Immunoenhancing composition containing amide compounds

Abstract

This specification relates to compositions comprising novel amide compounds derived from amino acid structures such as valine, leucine, phenylalanine, proline, or pipecolic acid. [Solution] The composition can exert an immune-enhancing effect by activating the phagocytic activity of macrophages, which are important components of the human immune system and help eliminate pathogens.

Description

[Technical Field]

[0001] This specification discloses immunoenhancing compositions comprising amide compounds. [Background technology]

[0002] Macrophages are an important component of the human immune system and play a crucial role in eliminating pathogens in the skin. Since pathogen infections can cause various skin problems such as acne, inflammation, and skin diseases, the phagocytosis of macrophages, which helps eliminate pathogens, is one of the important defense mechanisms that protect the skin from pathogens.

[0003] However, the discovery of substances that promote macrophage phagocytosis is still insufficient. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2003 / 101382 [Overview of the project] [Problems that the invention aims to solve]

[0005] One aspect of the present invention aims to provide an immunoenhancing composition comprising a novel compound derived from an amino acid structure such as valine, leucine, phenylalanine, proline, or pipecolic acid. [Means for solving the problem]

[0006] In one embodiment, this specification provides an immunoenhancing composition comprising a compound represented by the following general formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[0007] [ka]

[0008] In general formula (1), X is represented by any one of the following general formulas (1-1) to (1-5),

[0009] [Chemical formula]

[0010] [Chemical formula]

[0011] [Chemical formula]

[0012] [Chemical formula]

[0013] [Chemical formula] <​​​​​​​​​​​​​​​​​​Ar is a phenyl or unsubstituted naphthalene with 1 to 3 R3 groups. R3 is hydrogen, a C1-C4 alkyl group, or a phenyl group. If there is more than one R3 residue, all R3 residues are identical. In general formula (1-4), Ar is an unsubstituted or phenyl compound with 1 to 3 R4 groups. R4 is hydrogen, a phenyl group, a C1-C4 alkyl group, or a C1-C4 alkoxy group. If there is more than one R4 residue, all R4 residues are identical. In general formula (1-5), Ar is a phenyl compound substituted with 1 to 3 R5 groups. R5 is a C1-C4 alkyl group or a phenyl group. If there is more than one R5 residue, all R5 residues are identical. [Effects of the Invention]

[0015] In one embodiment, a composition comprising a novel amide compound disclosed herein can exert an immune-enhancing effect by activating the phagocytosis of macrophages. [Brief explanation of the drawing]

[0016] [Figure 1] This figure shows the results of observing the phagocytic activation effect of a composition according to one embodiment of the present disclosure. [Figure 2] This figure shows the results of observing the phagocytic activation effect of a composition according to one embodiment of the present disclosure. [Modes for carrying out the invention]

[0017] The present invention will be described in more detail below with reference to the following embodiments. However, the following embodiments are merely illustrative to aid in understanding the present invention, and the scope and nature of the present invention are not limited thereto.

[0018] An exemplary embodiment of this disclosure provides an immunoenhancing composition comprising a compound represented by the following general formula (1), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate or solvate as an active ingredient:

[0019] [ka]

[0020] In general formula (1), The aforementioned X is represented by one of the following general (1-1) to (1-5):

[0021] [ka]

[0022] [ka]

[0023] [ka]

[0024] [ka]

[0025] [ka]

[0026] In general formula (1-1), Ar is an unsubstituted or phenyl compound with 1 to 3 R1 atoms. R1 is hydrogen, a phenyl group, a C1-C4 alkoxy group, a C1-C4 alkyl group, a fluoro group, an adamantane group, an acetylamino group, or a hydroxyiminoethyl group. If there is more than one R1 residue, all R1 residues are identical. In general formula (1-2), Ar is a phenyl compound substituted with one R2. R2 is a C1-C4 alkyl group, a C1-C4 alkoxy group, an adamantane group, an acetyl group, or an acetylamino group. In general formula (1-3), Ar is a phenyl or unsubstituted naphthalene with 1 to 3 R3 groups. R3 is hydrogen, a C1-C4 alkyl group, or a phenyl group. If there is more than one R3 residue, all R3 residues are identical. In general formula (1-4), Ar is an unsubstituted or phenyl compound with 1 to 3 R4 groups. R4 is hydrogen, a phenyl group, a C1-C4 alkyl group, or a C1-C4 alkoxy group. If there is more than one R4 residue, all R4 residues are identical. In general formula (1-5), Ar is a phenyl compound substituted with 1 to 3 R5 groups. R5 is a C1-C4 alkyl group or a phenyl group. If there is more than one R5 residue, all R5 residues are identical.

[0027] For example, in the general formulas (1-1) to (1-5) above, R1 to R5 may each be substituted with the para position of Ar.

[0028] In this specification, the alkyl group may be linear or branched, and may be, for example, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0029] In this specification, the alkoxy group may be linear, branched, or cyclic, and may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, or sec-butoxy.

[0030] In this specification, the term "isomer" includes not only optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, or mixtures thereof), but also conformation isomers (i.e., isomers that differ only in the angle of at least one chemical bond), position isomers (e.g., tautomers), or geometric isomers (e.g., cis-trans isomers).

[0031] In this specification, the term "essentially pure," when used in relation to an enantiomer or diastereomer, means that the specific compound for which the enantiomer or diastereomer is exemplified is present in a proportion of about 90%, preferably about 95%, more preferably about 97% or about 98%, even more preferably about 99%, and most preferably about 99.5% or more (w / w).

[0032] In this specification, the term "pharmaceutically acceptable" means that a substance is approved, listed in a pharmacopoeia, or recognized as such by a government or equivalent regulatory body, for use in animals, more specifically in humans, by avoiding significant toxic effects when used in a normal medicinal dosage.

[0033] In this specification, the term “pharmaceutically acceptable salt” means a salt relating to one aspect of the present disclosure that is pharmaceutically acceptable and has the preferred pharmacological activity of the parent compound. The salt is (1) formed from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid Acid addition salts formed from organic acids such as folic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is substituted.

[0034] In this specification, the term "hydrate" refers to a compound to which water is bound, and is a broad concept that includes encapsulated compounds to which there is no chemical bonding force between water and the compound.

[0035] In this specification, the term "solvate" refers to a higher-order compound formed between molecules or ions of a solute and molecules or ions of a solvent.

[0036] Another exemplary embodiment of the present disclosure provides an immunoenhancing method comprising administering an effective amount of a composition containing a compound represented by the general formula (1), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate as an active ingredient to a subject requiring it.

[0037] Another exemplary embodiment of the present disclosure provides uses for the compound represented by general formula (1), its stereoisomers, its pharmaceutically acceptable salts, its hydrates or solvates for the production of immunoenhancing compositions.

[0038] Another exemplary embodiment of the present disclosure provides non-therapeutic uses of the compound represented by general formula (1), its stereoisomers, its pharmaceutically acceptable salts, its hydrates or solvates for enhancing immunity.

[0039] In one implementation example, the compound represented by the general formula (1) may be selected from any of the following compounds: N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-phenylpropanamide, N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamide)propanamide, N-hydroxy-2-(naphthalene-2-sulfonamide)-3-phenylpropanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide, 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide, 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide, 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide, N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide, and 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0040] In one implementation example, the compound represented by the general formula (1) may be represented by any of the following general formulas.

[0041] [ka]

[0042] In one example, the compound represented by the general formula (1) may be selected from any of the following compounds.

[0043] N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, and N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolin-2-carboxamide.

[0044] In one example, the compound represented by the general formula (1) may be derived from an amino acid.

[0045] For example, the compound represented by the general formula (1) may be derived from any of the following amino acids.

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] In one example, the composition may be intended to activate the phagocytic activity of macrophages.

[0052] In one example, the composition may be intended to activate the phagocytic activity of macrophages against Staphylococcus aureus (S. aureus).

[0053] In one example, the composition may be intended to strengthen the skin barrier.

[0054] In one example, the composition may be for the purpose of suppressing skin inflammation.

[0055] In one example, the composition may be a cosmetic composition.

[0056] In one embodiment, the appearance of the cosmetic composition may include a cosmetically or dermatologically acceptable medium or base. This is any formulation suitable for topical application and may be provided, for example, in the form of a solution, gel, solid, paste anhydrous product, emulsion obtained by dispersing an oil phase in an aqueous phase, suspension, microemulsion, microcapsule, microgranules or ionic (liposome) and nonionic vesicle dispersants, or in the form of a cream, lotion, emulsion, powder, ointment, spray or stick concealer. These compositions may be manufactured according to conventional methods of the art.

[0057] The compositions relating to this disclosure may also be used in the form of a foam or in the form of an aerosol composition further comprising a compressed propellant.

[0058] The cosmetic composition relating to this disclosure is not particularly limited in its formulation, and may be formulated into cosmetics such as, for example, softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, serum, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, cleansing tissue containing the cosmetic composition, pack, powder, body lotion, body cream, body oil, and body essence.

[0059] When the cosmetic composition formulation according to this disclosure is a paste, cream, or gel, animal fibers, plant fibers, waxes, paraffin, starch, tragacande, cellulose derivatives, polyethylene glycol, silicones, bentonite, silica, talc, or zinc oxide may be used as the carrier component.

[0060] When the cosmetic composition formulation according to this disclosure is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as the carrier component, and especially in the case of a spray, it may further contain propellants such as hydrochlorofluorocarbon, propane / butane, or dimethyl ether.

[0061] When the formulation of the cosmetic composition according to this disclosure is a solution or emulsion, a solvent, solvating agent, or emulsifying agent is used as the carrier component, and examples include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerin aliphatic ester, polyethylene glycol, or fatty acid ester of sorbitan.

[0062] When the formulation of the cosmetic composition according to this disclosure is a suspension, the carrier component may be a liquid diluent such as water, ethanol, or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, or microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth.

[0063] The cosmetic composition relating to this disclosure may further contain functional additives and components commonly found in cosmetic compositions. The functional additive may include components selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, squalane, sphingolipids, and seaweed extracts.

[0064] The cosmetic composition relating to this disclosure may further contain, as necessary, components commonly found in cosmetic compositions, along with the functional additives. Other components that may be included include oils and fats, humectants, emollients, emulsifiers, organic and inorganic pigments, organic powders, UV absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, dyes, fragrances, blood circulation promoters, cooling agents, antiperspirants, and purified water.

[0065] In one example, the composition may be a topical skin preparation.

[0066] The aforementioned topical skin preparations are a general term that may include any preparation applied to the skin, and may encompass a variety of cosmetic and pharmaceutical formulations.

[0067] In one example, the composition may be a food composition.

[0068] In one example, the composition may be an oral composition or a non-therapeutic oral composition.

[0069] The food composition or oral composition relating to this disclosure may be a liquid or solid formulation, and may be a tablet, capsule, soft capsule, pill, granule, beverage (drink), diet bar, chocolate, caramel formulation or confectionery formulation, and the formulation is not particularly limited.

[0070] In addition to the active ingredients, the food composition or oral composition of this disclosure may optionally contain excipients, sugars, flavorings, colorants, oils and fats, proteins, and the like.

[0071] In one example, the composition may be a pharmaceutical composition.

[0072] The pharmaceutical composition may further contain pharmaceutical adjuvants such as preservatives, stabilizers, hydrates or emulsifiers, salts and / or buffers for osmotic pressure adjustment, and other therapeutically useful substances, and may be formulated in various oral or parenteral forms according to conventional methods.

[0073] The oral preparations mentioned above include, for example, tablets, pills, hard and soft capsules, liquids, suspensions, emulsifiers, syrups, powders, granules, pellets, etc. These preparations may contain, in addition to the active ingredient, surfactants, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and polyethylene glycol). Tablets may further contain binders such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidine, and may optionally contain pharmaceutical additives such as disintegrants, absorbents, colorants, flavorings, and sweeteners, such as starch, agar, alginic acid or its sodium salt. The tablets may be manufactured by conventional mixing, granulation, or coating methods. Furthermore, the form of parenteral administration may be a transdermal formulation, such as an injection, infusion, ointment, lotion, gel, cream, spray, suspension, emulsion, suppository, or patch, but is not limited to these.

[0074] The pharmaceutical composition may be administered parenterally, rectally, topically, transdermally, subcutaneously, etc.

[0075] In one example, the pharmaceutical composition may be for the prevention, improvement, or treatment of skin inflammation.

[0076] In one example, the pharmaceutical composition may be used to treat a subject in which the phagocytic activity of macrophages is reduced.

[0077] In one example, the pharmaceutical composition may be used to treat a subject in which macrophage phagocytosis against S. aureus is reduced.

[0078] As used herein, the term "prevention" means any action that suppresses a disease or delays its onset by administering a pharmaceutical composition according to the present invention.

[0079] As used herein, the term “improvement” means any action that at least reduces a parameter relating to the condition being treated, such as the severity of a symptom.

[0080] As used herein, the term "treatment" means any action that improves or favorably alters the symptoms of a disease by administering a pharmaceutical composition according to the present invention.

[0081] In one example, the amount of the active ingredient may be 0.01 μM to 100 mM relative to the total volume of the composition.

[0082] For example, it may be 0.01 μM or more, 0.05 μM or more, 0.1 μM or more, 1 μM or more, 10 μM or more, 100 μM or more, 0.5 mM or more, 1 mM or more, 1.5 mM or more, 2 mM or more, 2.5 mM or more, 10 mM or more, or 50 mM or more, and it may also be 100 mM or less, 50 mM or less, 10 mM or less, 8 mM or less, 6 mM or less, 4 mM or less, 1 mM or less, 100 μM or less, 10 μM or less, 1 μM or less, 0.1 μM or less, or 0.05 μM or less.

[0083] For example, the content may be 0.01 μM to 100 mM, 0.05 μM to 10 mM, or 0.1 μM to 4 mM relative to the total volume of the composition.

[0084] If the concentration is less than 0.01 μM, the effect is minimal, and if it exceeds 100 mM, there is a risk of cytotoxicity due to high concentrations.

[0085] In one example, the daily dose of the active ingredient may be 1 to 1000 mg / kg.

[0086] For example, the daily dosage may be the daily administration amount, or it may mean the daily intake amount converted to the amount consumed by humans.

[0087] For example, the daily dose may be 1 mg / kg or more, 10 mg / kg or more, 100 mg / kg or more, 300 mg / kg or more, 500 mg / kg or more, 700 mg / kg or more, or 900 mg / kg or more, or 1000 mg / kg or less, 800 mg / kg or less, 600 mg / kg or less, 400 mg / kg or less, 200 mg / kg or less, 100 mg / kg or less, or 10 mg / kg or less.

[0088] In one implementation example, the active ingredient may be used to treat cells at a concentration of 1 to 100 μM.

[0089] For example, the active ingredient may be used to treat cells at concentrations of 1 μM or more, 10 μM or more, 30 μM or more, 50 μM or more, 70 μM or more, or 90 μM or more, or at concentrations of 100 μM or less, 80 μM or less, 60 μM or less, 40 μM or less, or 20 μM or less.

[0090] The present invention will be described in more detail below with reference to the following embodiments. However, the following embodiments are merely illustrative to aid in understanding the present invention, and the scope and nature of the present invention are not limited thereto.

[0091] [Embodiment] [Manufacturing example] The novel compounds were manufactured as follows. The IUPAC names of the novel compounds are shown in Table 1 below.

[0092] [Table 1]

[0093] (1) Synthesis of T-01 N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide 1.69 g of pipecolinic acid was thoroughly mixed with 30 mL of THF, and then 30 mL of 1 M Na2CO3 was added. 2 mL of benzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at the same temperature for 1 hour. The mixture was washed with 30 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 1.89 g of the intermediate 1-(phenylsulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0094] 1.89 g of 1-(phenylsulfonyl)piperidine-2-carboxylic acid was dissolved in 15 mL of THF with 0.85 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.73 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.73 g of hydroxylamine hydrochloride and 1.46 mL of triethylamine were added dropwise to a solution of DMF in 20 mL. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:2) to obtain 0.72 g of N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.62(s,1H),8.79(s,1H),7.78(m,2H),7.66(m,1H),7.57(m,2H), 4.34(m,1H),3.63(m,1H),3.47(m,1H),1.78(m,1H),1.55(m,1H)1.45-1.40(m,3H),1.17(m,1H)

[0095] (2) Synthesis of T-02 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide 0.65 g of pipecolinic acid was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.52 g of 4-biphenylsulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 0.78 g of the intermediate 1-([1,1'-biphenyl]-4-ylsulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0096] 0.7 g of 1-([1,1'-biphenyl]-4-ylsulfonyl)piperidine-2-carboxylic acid was dissolved in 20 mL of THF with 0.25 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine were added dropwise to a solution of 10 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:2) to obtain 0.26 g of 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide. 1 H-NMR (500MHz, DMSO-d6): δ10.67(s,1H),8.80(s,1H),7.87(m,4H),7.77(m,2H),7.52(m,2H),7.45(m,1H) ),4.38(m,1H),3.66(m,1H),3.50(m,1H),1.81(m,1H),1.59(m,1H),1.47-1.43(m,3H),1.26-1.15(m,1H)

[0097] (3) Synthesis of T-03 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide 0.65 g of pipecolinic acid was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.4 g of 4-tert-butylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 0.78 g of the intermediate 1-((4-(tert-butyl)phenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0098] 0.8 g of 1-((4-(tert-butyl)phenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 30 mL of THF with 0.29 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.25 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.25 g of hydroxylamine hydrochloride and 0.5 mL of triethylamine were added dropwise to a solution of DMF in 20 mL. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.41 g of 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.62(s,1H),8.81(s,1H),7.69(m,2H),7.59(m,2H),4.34(m,1H) ),3.59(m,1H),3.43(m,1H),1.78(m,1H),1.54(m,1H),1.44(m,3H),1.31(s,9H),1.16(m,1H)

[0099] (4) Synthesis of T-04 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide 0.65 g of pipecolinic acid was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.2 mL of 4-butoxybenzene-1-sulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 1.17 g of the intermediate 1-((4-butoxyphenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0100] 1.17 g of 1-((4-butoxyphenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 30 mL of THF with 0.42 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.36 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.36 g of hydroxylamine hydrochloride and 0.72 mL of triethylamine were added dropwise to a solution of DMF in 20 mL. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.37 g of 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ10.61(s,1H),8.77(s,1H),7.67(d,2H,J=8.5Hz), 7.06(d,2H,J=9Hz),4.30(m,1H),4.05(t,2H,J=7Hz),3.59(m,1H),3.44(m,1H) 1.77-1.69(m,3H),1.54-1.42(m,6H),1.18(m,1H),0.94(t,3H,J=7.5Hz)

[0101] (5) Synthesis of T-05 N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide 0.65 g of pipecolinic acid was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.31 g of 2-mesitylenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 0.71 g of the intermediate 1-(mesitylsulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0102] 0.69 g of 1-(mesitylsulfonyl)piperidine-2-carboxylic acid was dissolved in 20 mL of THF with 0.27 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.23 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.23 g of hydroxylamine hydrochloride and 0.46 mL of triethylamine were added dropwise to a solution in 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.14 g of N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide. 1H-NMR (500MHz, DMSO-d6): δ10.48(s,1H),8.86(s,1H),7.05(s,2H),3.69(t,1H,J=10.5Hz),3.32(s,3H),3.43(s,3H) 1.79(m,2H),1.65-1.50(m,6H),1.30-1.23(m,3H)

[0103] (6) Synthesis of T-07 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide 0.83 g of phenylalanine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.52 g of 4-biphenylsulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 1.26 g of the intermediate ([1,1'-biphenyl]-4-ylsulfonyl)phenylalanine. This intermediate was used in the next reaction without any special purification.

[0104] 1.2 g of ([1,1'-biphenyl]-4-ylsulfonyl)phenylalanine was dissolved in 20 mL of THF with 0.38 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.33 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.33 g of hydroxylamine hydrochloride and 0.66 mL of triethylamine were added dropwise to a solution in 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 2:1) to obtain 0.32 g of 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide. 1 H-NMR (500MHz, DMSO-d6): δ10.07(s,1H),8.88(s,1H),8.27(d,2H,J=9.0Hz),7.69(m,3H),7.59( m,2H),7.53(m,2H),7.43(m,1H),7.16(m,3H),7.07(m,2H),3.82(m,1H),2.80(m,1H),2.63(m,1H)

[0105] (7) Synthesis of T-08 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-phenylpropanamide 0.83 g of phenylalanine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.4 g of 4-tert-butylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 1.31 g of the intermediate ((4-(tert-butyl)phenyl)sulfonyl)phenylalanine. This intermediate was used in the next reaction without any special purification.

[0106] 1.2 g of ((4-(tert-butyl)phenyl)sulfonyl)phenylalanine was dissolved in 20 mL of THF with 0.4 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0°C. 0.35 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.35 g of hydroxylamine hydrochloride and 0.69 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.38 g of 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-phenylpropanamide. 1 H-NMR(500MHz,DMSO-d6):δ10.61(s,1H),8.88(s,1H),8.13(d,1H,J=8.5Hz),7.40( m,4H),7.12(m,3H),7.00(m,2H),3.71(m,1H),2.76(m,1H),2.55(m,1H),1.26(s,9H)

[0107] (8) Synthesis of T-10 N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamide)propanamide 0.83 g of phenylalanine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.31 g of 2-mesitylenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 1 g of the intermediate (mesitylsulfonyl)phenylalanine. This intermediate was used in the next reaction without any special purification.

[0108] Dissolve 1 g of (mesitylsulfonyl)phenylalanine in 20 mL of THF with 0.35 mL of NMO (N-Methylmorpholine-N-oxide), and then stir at 0°C. Slowly add 0.3 mL of ethyl chloroformate dropwise, and then stir at the same temperature for 30 minutes. Filter the solid from the reaction mixture, and then save the resulting filtrate separately. Add the filtrate dropwise to a solution of 0.3 g of hydroxylamine hydrochloride and 0.6 mL of triethylamine dissolved in 20 mL of DMF. Stir at room temperature for 30 minutes, and then remove the DMF by reducing the pressure. Add ethyl acetate and purified water and separate the layers, and then extract the aqueous layer twice more with ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.25 g of N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamide)propanamide. 1H-NMR(500MHz,DMSO-d6):δ10.59(s,1H),8.87(s,1H),7.89(d,1H,J=9.5Hz),7.07(m,3H), 6.95(m,2H),6.82(m,2H),3.67(m,1H),2.76(m,1H),2.60(m,1H),2.49(s,6H),2.26(s,3H)

[0109] (9) Synthesis of T-11 N-hydroxy-2-(naphthalene-2-sulfonamide)-3-phenylpropanamide 0.83 g of phenylalanine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.36 g of 2-naphtalenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 1.2 g of the intermediate (naphthalen-2-ylsulfonyl)phenylalanine. This intermediate was used in the next reaction without any special purification.

[0110] (Naphthalen-2-ylsulfonyl)phenylalanine (1.1 g) was dissolved in 20 mL of THF together with 0.37 mL of NMO (N-Methylmorpholine-N-oxide), and then stirred at 0 °C. 0.32 mL of ethyl chloroformate was slowly added dropwise, and then stirred at the same temperature for 30 minutes. The solid in the reaction solution was filtered, and then the obtained filtrate was separately stored. Then, it was added dropwise to a solution prepared by dissolving 0.32 g of hydroxylamine hydrochloride and 0.65 mL of triethylamine in 20 mL of DMF. Stirred at room temperature for 30 minutes, and then DMF was removed by concentration under reduced pressure. Ethyl acetate and purified water were added for liquid separation, and then the aqueous layer was further extracted twice with ethyl acetate. The organic layer was collected, and then concentrated under reduced pressure. The obtained solid was purified by column chromatography (hexane:ethyl acetate = 1:2) to obtain 0.21 g of N-hydroxy-2-(naphthalen-2-sulfonamido)-3-phenylpropanamide. 1 H-NMR (500 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.84 (s, 1H), 8.32 (d, 1H, J = 9.5 Hz), 8.19 (s, 1H), 8.19 (m, 2H), 7.92 (d, 1H, J = 9.5 Hz), 7.65 (m, 2H), 7.56 (m, 1H), 7.28 - 7.00 (m, 5H), 3.84 (q, 1H), 2.78 (m, 1H), 2.59 (m, 1H)

[0111] (10) Synthesis of T-12 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide 0.66 g of leucine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.52 g of 4-biphenylsulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 0.64 g of the intermediate ([1,1'-biphenyl]-4-ylsulfonyl)leucine. This intermediate was used in the next reaction without any special purification.

[0112] 0.6 g of ([1,1'-biphenyl]-4-ylsulfonyl)leucine was dissolved in 20 mL of THF with 0.21 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.18 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.18 g of hydroxylamine hydrochloride and 0.36 mL of triethylamine were added dropwise to a solution of 10 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.34 g of 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-4-methylpentanamide. 1H-NMR (500MHz, DMSO-d6): δ10.66(s,1H),8.81(s,1H),8.03(d,1H,J=6.0Hz),7.83(m,4H),7.73(d,2H,J=7.0Hz),7 .51(m,2H),7.43(m,1H),3.59(q,1H),1.41(m,1H),1.33-1.21(m,2H),0.75(d,3H,J=6.5Hz),0.64(d,3H,J=7.0Hz)

[0113] (11) Synthesis of T-13 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide 0.66 g of leucine was thoroughly mixed with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.4 g of 4-tert-butylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 1.09 g of the intermediate ((4-(tert-butyl)phenyl)sulfonyl)leucine. This intermediate was used in the next reaction without any special purification.

[0114] 1.07 g of ((4-(tert-butyl)phenyl)sulfonyl)leucine was dissolved in 20 mL of THF with 0.4 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.35 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.35 g of hydroxylamine hydrochloride and 0.7 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.15 g of 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide. 1 H-NMR (500MHz, DMSO-d6): δ10.64(s,1H),8.83(s,1H),7.88(m,1H),7.70(d,2H,J=9.0Hz),7.57(d,2H ,J=8.5Hz),3.49(m,1H),1.32-1.24(m,11H),1.12(m,1H),0.69(d,3H,J=6.5Hz),0.55(d,3H,J=6.5Hz)

[0115] (12) Synthesis of T-14 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide 0.66 g of leucine was thoroughly mixed with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.2 mL of 4-butoxybenzene-1-sulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 1 g of the intermediate ((4-butoxyphenyl)sulfonyl)leucine. This intermediate was used in the next reaction without any special purification.

[0116] 1 g of ((4-butoxyphenyl)sulfonyl)leucine was dissolved in 20 mL of THF with 0.35 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.3 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.3 g of hydroxylamine hydrochloride and 0.6 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 40 mg of 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide. 1H-NMR(500MHz,DMSO-d6):δ10.61(s,1H),8.77(s,1H),7.76(m,1H),7.67(d,2H,J=9.0Hz),7.04(d,2H,J=8.5Hz),4.04(t,2H,J=6.5Hz),3 .50(m,1H),1.70(m,2H),1.45(m,3H),1.27(m,1H),1.19(m,1H),0.93(t,3H,J=7.0Hz),0.77-0.72(d,3H,J=6.5Hz),0.63(d,3H,J=6.0Hz)

[0117] (13) Synthesis of T-15 N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide 0.66 g of leucine was thoroughly mixed with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.31 g of 2-mesitylenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 0.76 g of the intermediate (mesitylsulfonyl)leucine. This intermediate was used in the next reaction without any special purification.

[0118] 0.75 g of (mesitylsulfonyl)leucine was dissolved in 20 mL of THF with 0.29 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.25 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.25 g of hydroxylamine hydrochloride and 0.5 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.14 g of N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide. 1 H-NMR (500MHz, DMSO-d6): δ10.51(s,1H),8.88(s,1H),7.77(m,1H),6.98(s,2H),3.45(m,1H),2.55(s,3H) ),2.50(s,3H),2.24(s,3H),1.41(m,1H),1.33-1.20(m,2H),0.73(d,3H,J=6.5Hz),0.55(d,3H,J=6.5Hz)

[0119] (14) Synthesis of T-17 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide 0.59 g of valine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.52 g of 4-biphenylsulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 0.48 g of the intermediate ([1,1'-biphenyl]-4-ylsulfonyl)valine. This intermediate was used in the next reaction without any special purification.

[0120] 0.48 g of ([1,1'-biphenyl]-4-ylsulfonyl)valine was dissolved in 20 mL of THF with 0.17 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.15 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.15 g of hydroxylamine hydrochloride and 0.3 mL of triethylamine were added dropwise to a solution of 10 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.1 g of 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide. 1H-NMR(500MHz,DMSO-d6):δ10.56(s,1H),8.79(s,1H),8.00(s,1H),7.83(m,4H),7.73(d,2H,J=7.0H z),7.51(m,2H),7.43(m,1H),3.33(m,1H),1.77(m,1H),0.77(d,3H,J=6.5Hz),0.75(d,3H,J=5.5Hz)

[0121] (15) Synthesis of T-18 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide 0.59 g of valine was mixed thoroughly with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.4 g of 4-tert-butylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain the intermediate ((4-(tert-butyl)phenyl)sulfonyl)valine 0.71 g. This intermediate was used in the next reaction without any special purification.

[0122] 0.7 g of ((4-(tert-butyl)phenyl)sulfonyl)valine was dissolved in 20 mL of THF with 0.25 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.3 g of 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide. 1 H-NMR(500MHz,DMSO-d6):δ10.50(s,1H),8.80(s,1H),7.81(m,1H),7.68(d,2H,J=8.0Hz),7.54(d ,2H,J=8.0Hz),3.27(m,1H),1.75(m,1H),1.29(s,9H),0.73(d,3H,J=6.5Hz),0.70(d,3H,J=6.5Hz)

[0123] (16) Synthesis of T-20 N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide 0.59 g of valine was thoroughly mixed with 20 mL of THF, and then 11.5 mL of 1 M Na2CO3 was added. 1.31 g of 2-mesitylenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 50 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 100 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 0.53 g of the intermediate (mesitylsulfonyl) valine. This intermediate was used in the next reaction without any special purification.

[0124] 0.52 g of (mesitylsulfonyl)valine was dissolved in 20 mL of THF with 0.25 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine were added dropwise to a solution of 20 mL of DMF. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.14 g of N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide. 1H-NMR(500MHz,DMSO-d6):δ10.43(s,1H),8.80(s,1H),7.59(d,1H,J=9.5Hz),6.98(s ,2H),3.18(t,1H,J=8.0Hz),2.59-2.50(m,6H),2.24(s,3H),1.76(m,1H),0.70(m,6H)

[0125] (17) Synthesis of T-21 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide 500 mg of pipecolinic acid was thoroughly mixed with 8 mL of THF, and then 9.6 mL of 1 M Na2CO3 was added. 904 mg of 4-fluorobenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 20 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 608 mg of the intermediate 1-((4-fluorophenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0126] 550 mg of 1-((4-fluorophenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF with 0.23 mL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 0.2 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 0.2 g of hydroxylamine hydrochloride and 0.4 mL of triethylamine were added dropwise to a solution of 2 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 0.14 g of 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ10.63(s,1H),8.76(s,1H),7.82(m,2H),7.42(m,2H),4.32(m ,1H),3.62(m,1H),3.46(m,1H),1.80(m,1H),1.77(m,1H),1.51-1.39(m,3H),1.19(m,1H)

[0127] (18) Synthesis of T-23 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide 50 mg of pipecolinic acid was mixed thoroughly with 0.8 mL of THF, and then 0.9 mL of 1 M Na2CO3 was added. 144 mg of 4-(1-Adamantyl)benzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 2 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 2 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 90 mg of the intermediate 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0128] 50 mg of 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 1 mL of THF with 15 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 13 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 12.9 mg of hydroxylamine hydrochloride and 26 μL of triethylamine were added dropwise to a solution in 1 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 30 mg of 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.61(s,1H),8.81(s,1H),7.70(m,2H),7.55(m,2H),4.33(m,1H),3.59 (m,1H),3.45(m,1H),2.07(s,3H),1.89(m,7H),1.77(m,7H),1.52(m,1H),1.43(m,2H),1.19(m,1H)

[0129] (19) Synthesis of T-24 N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide 500 mg of pipecolinic acid was mixed thoroughly with 8 mL of THF, and then 8.9 mL of 1 M Na2CO3 was added. 831 μL of 4-n-Propylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 888 mg of the intermediate 1-((4-propylphenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0130] 700 mg of 1-((4-propylphenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF with 272 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 236 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 234 mg of hydroxylamine hydrochloride and 470 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 0.16 g of N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide. 1 H-NMR (500MHz, DMSO-d6): δ10.61(s,1H),8.79(s,1H),7.65(m,2H),7.38(m,2H),4.33(m,1H),3.61(m,1H) ),3.45(m,1H),2.43(t,2H,J=7.5Hz),1.76(m,1H),1.59-1.38(m,6H),1.16(m,1H),0.90(t,3H,J=7.5Hz)

[0131] (20) T-25 Synthesis of 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide 500 mg of pipecolinic acid was mixed thoroughly with 8 mL of THF, and then 8.9 mL of 1 M Na2CO3 was added. 1.09 g of N-acetylsulfanilyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 935 mg of the intermediate 1-((4-acetamidophenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0132] 800 mg of 1-((4-acetamidophenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF with 296 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 258 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 256 mg of hydroxylamine hydrochloride and 512 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by concentrating under reduced pressure. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 0.18 g of 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.60(s,1H),10.32(s,1H),8.78(s,1H),7.74(m,2H),7.68(m,2H),4.3 0(m,1H),3.61(m,1H),3.45(m,1H),2.09(s,3H),1.76(m,1H),1.51(m,1H),1.39(m,3H),1.16(m,1H)

[0133] (21) Synthesis of T-28 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide 500 mg of proline was mixed thoroughly with 9 mL of THF, and then 10 mL of 1 M Na2CO3 was added. 1.21 g of 4-tert-butylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain the intermediate ((tert-butyl)phenyl)sulfonyl)proline 860 mg. This intermediate was used in the next reaction without any special purification.

[0134] 700 mg of ((4-(tert-butyl)phenyl)sulfonyl)proline was dissolved in 5 mL of THF with 272 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0°C. 236 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 234 mg of hydroxylamine hydrochloride and 470 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added, and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 546 mg of 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ10.66(s,1H),8.94(s,1H),7.78(m,2H),7.64(m,2H),3.91(m,1H),3.30(m,1H),3.13(m,1H),1.88(m,1H) 1.75(m,1H) 1.66(m,1H),1.46(m,1H),1.31(s,9H)

[0135] (22) T-29 Synthesis of 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide 500 mg of proline was thoroughly mixed with 9 mL of THF, and then 10 mL of 1 M Na2CO3 was added. 1.30 g of 4-butoxybenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, then dried over MgSO4, and concentrated under reduced pressure to obtain 1.2 g of the intermediate ((4-butoxyphenyl)sulfonyl)proline. This intermediate was used in the next reaction without any special purification.

[0136] 1 g of ((4-butoxyphenyl)sulfonyl)proline was dissolved in 7 mL of THF with 369 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 321 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 318 mg of hydroxylamine hydrochloride and 639 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 370 mg of 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide. 1H-NMR (500MHz, DMSO-d6): δ10.65(s,1H),8.93(s,1H),7.76(m,2H),7.12(m,2H),4.07(t,2H,J=6.5Hz),3.88 (m,1H),3.39(m,1H),3.11(m,1H),1.83(m,1H),1.74(m,3H),1.63(m,1H),1.45(m,3H),0.94(t,3H,J=8.5Hz)

[0137] (23) Synthesis of T-32 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide 50 mg of proline was thoroughly mixed with 0.9 mL of THF, and then 1 mL of 1 M Na2CO3 was added. 162 mg of 4-(1-Adamantyl)benzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 2 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 2 mL of ethyl acetate, then dried over MgSO4, and concentrated under reduced pressure to obtain 171 mg of the intermediate ((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)proline. This intermediate was used in the next reaction without any special purification.

[0138] 130 mg of ((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)proline was dissolved in 2 mL of THF with 40 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 35 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 35 mg of hydroxylamine hydrochloride and 70 μL of triethylamine were added dropwise to a solution in 1 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 90 mg of 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ10.66(s,1H),8.95(s,1H),7.77(m,2H),7.62(m,2H),3.91(m,1H),3 .39(m,1H),3.12(m,1H),2.15(s,3H),1.89-1.75(m,13H),1.65(m,1H),1.50(m,1H),1.16(m,1H)

[0139] (24) Synthesis of T-33 N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide 500 mg of proline was thoroughly mixed with 9 mL of THF, and then 10 mL of 1 M Na2CO3 was added. 932 μL of 4-n-Propylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, then dried over MgSO4, and concentrated under reduced pressure to obtain 1 g of the intermediate ((4-propylphenyl)sulfonyl)proline. This intermediate was used in the next reaction without any special purification.

[0140] 900 mg of ((4-propylphenyl)sulfonyl)proline was dissolved in 6 mL of THF with 366 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 318 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 315 mg of hydroxylamine hydrochloride and 633 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 665 mg of N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.66(s,1H),8.94(s,1H),7.76(m,2H),7.46(m,2H),3.90(m,1H),3.38(m,1H), 3.14(m,1H),2.66(t,2H,J=9Hz),1.83(m,1H),1.75(m,1H),1.65(m,2H),1.44(m,2H),0.89(t,3H,J=7.5Hz)

[0141] (25) T-34 Synthesis of 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide 500 mg of proline was thoroughly mixed with 9 mL of THF, and then 10 mL of 1 M Na2CO3 was added. 1.14 g of 4-Acetylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 20 mL of ethyl acetate, then dried with MgSO4, and concentrated under reduced pressure to obtain the intermediate ((4-acetylphenyl)sulfonyl)proline 958 mg. This intermediate was used in the next reaction without any special purification.

[0142] 800 mg of ((4-acetylphenyl)sulfonyl)proline was dissolved in 6 mL of THF with 325 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 283 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 280 mg of hydroxylamine hydrochloride and 563 μL of triethylamine were added dropwise to a solution in 4 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 110 mg of 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ10.72(s,1H),8.97(s,1H),8.15(m,2H),7.97(m,2H),3.95 (m,1H),3.43(m,1H),3.13(m,1H),2.65(s,3H),1.86(m,1H),1.72(m,2H),1.48(m,1H)

[0143] (26) Synthesis of T-35 N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide 1 g of pipecolinic acid was mixed thoroughly with 16 mL of THF, and then 17.8 mL of 1 M Na2CO3 was added. 2.04 g of 4-acetylbenzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 20 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 40 mL of ethyl acetate, dried over MgSO4, and then concentrated under reduced pressure to obtain 1.21 g of the intermediate 1-((4-(1-(hydroxyamino)ethyl)phenyl)sulfonyl)piperidine-2-carboxylic acid. This intermediate was used in the next reaction without any special purification.

[0144] 1 g of 1-((4-(1-(hydroxyamino)ethyl)phenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 10 mL of THF with 388 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 338 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 446 mg of hydroxylamine hydrochloride and 895 μL of triethylamine were added dropwise to a solution in 6 mL of DMF. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 0.18 g of N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide. 1H-NMR (500MHz, DMSO-d6): δ11.55(s,1H),10.63(s,1H),8.79(s,1H),7.82(m,2H),7.75(m,2H),4.3 5(m,1H),3.63(m,1H),3.47(m,1H),3.32(s,3H),1.74(m,1H),1.54(m,1H),1.45(m,3H),1.20(m,1H)

[0145] (27) Synthesis of T-36 N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide 500 mg of leucine was thoroughly mixed with 8 mL of THF, and then 8.8 mL of 1 M Na2CO3 was added. 584 μL of benzenesulfonyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was washed twice with 10 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. The mixture was extracted with 20 mL of ethyl acetate, dried with MgSO4, and then concentrated under reduced pressure to obtain 444 mg of the intermediate (phenylsulfonyl)leucine. This intermediate was used in the next reaction without any special purification.

[0146] 400 mg of (phenylsulfonyl)leucine was dissolved in 5 mL of THF with 178 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 155 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 154 mg of hydroxylamine hydrochloride and 308 μL of triethylamine were added dropwise to a solution of DMF in 2 mL. The mixture was stirred at room temperature for 30 minutes, and then the DMF was removed by reducing the pressure of the solution. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was recovered and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (Hexane:Ethyl acetate = 1:1) to obtain 0.11 g of N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide. 1 H-NMR (500MHz, DMSO-d6): δ10.65(s,1H),8.81(s,1H),8.00(m,1H),7.77(m,2H),7.57(m,1H),7.5 5(m,2H),3.48(m,1H),1.43(m,1H),1.35-1.20(m,2H),0.72(d,3H,J=6.5Hz),0.60(d,3H,J=7.0Hz)

[0147] (28) Synthesis of T-40 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide 1 g of proline was thoroughly mixed with 18 mL of THF, and then 20 mL of 1 M Na2CO3 was added. 2.44 g of N-acetylsulfanilyl chloride was slowly added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was washed twice with 20 mL of diethyl ether, and then the pH of the aqueous layer was adjusted to pH 2 with 3 M HCl. The mixture was extracted twice with 40 mL of ethyl acetate, then dried with MgSO4, and concentrated under reduced pressure to obtain the intermediate ((4-acetamidophenyl)sulfonyl)proline 483 mg. This intermediate was used in the next reaction without any special purification.

[0148] 450 mg of ((4-acetamidophenyl)sulfonyl)proline was dissolved in 6 mL of THF with 174 μL of NMO (N-Methylmorpholine-N-oxide) and stirred at 0°C. 152 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred at the same temperature for 2 hours. The solid in the reaction mixture was filtered, and the resulting filtrate was stored separately. Then, 200 mg of hydroxylamine hydrochloride and 401 μL of triethylamine were dissolved in 1.5 mL of DMF and added dropwise. The mixture was stirred at room temperature for 2 hours, and then the DMF was removed by reducing the pressure of the concentration. Ethyl acetate and purified water were added and the layers were separated. The aqueous layer was then extracted twice more using ethyl acetate. The organic layer was collected and then concentrated under reduced pressure. The resulting solid was purified by column chromatography (5% MeOH in DCM) to obtain 120 mg of 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide. 1H-NMR(500MHz,DMSO-d6):δ10.64(s,1H),10.38(s,1H),8.91(s,1H),7.79(m,4H),3.9 0(m,1H),3.41(m,1H),3.11(m,1H),2.09(s,3H),1.82(m,1H),1.70(m,2H),1.42(m,1H)

[0149] [Example of experiment] Human monocyte cell line THP-1 cells were seeded at 1 × 10⁶ cells / well in 96-well clear-bottom blackwells and treated with 20 ng / mL PMA (phorbol 12-myristate 13-acetate) to induce macrophage differentiation. After culturing for 3 days, 28 experimental amide compounds were dissolved in DMSO at 1000× and added to the culture medium to a concentration of 1 μM or 10 μM, and the cells were treated and cultured for 24 hours. Cytochalasin D, known to inhibit phagocytosis, was used as a negative control.

[0150] 0.5 mg / mL pHrodo in each well TM Red S. aureus BioParticles TM Each group was treated with 80 μL of Conjugate (ThermoFisher Scientific) and incubated at 37°C for 3 hours. Fluorescence was then measured using a fluorometer (emission 560 nm / excitation 585 nm). Since pHrodo fluoresces only under acidic conditions, an increase in the fluorescence signal indicates increased phagocytosis of S. aureus. Fluorometry measurements confirmed increased phagocytosis of S. aureus by macrophages in groups treated with 13 novel amide compounds (T01, T02, T03, T07, T13, T14, T15, T17, T23, T29, T33) (Figures 1 and 2).

Claims

1. An immunoenhancing composition comprising a compound represented by the following general formula (1), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate as an active ingredient. 【Chemistry 1】 In general formula (1), The aforementioned X is represented by one of the following general (1-1) to (1-5): 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 In general formula (1-1), Ar is unsubstituted or has 1 to 3 R １ It is a phenyl substituted with, R １ These are hydrogen, a phenyl group, a C1-C4 alkoxy group, a C1-C4 alkyl group, a fluoro group, an adamantane group, an acetylamino group, or a hydroxyiminoethyl group. R １ If there is more than one residue, all R １ The residues are identical, In general formula (1-2), Ar is one R ２ It is a phenyl substituted with, R ２ These are C1-C4 alkyl groups, C1-C4 alkoxy groups, adamantane groups, acetyl groups, or acetylamino groups. In general formula (1-3), Ar has 1 to 3 R ３ A phenyl or unsubstituted naphthalene, R ３ is hydrogen, or a C1-C4 alkyl group or phenyl group, R ３ When there is more than one residue, all R ３ residues are the same, In general formula (1-4), Ar is unsubstituted or has 1 to 3 R ４ It is a phenyl substituted with, R ４ These are hydrogen, a phenyl group, a C1-C4 alkyl group, or a C1-C4 alkoxy group. R ４ If there is more than one residue, all R ４ The residues are identical, In general formula (1-5), Ar has 1 to 3 R ５ It is a phenyl substituted with, R ５ These are C1-C4 alkyl groups or phenyl groups. R ５ If there is more than one residue, all R ５ The residues are identical.

2. The composition according to claim 1, wherein the compound represented by the general formula (1) is selected from the following compounds. N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-phenylpropanamide, N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamide)propanamide, N-hydroxy-2-(naphthalene-2-sulfonamide)-3-phenylpropanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide, 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide, 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide, 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide, N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide, and 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

3. The composition according to claim 1, wherein the compound represented by the general formula (1) is selected from the following compounds. N-hydroxy-1-(phenylsulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-phenylpropanamide, 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)pentanamide, 2-([1,1'-biphenyl]-4-sulfonamide)-N-hydroxy-3-methylbutanamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, and N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide.

4. The composition according to claim 1, wherein the compound represented by the general formula (1) is derived from an amino acid.

5. The composition according to claim 1, wherein the composition is for activating the phagocytic activity of macrophages.

6. The composition according to claim 1, wherein the composition is for activating macrophage phagocytosis against Staphylococcus aureus.

7. The composition according to claim 1, wherein the composition is for strengthening the skin barrier.

8. The composition according to claim 1, wherein the composition is for suppressing skin inflammation.

9. The composition according to any one of claims 1 to 8, wherein the composition is a cosmetic composition.

10. The composition according to any one of claims 1 to 8, wherein the composition is a topical skin preparation.

11. The composition according to any one of claims 1 to 8, wherein the composition is a food composition.

12. The composition according to any one of claims 1 to 8, wherein the composition is a pharmaceutical composition.

13. The composition according to claim 12, wherein the pharmaceutical composition is for the prevention, improvement, or treatment of skin inflammation.

14. The composition according to any one of claims 1 to 8, wherein the amount of the active ingredient is 0.01 μM to 100 mM relative to the total volume of the composition.

15. The composition according to any one of claims 1 to 8, wherein the daily dose of the active ingredient is 1 to 1000 mg / kg.

16. The composition according to any one of claims 1 to 8, wherein the active ingredient is used to treat cells at a concentration of 1 to 100 μM.

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