Novel amide compounds and compositions containing the same

Abstract

This specification relates to novel amide compounds derived from amino acid structures such as valine, leucine, phenylalanine, proline, or pipecolic acid, which have MMP-1, MMP-2, or MMP-9 inhibitory effects even in trace amounts, their isomers, pharmaceutically acceptable salts thereof, their hydrates, or solvates, and compositions containing the same.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority based on Republic of Korea Patent Application No. 10-2023-0042219 filed on 30 March 2023 and Republic of Korea Patent Application No. 10-2024-0041934 filed on 27 March 2024, and the entirety of this specification is incorporated as a reference to this application.

[0002] This specification discloses novel amide compounds and compositions containing the same. [Background technology]

[0003] Amino acids are organic compounds that contain an amino group, a carboxyl group, and a specific side chain (R group). The elements present in all amino acids are carbon (C), hydrogen (H), oxygen (O), and nitrogen (N). Sulfur (S) is present in the side chains of cysteine ​​and methionine, and selenium (Se) is present in the side chain of selenocysteine, a less common amino acid. In particular, of the 21 amino acids common to all living organisms, nine—phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine—are essential amino acids that humans cannot synthesize.

[0004] Meanwhile, the need for novel compounds remains high in order to secure the fundamental technologies necessary for revitalizing the South Korean cosmetics industry. Therefore, novel compounds derived from well-known amino acid compounds such as valine, leucine, phenylalanine, proline, and pipecolic acid (a proline analog) have been synthesized to develop new functional cosmetic materials. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Korean Published Patent Publication No. 10-2008-0104347 [Non-patent literature]

[0006] [Non-Patent Document 1] SCOZZAFAVA, A, et al., Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with < <P inhibitory properties act as efficient inhibitors of CA isozymes I, II and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes, J. Med. Chem. 2000, vol. 43, pp. 3677-3687. [Non-Patent Document 2] ALMSTEAD, NG et al., Design, synthesis and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors, J. Med. Chem. 1999, vol. 42, pp. 4547-4542. [Non-Patent Document 3] LENCI, E. et al., Identification of highly potent and selective MMP2 inhibitors addressing the S1' subsite with D-proline-based compounds, Bioorganic & medicinal chemistry, 2019, vol. 27, pp. 1891-1902. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In one aspect of the present disclosure, this specification aims to provide novel compounds derived from amino acid structures such as valine, leucine, phenylalanine, proline, or pipecolic acid, and compositions containing them.

[0008] In one aspect of the present disclosure, this specification aims to provide novel compounds having an inhibitory effect on MMP (Matrix MetalloProteinase) and compositions containing the same.

Means for Solving the Problems

[0009] In one aspect, this specification provides a compound represented by the following general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0010]

Chemical Formula

[0011] In the general formula (1), the X is represented by any one of the following general formulas (1-1) to (1-5),

[0012]

Chemical Formula

[0013]

Chemical Formula

[0014]

Chemical Formula

[0015]

Chemical Formula

[0016]

Chemical Formula

[0017] 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 are two or three R1 residues, the 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 are two or three R3 residues, the 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 are two or three R4 residues, the 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 are two or three R5 residues, the R5 residues are identical.

[0018] In another embodiment, this specification provides a composition comprising a compound represented by the general formula (1) as an active ingredient.

[0019] In another embodiment, this specification provides a method for producing the compound represented by the general formula (1), comprising the step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with a sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide. [Effects of the Invention]

[0020] In one embodiment, the novel compounds disclosed herein and compositions containing the same can exert inhibitory effects on various MMPs (Matrix MetalloProteinases) at low nanomolar concentrations (nM), such as 500 nM or less. [Modes for carrying out the invention]

[0021] The present disclosure will be described in more detail below by the embodiments described. However, the embodiments described below are merely illustrative to aid in understanding the present disclosure, and the scope and nature of the present disclosure are not limited thereto.

[0022] Exemplary embodiments of the present disclosure provide compounds represented by the following general (1), their isomers, pharmaceutically acceptable salts thereof, their hydrates or solvates.

[0023] [ka] In general formula (1), The aforementioned X is represented by one of the following general (1-1) to (1-5):

[0024] [ka]

[0025] [ka]

[0026] [ka]

[0027] [ka]

[0028] [ka]

[0029] 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 are two or three R1 residues, the 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 are two or three R3 residues, the 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 are two or three R4 residues, the 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 are two or three R5 residues, the R5 residues are identical.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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).

[0034] 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).

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] According to an example of the implementation of this disclosure, the compound represented by the general formula (1) is a novel activating functional cosmetic material for the Korean cosmetics industry, a novel compound derived from an amino acid structure, and may be a novel multifunctional compound that exhibits an inhibitory effect on MMP-1 (Collagenase) and / or MMP-2 & MMP-9 (Gelatinases) at low nanomolar concentrations (nM), such as 500 nM or less, for example, on food compositions or cosmetic compositions.

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

[0041] In one example, the compound represented by the general formula (1) may be represented by any of the following general formulas.

[0042] [ka]

[0043] In one example, the compound represented by the general formula (1) may be derived from an amino acid. For example, the compound represented by the general formula (1) may be derived from any of the following amino acids.

[0044] [ka]

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] Another exemplary embodiment of the present disclosure provides a composition comprising at least one compound represented by the general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[0050] In one example, the content of the compound represented by the general formula (1) may be 0.01 μM to 100 mM relative to the total volume of the composition.

[0051] 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.

[0052] For example, the content may be 0.01 μM to 100 mM, preferably 0.05 μM to 10 mM, and more preferably 0.1 μM to 4 mM, relative to the total volume of the composition.

[0053] 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.

[0054] In one implementation example, the composition may be used for inhibiting MMP-1 activity.

[0055] In one implementation example, the composition may be used for inhibiting MMP-2 activity.

[0056] Compositions containing the novel compounds described herein may, in particular, be used to inhibit MMP-2 activity. MMP-2 is a gelatinase that degrades basement membrane collagen IV and is effective in the skin. MMP-2 plays a particularly important role in the dermis and is crucial for maintaining and protecting collagen IV at healthy levels.

[0057] In one implementation example, the composition may be used for inhibiting MMP-9 activity.

[0058] In one example, the composition may be a cosmetic composition containing at least one compound represented by the general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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 stearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, or microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth.

[0066] 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.

[0067] 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.

[0068] In one example, the composition may be a food composition containing at least one compound represented by the general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[0069] 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.

[0070] Another exemplary embodiment of the present disclosure provides a method for producing the compound represented by the general formula (1), comprising the step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with a sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide.

[0071] In one implementation example, the sulfonyl halide may be a sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide.

[0072] In one implementation example, the sulfanilyl halide may be sulfanilyl fluoride, sulfanilyl chloride, sulfanilyl bromide, or sulfanilyl iodide.

[0073] In one embodiment, the production method may further include the step of reacting the intermediate obtained by the reaction with hydroxylamine (free form) or a hydroxylamine salt (salt form) to obtain a compound represented by general formula (1).

[0074] In one example, the hydroxylamine salt may be hydroxylamine hydrochloride.

[0075] In one example, the sulfonyl chloride is selected from the group consisting of benzenesulfonyl chloride, 4-biphenylsulfonyl chloride, 4-butoxybenzene-1-sulfonyl chloride, 2-mesitylenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(1-adamantyl)benzenesulfonyl chloride, 4-n-propylbenzenesulfonyl chloride, and 4-acetylbenzenesulfonyl chloride, and the sulfanillyl chloride may be N-acetylsulfanillyl chloride.

[0076] Another exemplary embodiment of the present disclosure provides a method for inhibiting the activity of MMP-1, comprising administering an effective amount of a composition containing the compound represented by the general formula (1), its isomers, pharmaceutically acceptable salts thereof, its hydrates or solvates as an active ingredient to a subject requiring it.

[0077] Another exemplary embodiment of the present disclosure provides a method for inhibiting the activity of MMP-2, comprising administering an effective amount of a composition containing the compound represented by the general formula (1), its isomers, pharmaceutically acceptable salts thereof, its hydrates or solvates as an active ingredient to a subject requiring it.

[0078] Another exemplary embodiment of the present disclosure provides a method for inhibiting the activity of MMP-9, comprising administering an effective amount of a composition containing the compound represented by the general formula (1), its isomers, pharmaceutically acceptable salts thereof, its hydrates or solvates as an active ingredient to a subject requiring it.

[0079] Another exemplary embodiment of the present disclosure provides uses for the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for producing compositions for inhibiting MMP-1 activity.

[0080] Another exemplary embodiment of the present disclosure provides uses for the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for producing compositions for inhibiting MMP-2 activity.

[0081] Another exemplary embodiment of the present disclosure provides uses for the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for producing MMP-9 activity inhibitory compositions.

[0082] Another exemplary embodiment of the present disclosure provides non-therapeutic uses of the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for inhibiting MMP-1 activity.

[0083] Another exemplary embodiment of the present disclosure provides non-therapeutic uses of the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for inhibiting MMP-2 activity.

[0084] Another exemplary embodiment of the present disclosure provides non-therapeutic uses of the compound represented by general formula (1), its isomers, its pharmaceutically acceptable salts, its hydrates or solvates for inhibiting MMP-9 activity.

[0085] [Specific example] Specific example 1: Compounds represented by the general (1) below, their isomers, their pharmaceutically acceptable salts, their hydrates or solvates:

[0086] [ka]

[0087] In general formula (1), The aforementioned X is represented by one of the following general (1-1) to (1-5):

[0088] [ka]

[0089] [ka]

[0090] [ka]

[0091] [ka]

[0092] [ka]

[0093] 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 are two or three R1 residues, the 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 are two or three R3 residues, the 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 are two or three R4 residues, the 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 are two or three R5 residues, the R5 residues are identical.

[0094] Specific Example 2: In Specific Example 1, the compound represented by the general formula (1) is one 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.

[0095] Specific example 3: In Specific example 1 or 2, the compound represented by the general formula (1) is one 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, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide, 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide, 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-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, and N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide.

[0096] Specific Example 4: In any one of Specific Examples 1 to 3, the compound represented by the general formula (1) is one of the following compounds: 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, and 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0097] Specific example 5: In any one of Specific Examples 1 to 4, the compound represented by the general formula (1) is a compound derived from an amino acid.

[0098] Specific example 6: A cosmetic composition containing as an active ingredient a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, its isomer, a pharmaceutically acceptable salt thereof, its hydrate or solvate.

[0099] Specific Example 7: A cosmetic composition in which, in Specific Example 6, the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM relative to the total volume of the composition.

[0100] Specific example 8: A food composition containing as an active ingredient a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, its isomer, a pharmaceutically acceptable salt thereof, its hydrate or solvate.

[0101] Specific example 9: A food composition in which, in Specific Example 8, the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM relative to the total volume of the composition.

[0102] Specific Example 10: A composition for inhibiting MMP-1 activity, comprising as an active ingredient a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, its isomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

[0103] Specific Example 11: In Specific Example 10, the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM relative to the total volume of the composition, for use as an MMP-1 activity inhibitor.

[0104] Specific Example 12: A composition for inhibiting MMP-2 activity, comprising as an active ingredient a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, its isomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

[0105] Specific Example 13: A composition for inhibiting MMP-2 activity, wherein, in Specific Example 12, the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM relative to the total volume of the composition.

[0106] Specific Example 14: A composition for inhibiting MMP-9 activity, comprising as an active ingredient a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, its isomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

[0107] Specific Example 15: In Specific Example 14, the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM relative to the total volume of the composition, for use as an MMP-9 activity inhibitor.

[0108] Specific Example 16: A method for producing a compound represented by general formula (1) relating to any one of Specific Examples 1 to 5, A method for producing a product, comprising the step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with a sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide.

[0109] Specific Example 17: The manufacturing method in Specific Example 16 further comprises the step of reacting the intermediate obtained by the reaction with hydroxylamine (free form) or a hydroxylamine salt (salt form) to obtain a compound represented by general formula (1).

[0110] Specific Example 18: A method for producing the sulfonyl halide in Specific Example 16 or 17, wherein the sulfonyl halide is sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide, and the sulfanilyl halide is sulfanilyl fluoride, sulfanilyl chloride, or sulfanilyl iodide.

[0111] Specific Example 19: In any one of Specific Examples 16 to 18, the sulfonyl chloride is selected from the group consisting of benzenesulfonyl chloride, 4-biphenylsulfonyl chloride, 4-butoxybenzene-1-sulfonyl chloride, 2-mesitylenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(1-adamantyl)benzenesulfonyl chloride, 4-n-propylbenzenesulfonyl chloride, and 4-acetylbenzenesulfonyl chloride. A method for producing the sulfanillyl chloride, wherein the sulfanillyl chloride is N-acetylsulfanillyl chloride.

[0112] [Embodiment] The present disclosure will be described in more detail below by the embodiments described. However, the embodiments described below are merely illustrative to aid in understanding the present disclosure, and the scope and nature of the present disclosure are not limited thereto.

[0113] [Examples] [Manufacturing example] The following novel compounds were synthesized. The IUPAC names of the 25 novel compounds are shown in Table 1 below.

[0114] [Table 1]

[0115] (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.

[0116] 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):δ 10.62(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)

[0117] (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.

[0118] 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):δ 10.67(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)

[0119] (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.

[0120] 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):δ 10.61(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)

[0121] (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.

[0122] 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 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-1-(mesitylsulfonyl)piperidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ 10.48(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)

[0123] (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.

[0124] 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):δ 10.61(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)

[0125] (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.

[0126] 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):δ 10.59(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)

[0127] (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.

[0128] 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):δ 10.63(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)

[0129] (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.

[0130] 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):δ 10.66(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)

[0131] (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.

[0132] ((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 the solution was 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. Subsequently, 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-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)

[0133] (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.

[0134] 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):δ 10.61(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)

[0135] (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.

[0136] 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):δ 10.51(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)

[0137] (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.

[0138] 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):δ 10.50(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)

[0139] (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.

[0140] 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):δ 10.43(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)

[0141] (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.

[0142] 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):δ 10.63(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)

[0143] (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.

[0144] 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 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 30 mg of 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide. 1 H-NMR(500MHz,DMSO-d6):δ 10.61(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)

[0145] (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.

[0146] 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):δ 10.61(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)

[0147] (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.

[0148] 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):δ 10.60(s,1H),10.32(s,1H),8.78(s,1H),7.74(m,2H),7.68(m,2H),4.30(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)

[0149] (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.

[0150] 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):δ 10.66(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)

[0151] (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.

[0152] 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):δ 10.65(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)

[0153] (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.

[0154] 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):δ 10.66(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)

[0155] (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.

[0156] 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):δ 10.66(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)

[0157] (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.

[0158] 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. 1H-NMR(500MHz,DMSO-d6):δ 10.72(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)

[0159] (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.

[0160] 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):δ 11.55(s,1H),10.63(s,1H),8.79(s,1H),7.82(m,2H),7.75(m,2H),4.35(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)

[0161] (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.

[0162] 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):δ 10.65(s,1H),8.81(s,1H),8.00(m,1H),7.77(m,2H),7.57(m,1H),7.55(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)

[0163] (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.

[0164] 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):δ 10.64(s,1H),10.38(s,1H),8.91(s,1H),7.79(m,4H),3.90(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)

[0165] [Example of experiment] The MMP inhibitory effect of the novel compound was confirmed by experiment as follows.

[0166] 1. Experimental Design The enzyme activity (%) at the same concentration was compared by treating MMP-1 at 0.5 μM and MMP-2 and MMP-9 at 50 nM (n=2). Here, enzyme activity (%) refers to the enzyme activity (%) of the experimental group, with the enzyme activity of the untreated group set to 100%.

[0167] 2. Evaluation of MMP activity To evaluate the effect of novel compounds on enzyme activity, the color change was measured using a commercially available kit from abchem, following the protocol provided below. Enzyme activity was determined by comparing the absorbance per minute with that of the untreated group. -MMP1 Inhibitor Screening Assay Kit(ab139443) -MMP2 Inhibitor Screening Assay Kit(ab139446) -MMP9 Inhibitor Screening Assay Kit(ab139448)

[0168] 3. Principles of MMP Activity Evaluation As MMP activity increases, substrate degradation occurs, leading to an increase in the OD412 value. Therefore, the change in the OD412 value (OD value) per minute was measured and calculated according to the following enzyme activity calculation formula. Here, OD412 refers to the optical density or absorbance at 412 nm. - As a chromogenic substrate, thiopeptide (Ac-PLG-[2-mercapto-4-methyl-pentanoyl]-LG-OC2H5) - The peptide bond at the MMP cleavage site was replaced with the thioester bond of the thiopeptide. Hydrolysis of this bond by MMP generates a sulfhydryl group, which reacts with DTNB [5,5''-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be measured by absorbance at 412 nm (ε = 13,600 M at pH 6.0 or higher). -1 cm -1 )

[0169] <Enzyme activity calculation formula> Novel compound enzyme activity (%) = (V 新規化合物 / V 非処理群 )*100 V = Change in OD value per minute

[0170] The enzyme activity calculation formula can also be expressed as follows.

[0171] <Inhibition effect calculation formula> Inhibition effect (%) of the novel compound = Enzyme activity of the non-treated group - Enzyme activity of the novel compound = 100 - Enzyme activity of the novel compound

[0172] 4. Experimental results The results of comparative evaluation of the single concentrations of 25 novel compounds on MMPs enzyme activity and inhibition effect are shown in Table 2 (enzyme activity, unit: %) and Table 3 (inhibition activity, unit: %) below.

[0173] [Table 2]

[0174] [Table 3]

[0175] Table 2 and Table 3 show three sets of different experimental results. For example, in the case of T-01, when treated with MMP-1 at 0.5 μM, the enzyme activity of MMP-1 remained at 34.2% (relative to 100%). In the case of MMP-2, when treated with 50 nM of T-01, the enzyme activity was 81.6% (relative to 100%). In the case of MMP-9, when treated with 50 nM of T-01, the enzyme activity was 79.1% (relative to 100%).

[0176] As can be seen from the experimental results, most of MMP-2 and MMP-9 were inhibited even at the 50 nM level, while MMP-1 was confirmed to be inhibited at the 0.5 μM level, which is 10 times higher than that.

[0177] Also, each compound showed different levels of activity inhibition against each of the three enzymes, namely MMP-1, MMP-2, and MMP-9, which is considered to be the result of the binding difference between compounds due to the structural characteristics of MMP-1, MMP-2, and MMP-9.

[0178] In other words, the reason why the inhibitory strengths of T-01 to T-40 against MMPs are different is the result of their subtle structural differences. It was confirmed that differences in structure cause differences in enzyme-binding ability, and thereby also cause differences in the inhibitory effect.

[0179] Table 4 below shows the enzyme activity (%) during high-concentration treatment, and the treatment was carried out according to the following conditions. MMP-1 (%): T-05 to 20 at 10 uM, T-23 to 34 at 5 uM MMP-2 (%): T-05 to 20 at 10 uM, T-23 to 34 at 0.5 uM MMP-9 (%): T-05 to 20 not tested, T-23 to 34 at 0.5 uM

[0180]

Table 4

[0181] Table 5 below shows the inhibitory effect (%) during high-concentration treatment, and the treatment was carried out according to the following conditions. MMP-1 (%): T-05 to 20 at 10 uM, T-23 to 34 at 5 uM MMP-2 (%): T-05 to 20 at 10 uM, T-23 to 34 at 0.5 uM MMP-9 (%): T-05 to 20 not tested, T-23 to 34 at 0.5 uM

[0182]

Table 5

Claims

1. Compounds represented by the following general (1), their isomers, their pharmaceutically acceptable salts, their hydrates or solvates. 【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 compound according to claim 1, wherein the compound represented by the general formula (1) is 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.

3. The compound according to claim 1, wherein the compound represented by the general formula (1) is 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, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butanamide, 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide, 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-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, and N-hydroxy-4-methyl-2-(phenylsulfonamide)pentanamide.

4. The compound according to claim 1, wherein the compound represented by the general formula (1) is any of the following compounds. 2-((4-(tert-butyl)phenyl)sulfonamide)-N-hydroxy-3-methylbutanamide, 1-((4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, and 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

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

6. A cosmetic composition comprising a compound represented by general formula (1) as described in any one of claims 1 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

7. The cosmetic composition according to claim 6, wherein the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM with respect to the total volume of the composition.

8. A food composition comprising a compound represented by general formula (1) as described in any one of claims 1 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

9. The food composition according to claim 8, wherein the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM with respect to the total volume of the composition.

10. A composition for inhibiting MMP-1 activity, comprising as an active ingredient a compound represented by general formula (1) as described in any one of claims 1 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

11. The MMP-1 activity inhibitory composition according to claim 10, wherein the content of the compound represented by the general formula (1), its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is 0.01 μM to 100 mM with respect to the total volume of the composition.

12. A composition for inhibiting MMP-2 activity, comprising as an active ingredient a compound represented by general formula (1) as described in any one of claims 1 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

13. The MMP-2 activity inhibitory composition according to claim 12, wherein the content of the compound represented by the general formula (1), its isomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate is 0.01 μM to 100 mM with respect to the total volume of the composition.

14. A composition for inhibiting MMP-9 activity, comprising as an active ingredient a compound represented by general formula (1) as described in any one of claims 1 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

15. The MMP-9 activity inhibitory composition according to claim 14, wherein the content of the compound represented by the general formula (1), its isomer, a pharmaceutically acceptable salt thereof, its hydrate, or its solvate is 0.01 μM to 100 mM with respect to the total volume of the composition.

16. A method for producing a compound represented by general formula (1) according to any one of claims 1 to 5, A method for producing a product, comprising the step of reacting an amino acid selected from pipecolic acid, phenylalanine, leucine, valine, and proline with a sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide.

17. The manufacturing method according to claim 16, further comprising the step of reacting the intermediate obtained by the reaction with hydroxylamine (free form) or a hydroxylamine salt (salt form) to obtain a compound represented by general formula (1).

18. The manufacturing method according to claim 16, wherein the sulfonyl halide is sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide, and the sulfanilyl halide is sulfanilyl fluoride, sulfanilyl chloride, or sulfanilyl iodide.

19. The sulfonyl chloride is one selected from the group consisting of benzenesulfonyl chloride, 4-biphenylsulfonyl chloride, 4-butoxybenzene-1-sulfonyl chloride, 2-mesitylenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(1-adamantyl)benzenesulfonyl chloride, 4-n-propylbenzenesulfonyl chloride, and 4-acetylbenzenesulfonyl chloride. The manufacturing method according to claim 18, wherein the sulfanillyl chloride is N-acetylsulfanillyl chloride.

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