Compositions containing amide compounds for anti-aging, skin whitening, or reverse skin aging

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 restores the size and number of projections of aged melanin-producing cells to those of young cells, thereby exhibiting an anti-aging or reverse-aging effect on the skin. As a result, it can exert a skin whitening effect by suppressing the amount of melanin produced by melanin-producing cells.

Description

[Technical Field]

[0001] The present invention discloses compositions comprising amide compounds for skin anti-aging, skin whitening, or skin reverse-aging. [Background technology]

[0002] Melanin-producing cells in human skin, when aged by light, produce excessive melanin, leading to age-related hyperpigmentation.

[0003] Specifically, when exposed to ultraviolet (UV) light, the skin produces melanin for self-protection, and returns to its original state when the UV light is removed. However, with age, even without UV light, the skin continues to produce excessive melanin due to the memory of past UV exposure, leading to hyperpigmentation such as moles and melasma.

[0004] Conventional skin tone care products designed to address this problem primarily focus on preventative effects. Therefore, there are few active ingredients that can treat skin pigmentation that has already occurred due to causes such as UV radiation or inflammation. However, to suppress excessive skin pigmentation, both prevention and treatment are necessary. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2003 / 101382 [Overview of the project] [Problems that the invention aims to solve]

[0006] In one aspect of the present disclosure, an object of the present invention is to provide a composition for skin anti-aging, skin whitening or skin reverse aging, which contains a novel compound derived from an amino acid structure such as valine, leucine, phenylalanine, proline, or pipecolic acid.

Means for Solving the Problems

[0007] In one aspect, the present specification provides a composition for skin anti-aging, skin whitening or skin reverse aging, which contains, as an active ingredient, a compound represented by the following general formula (1), its stereoisomer, its pharmaceutically acceptable salt, its hydrate or its solvate.

[0008]

Chemical Formula

[0009] In general formula (1), X is represented by any one of the following general (1-1) to (1-5),

[0010]

Chemical Formula

[0011]

Chemical Formula

[0012]

Chemical Formula

[0013]

Chemical Formula

[0014]

Chemical Formula

[0015] 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-C3 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 or a C1-C4 alkyl group. If there is more than one R3 residue, all R3 residues are identical, and preferably, R3 is a C1-C4 alkyl group. 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. If there is more than one R5 residue, all R5 residues are identical. [Effects of the Invention]

[0016] In one embodiment, a composition comprising the novel amide compounds disclosed herein can exert a reverse aging effect by restoring the size and number of projections of aged melanin-producing cells to those of young cells, and as a result, can exert a skin whitening effect by suppressing the amount of melanin produced by melanin-producing cells. [Brief explanation of the drawing]

[0017] [Figure 1A] This figure shows the results of observing the cellular anti-aging effect of a composition according to one embodiment of this disclosure. [Figure 1B] This figure shows the results of observing the cellular anti-aging effect of a composition according to one embodiment of this disclosure. [Figure 2A] This figure shows the results of observing the melanin production inhibitory effect of a composition according to one embodiment of this disclosure. [Figure 2B] This figure shows the results of observing the melanin production inhibitory effect of a composition according to one embodiment of this disclosure. [Figure 3A] This figure shows the results of observing the gene expression inhibitory effect of a composition according to one embodiment of this disclosure on the melanin-producing enzyme (TRP2). [Figure 3B] This figure shows the results of observing the melanin-degrading effect of a composition according to one embodiment of the present disclosure. [Figure 4A] This figure shows the results of observing the inhibitory effect of a composition according to one embodiment of this disclosure on the expression of the senescence gene (p21). [Figure 4B] This figure shows the results of observing the inhibitory effect of a composition according to one embodiment of this disclosure on the expression of the senescence gene (p16). [Figure 5] This figure shows the results of observing the melanin-degrading effect of a composition according to one embodiment of the present disclosure. [Figure 6] This figure shows the results of observing the gene expression inhibitory effect of a composition according to one embodiment of this disclosure on the melanin-producing enzyme (TRP2). [Figure 7] This figure shows the results of observing the inhibitory effect of a composition according to one embodiment of this disclosure on the expression of the senescence gene (p16). [Modes for carrying out the invention]

[0018] The Disclosure will be described in more detail below with reference to the embodiments described. However, the embodiments described below are merely illustrative to aid in understanding the Disclosure, and the scope and nature of the Disclosure are not limited thereto.

[0019] In exemplary implementations of this disclosure, compositions for anti-aging, skin whitening, or reverse skin aging are provided, comprising as active ingredients a compound represented by the following general formula (1), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

[0020] [ka]

[0021] In general formula (1), The aforementioned X is represented by one of the following general (1-1) to (1-5):

[0022] [ka]

[0023] [ka]

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027] 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-C3 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 or a C1-C4 alkyl group. If there is more than one R3 residue, all R3 residues are identical, and preferably, R3 is a C1-C4 alkyl group. 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. If there is more than one R5 residue, all R5 residues are identical.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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).

[0032] 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).

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] Another exemplary embodiment of the present disclosure provides a method for anti-aging, skin whitening, or skin re-aging, comprising administering 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, in an effective amount to a subject requiring it.

[0038] In another exemplary embodiment of the present disclosure, uses of the compound represented by general formula (1), its stereoisomers, its pharmaceutically acceptable salts, its hydrates or solvates for the production of compositions for anti-aging, skin whitening, or reverse skin aging are provided.

[0039] In another exemplary embodiment of the present disclosure, non-therapeutic uses of the compound represented by general formula (1), its stereoisomers, its pharmaceutically acceptable salts, its hydrates or solvates for skin anti-aging, skin whitening, or skin reverse aging are provided.

[0040] According to this disclosure, treatment with the aforementioned active ingredients can reduce the size and number of dendrites of model cells that have enlarged in size and developed many protrusions due to aging, making them smaller and more like young cells. Furthermore, it can inhibit the expression of aging genes, inhibit the expression of melanin-producing enzymes, and reduce excessive melanin production to the level of young cells.

[0041] For example, the anti-aging composition may be for anti-aging of the skin or for anti-aging of melanin-producing cells.

[0042] 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-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide, 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-((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.

[0043] In one implementation example, the compound represented by the general formula (1) may be represented by any of the following general formulas.

[0044] [ka]

[0045] In one 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, 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-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, and N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolin-2-carboxamide.

[0046] In one example, the compound represented by the general formula (1) may be derived from an amino acid.

[0047] For example, the compound represented by the general formula (1) may be derived from any of the following amino acids.

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] In one example, the composition may be intended to restore aged melanin-producing cells to young melanin-producing cells.

[0054] In one embodiment, the composition may be for inhibiting the expression of at least one gene, P21, and P16.

[0055] In one example, the composition may be for the purpose of suppressing melanin production.

[0056] In one implementation example, the composition may be for inhibiting the mRNA expression of tyrosinase-related protein 2.

[0057] In one example, the composition may be a cosmetic composition.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] In one example, the composition may be a topical skin preparation.

[0068] 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.

[0069] In one example, the composition may be a food composition.

[0070] The food 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. In addition to the active ingredients, the food composition relating to this disclosure may optionally contain excipients, sugars, flavorings, colorings, oils and fats, proteins, etc.

[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 excessive skin pigmentation.

[0076] In one example, the pharmaceutical composition may be for treating a subject in which the expression of at least one gene, P21 and P16, is activated.

[0077] In one example, the pharmaceutical composition may be for treating a subject in which melanin production is activated.

[0078] In one example, the pharmaceutical composition may be for treating a subject in which the mRNA expression of tyrosinase-related protein 2 is activated.

[0079] As used herein, the term “prevention” means any action that suppresses or delays the onset of a disease by administering the pharmaceutical composition relating to this disclosure.

[0080] 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.

[0081] As used herein, the term “treatment” means any action that improves or favorably alters the symptoms of a disease by administering the pharmaceutical composition relating to this disclosure.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] In one example, the daily dose of the active ingredient may be 1 to 1000 mg / kg.

[0087] 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.

[0088] 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.

[0089] In one implementation example, the active ingredient may be used to treat cells at a concentration of 1 to 100 μM.

[0090] 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.

[0091] The Disclosure will be described in more detail below with reference to the embodiments described. However, the embodiments described below are merely illustrative to aid in understanding the Disclosure, and the scope and nature of the Disclosure are not limited thereto.

[0092] [Embodiment] [Manufacturing example] The following novel compounds were synthesized. The IUPAC names of the 25 novel compounds are shown in Table 1 below.

[0093] [Table 1]

[0094] (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.

[0095] 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)

[0096] (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.

[0097] 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)

[0098] (3) 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.

[0099] 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. 1H-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)

[0100] (4) 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.

[0101] 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. 1 H-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)

[0102] (5) 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.

[0103] 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)

[0104] (6) 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.

[0105] 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)

[0106] (7) 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.

[0107] 1.1 g of (naphthalen-2-ylsulfonyl)phenylalanine was dissolved in 20 mL of THF with 0.37 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0°C. 0.32 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, 0.32 g of hydroxylamine hydrochloride and 0.65 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 0.21 g of N-hydroxy-2-(naphthalene-2-sulfonamide)-3-phenylpropanamide. 1 H-NMR (500MHz, DMSO-d6): δ10.63(s,1H),8.84(s,1H),8.32(d,1H,J=9.5Hz),8.19(s,1H),8.19(m,2H),7 .92(d,1H,J=9.5Hz),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)

[0108] (8) Synthesis of T-12 2-([1,1'-biphenyl]-4-sulfonamide)-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.

[0109] 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)

[0110] (9) 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.

[0111] ((4-(tert-Butyl)phenyl)sulfonyl)leucine (1.07 g) was dissolved in 20 mL of THF together 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 then the mixture was 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 0.35 g of hydroxylamine hydrochloride and 0.7 mL of triethylamine in 20 mL of DMF. The mixture was 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 = 1:1) to obtain 0.15 g of 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide. 1 H-NMR (500 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.83 (s, 1H), 7.88 (m, 1H), 7.70 (d, 2H, J = 9.0 Hz), 7.57 (d, 2H, J = 8.5 Hz), 3.49 (m, 1H), 1.32 - 1.24 (m, 11H), 1.12 (m, 1H), 0.69 (d, 3H, J = 6.5 Hz), 0.55 (d, 3H, J = 6.5 Hz)

[0112] (10) Synthesis of 2-((4-butoxyphenyl)sulfonamido)-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.

[0113] 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)

[0114] (11) 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.

[0115] 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)

[0116] (12) 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.

[0117] 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. 1H-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)

[0118] (13) 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.

[0119] 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. 1 H-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)

[0120] (14) 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.

[0121] 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. 1H-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)

[0122] (15) 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.

[0123] 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. 1 H-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)

[0124] (16) 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.

[0125] 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. 1H-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)

[0126] (17) 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.

[0127] 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. 1 H-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)

[0128] (18) 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.

[0129] 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. 1H-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)

[0130] (19) Synthesis of T-29 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.

[0131] 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. 1 H-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)

[0132] (20) 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.

[0133] 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. 1H-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)

[0134] (21) 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.

[0135] 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 of DMF in 4 mL. 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 separated from the aqueous layer by ethyl acetate. The mixture was extracted twice more using 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. 1 H-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)

[0136] (22) 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.

[0137] 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)

[0138] (23) 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.

[0139] 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. 1 H-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)

[0140] (24) 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.

[0141] 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. 1H-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)

[0142] (25) T-40 Synthesis of 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.

[0143] 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, then concentrated under reduced pressure, and 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. 1 H-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)

[0144] [Example of experiment] The anti-aging and skin whitening effects of the novel compound were experimentally confirmed as follows. Specifically, low-dose ultraviolet light was irradiated, and then, after some time, aged skin melanin-forming cells were observed to produce excessive melanin and exhibit aging phenotypes such as enlargement in size. This was developed as an aged skin model cell. These cells were treated with the active ingredient related to this disclosure, and the anti-aging (reverse aging) and skin whitening effects were confirmed.

[0145] <Experimental Example 1> Skin anti-aging or reverse aging effect [Creation and processing of aged, hyperpigmented, human normal melanin-producing model cells] Melanocytes isolated from normal human skin (Normal human epidermal melanocytes) were placed in a 6-well cell culture plate in a 2x10⁶ format. 4 Seeding was performed to obtain individual cells. The following day, it was confirmed that the cells adhered well to the culture medium and proliferated, and irradiation with UVB (312 nm) 11 mJ was performed once every two days for a total of three times. After the completion of UV irradiation, the cells were cultured for more than a week to create an aged, hyperpigmented skin cell model (untreated with the compound). Changes in cell shape and gene expression were used to confirm that the model cells had been successfully created. Subsequently, the experimental substance, a novel amide compound, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02), was diluted 1000-fold in DMSO and added to the culture medium to a concentration of 10 μM, and the cells were treated with this solution. Cells treated with DMSO alone were used as the control group (untreated with the compound). The cells were grown in a 37°C, 5% CO2 incubator for a maximum of 4 days, with the culture medium containing the experimental substance being replaced every two days.

[0146] [Evaluation of the effect of re-aging aged, hyperpigmented model cells into younger cells] When hyper-aged pigmentation model cells, repeatedly treated with low-dose UVB, were treated with 10 μM of the novel amide compound 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02), a change in cell morphology from senescent cells to young cells was observed (Figure 1A).

[0147] Cell size enlargement due to aging is a common phenotype of aging that is shared by many cells. Furthermore, during melanin production in melanocytes in the skin, the dendrites of melanocytes are involved in the dispersion of melanin to surrounding keratinocytes. It is known that an increase in the number of cell dendrites increases melanin dispersion and promotes skin pigmentation.

[0148] Incidentally, it was confirmed that treatment with 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02) restored the size of cells that had enlarged due to aging to the level of young cells, and also reduced the number of cellular protrusions, making them thinner.

[0149] At that time, RNA expression of p21 and p16, known as aging genes, was increased in photoaccelerated aging pigmentation model cells. However, treatment with 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02) was found to statistically significantly reduce the increased levels of p21 and p16 (Figure 1B). (**Control group for P<0.01)

[0150] <Experimental Example 2> Skin anti-aging effect [Quantitative analysis of melanin and gene expression in aged, hyperpigmented model cells] After the experiment in Experiment Example 1 was completed, cells were photographed using an optical microscope, and changes in cell size and shape were observed. The microscopically observed cells were measured at 2 × 10⁶ cells per sample. 5 The relative amount of melanin was compared by collecting the same number of cells from each group, dissolving them in 1N NaOH, and measuring the absorbance at 475 nm. The cells were also recovered by dissolving them in TRIzol, and total RNA was isolated. Next, cDNA was synthesized from this RNA, and real-time PCR was performed to compare the relative expression levels of each gene. The RNA was quantified, and the same amount of RNA was added to each experimental group. The expression of each gene was corrected by the expression of the cell-keeping gene GAPDH, and the relative expression levels were compared. *The gene primers used were purchased from APPLIED BIOSYSTEMS. Tyrosinase-related protein 2 (Hs01095856_m1), GAPDH (Hs02786624_g1), p21 (Hs00355782_m1), p16 (Hs00923894_m1)

[0151] [Evaluation of the melanin production inhibitory effect in aged, hyperpigmented model cells] In a hyper-aged pigmentation model cell induced by repeated low-dose UVB exposure, melanin production per cell increased by approximately three times compared to the control group. However, treatment with 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02) reduced melanin production to approximately the same level as the control group (Figure 2A). This study examined the decomposition and subsequent removal of the produced melanin.

[0152] mRNA expression of tyrosinase-related protein 2, one of the enzymes involved in melanin production, is also increased in accelerated aging pigmentation model cells. However, it was confirmed that 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide (T-02) statistically significantly suppresses this expression (Figure 2B). This is the result of examining the aspect of pre-suppressing melanin production. (**Control group for P<0.01)

[0153] <Experiment Example 3> Whitening effect Using the same method as in Experimental Example 2, we observed the presence or absence of inhibition of the gene expression of the melanin-producing enzyme (Tyrosinase-related protein 2; TRP2) and the effect of melanin degradation.

[0154] As shown in Figures 3A and 3B, statistically significant inhibition of TRP2 gene expression and a decrease in melanin levels were observed in T01, T02, T11, T13, T18, and T33.

[0155] Furthermore, as shown in Figure 5, excellent melanin-degrading effects were confirmed in T02 and T12.

[0156] Furthermore, as shown in Figure 6, when we observed whether or not TRP2 (Tyrosinase-related protein 2) gene expression was inhibited, it was confirmed that the T12 compound exhibited excellent TRP2 inhibitory effects.

[0157] In the case of skin whitening, inhibition of TRP2 expression can be interpreted as a preventative suppression of new melanin production (anti-aging). However, since the target compound is applied to pigmentation model cells that have already undergone accelerated aging through repeated low-dose UVB treatment, it can also be considered that an effect closer to reverse aging (treatment) is obtained. The melanin-degrading effect is the result of applying the test substance to cells that have already undergone excessive melanin production, and can therefore be explained as a therapeutic effect (reverse aging) through removal or degradation.

[0158] <Experimental Example 4> Anti-aging or reverse-aging effect Using the same method as in Experimental Example 1, we observed the inhibition of RNA expression of p21 and p16, which are known as aging genes.

[0159] As shown in Figures 4A and 4B, it was confirmed that T01, T02, T11, T18, and T33 exhibited statistically significant superior inhibitory effects on the expression of aging genes.

[0160] Furthermore, as shown in Figure 7, the inhibitory effect of T12 on the expression of the p16 gene was confirmed.

[0161] Since this experiment was conducted by post-treating cells that had been induced to produce excessive melanin with the test substance, the experimental results should be interpreted as an effect of melanin degradation. Furthermore, the melanin production inhibitory effect was judged to be the suppression of new melanin production by inhibiting the expression of melanin-producing enzymes, and this analysis is supported by the results of TRP2 analysis.

Claims

1. A composition for anti-aging, whitening, or reverse aging of the skin, comprising as an active ingredient a compound represented by the following general formula (1), its stereoisomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate. 【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-C3 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, R ３ When there is more than one residue, all R ３ residues are the same, and preferably, R ３ is a C1-C4 alkyl group, 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, 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-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(mesitylsulfonyl)piperidine-2-carboxamide, 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-((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, 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-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, 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 restoring aged melanin-producing cells to young melanin-producing cells.

6. The composition according to claim 1, wherein the composition is for inhibiting the expression of at least one gene, P21 and P16.

7. The composition according to claim 1, wherein the composition is for suppressing melanin production.

8. The composition according to claim 1, wherein the composition is for inhibiting the mRNA expression of tyrosinase-related protein 2.

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 excessive pigmentation of the skin.

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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