control, Nofloxacin and Vancomycin were used. The results are shown in Tables 5 to 8.

    TABLE-US-00005 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-US-00006 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-US-00007 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-US-00008 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 Activities

    [0399] The anti-inflammatory effects of the compounds of the present invention were evaluated using RAW264.7 cells which were stimulated to secrete interleukin 6 (IL-6). Specifically, RAW264.7 cells (obtained from Korean Cell Line Bank), mouse macrophages, were inoculated into a 12-well plate at 5×10.sup.5 cells/well and incubated at 37° C. for 16 to 24 hours. The compounds of the present invention were added to the cell culture medium containing RAW264.7 cells incubated as above at a final concentration of 0 or 8 μg/custom-character, and then incubated at 37° C. for 1 hour. Next, lipopolysaccharide (LPS, Sigma-Aldrich, USA) was further added to the medium at a final concentration of 1 μg/custom-character, and the medium was incubated at 37° C. for 24 hours to induce IL-6 expression. Thereafter, IL-6 levels produced by the 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, IL6 levels were expressed as a relative percentage (%) between LPS-induced IL6 levels after the treatment with the compound of the present invention and LPS-induced IL6 levels without the treatment of the compound of the present invention.

    TABLE-US-00009 TABLE 9 Compound 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

    [0400] The present invention relates to a novel compound and the use of the same, can be used for the preparation of antifungal and antibacterial compositions, and can be used for the development of a pharmaceutical composition for preventing and treating fungal infection diseases.