Novel amide-based compound and composition comprising same

Abstract

The present specification relates to: a novel amide-based compound which is derived from an amino acid structure such as valine, leucine, phenylalanine, proline, or piperidine acid, and which has the efficacy of inhibiting MMP-1, MMP-2, or MMP-9 even in an extremely small amount; an isomer thereof; a pharmaceutically acceptable salt thereof;

Description

Technical Field

[0001] [Cross-references to related applications]

[0002] This application claims priority to Korean Patent Application No. 10-2023-0042219, filed on March 30, 2023, and Korean Patent Application No. 10-2024-0041934, filed on March 27, 2024, the contents of which are incorporated herein by reference in their entirety.

[0003] This specification discloses novel amide compounds and compositions comprising them. Background Technology

[0004] Amino acids are organic compounds containing 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 the less common amino acid selenocysteine. In particular, of the 21 amino acids common to all organisms, nine are essential amino acids that the human body cannot synthesize: phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine.

[0005] On the other hand, the demand for novel compounds continues to grow in order to ensure the basic technologies for activation used in the domestic cosmetics industry. Therefore, in order to develop new functional cosmetic materials, novel compounds derived from well-known amino acids such as valine, leucine, phenylalanine, proline, and piperidine acid (proline analogues) have been synthesized. Summary of the Invention

[0006] In one aspect of this disclosure, the aim is to provide novel compounds derived from amino acid structures such as valine, leucine, phenylalanine, proline, or piperidine, as well as compositions comprising the same.

[0007] In one aspect of this disclosure, the aim is to provide novel compounds with inhibitory effects on MMPs (Matrix Metalloproteinases) and compositions comprising the same.

[0008] In one respect, this specification provides compounds represented by the following chemical formula 1, their isomers, their pharmaceutically acceptable salts, their hydrates, or their solvates.

[0009] [Chemical Formula 1]

[0010]

[0011] In chemical formula 1,

[0012] X is represented by any one of the following chemical formulas 1-1 to 1-5.

[0013] [Chemical Formula 1-1]

[0014]

[0015] [Chemical Formula 1-2]

[0016]

[0017] [Chemical Formulas 1-3]

[0018]

[0019] [Chemical Formulas 1-4]

[0020]

[0021] [Chemical Formulas 1-5]

[0022]

[0023] In chemical formula 1-1,

[0024] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R1 atoms.

[0025] R1 is hydrogen, phenyl, C1-C4 alkoxy, C1-C3 alkyl, fluoro, adamantyl, acetamino, or hydroxyiminoethyl.

[0026] When there are two or three R1 groups, the R1 groups are identical to each other.

[0027] In chemical formulas 1-2,

[0028] Ar represents a phenyl group substituted with one R2 molecule.

[0029] R2 is a C1-C4 alkyl, C1-C4 alkoxy, adamantyl, acetyl, or acetamido.

[0030] In chemical formulas 1-3,

[0031] Ar represents a phenyl group substituted with 1 to 3 R3 radicals or an unsubstituted naphthalene group.

[0032] R3 is hydrogen or a C1-C4 alkyl group.

[0033] When there are two or three R3 groups, the R3 groups are all the same, and preferably R3 is a C1-C4 alkyl group.

[0034] In chemical formulas 1-4,

[0035] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R4 groups.

[0036] R4 is hydrogen, phenyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0037] When there are two or three R4 groups, the R4 groups are identical to each other.

[0038] In chemical formulas 1-5,

[0039] Ar is a phenyl group substituted with 1 to 3 R5 radicals.

[0040] R5 is a C1-C4 alkyl group.

[0041] When there are two or three R5 groups, the R5 groups are identical to each other.

[0042] On the other hand, this specification provides compositions comprising, as active ingredients, compounds represented by the aforementioned chemical formula 1.

[0043] On the other hand, this specification provides a method for preparing the compound represented by the aforementioned chemical formula 1, the method comprising the step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide.

[0044] In one respect, the novel compounds disclosed in this specification and compositions comprising them can exhibit inhibitory effects on a variety of MMPs (Matrix Metalloproteinases) at low nanomolar concentrations (nM), such as below 500 nM. Detailed Implementation

[0045] The present disclosure will now be described in more detail through the following embodiments. However, the following embodiments are provided to help understand that the present disclosure is provided for illustrative purposes only, and its scope and extent are not limited thereto.

[0046] In exemplary embodiments of this disclosure, compounds represented by the following chemical formula 1, their isomers, pharmaceutically acceptable salts, their hydrates, or their solvates are provided.

[0047] [Chemical Formula 1]

[0048]

[0049] In chemical formula 1,

[0050] X is represented by any one of the following chemical formulas 1-1 to 1-5.

[0051] [Chemical Formula 1-1]

[0052]

[0053] [Chemical Formula 1-2]

[0054]

[0055] [Chemical Formulas 1-3]

[0056]

[0057] [Chemical Formulas 1-4]

[0058]

[0059] [Chemical Formulas 1-5]

[0060]

[0061] In chemical formula 1-1,

[0062] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R1 atoms.

[0063] R1 is hydrogen, phenyl, C1-C4 alkoxy, C1-C3 alkyl, fluoro, adamantyl, acetamino, or hydroxyiminoethyl.

[0064] When there are two or three R1 groups, the R1 groups are identical to each other.

[0065] In chemical formulas 1-2,

[0066] Ar represents a phenyl group substituted with one R2 molecule.

[0067] R2 is a C1-C4 alkyl, C1-C4 alkoxy, adamantyl, acetyl, or acetamido.

[0068] In chemical formulas 1-3,

[0069] Ar represents a phenyl group substituted with 1 to 3 R3 radicals or an unsubstituted naphthalene group.

[0070] R3 is hydrogen or a C1-C4 alkyl group.

[0071] When there are two or three R3 groups, the R3 groups are all the same, and preferably R3 is a C1-C4 alkyl group.

[0072] In chemical formulas 1-4,

[0073] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R4 groups.

[0074] R4 is hydrogen, phenyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0075] When there are two or three R4 groups, the R4 groups are identical to each other.

[0076] In chemical formulas 1-5,

[0077] Ar is a phenyl group substituted with 1 to 3 R5 radicals.

[0078] R5 is a C1-C4 alkyl group.

[0079] When there are two or three R5 groups, the R5 groups are identical to each other.

[0080] For example, in the chemical formulas 1-1 to 1-5, R1 to R5 can be groups that are para-substituted at the Ar position.

[0081] In this specification, the alkyl group can be straight-chain or branched, for example, it can be methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl or sec-butyl.

[0082] In this specification, the alkoxy group can be straight-chain, branched, or cyclic, for example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, i-propoxy, n-butoxy, isobutoxy, tert-butoxy, or sec-butoxy.

[0083] In the specification, the term "isomer" specifically 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 one or more chemical bonds), position isomers (especially tautomers), or geometric isomers (e.g., cis-trans isomers).

[0084] In this specification, the term "essentially pure" means, for example, that when the relevant enantiomers or diastereomers are used, that the specific compound, exemplified by the enantiomers or diastereomers, is present in about 90% or more, preferably about 95% or more, more preferably about 97% or more, or about 98% or more, more preferably about 99% or more, and even more preferably about 99.5% or more (w / w).

[0085] In this specification, the term "pharmaceutical acceptable" means that when used at the usual drug dosage, significant toxic effects are avoided, thereby obtaining or receiving approval from a government or equivalent regulatory body for use in animals, more specifically in humans, or as enumerated in a pharmacopoeia or other generally recognized pharmacopoeia.

[0086] In this specification, the term "pharmaceutically acceptable salt" means a salt according to one aspect of this disclosure that is pharmaceutically acceptable and has the preferred pharmacological activity of a parent compound. The salt may comprise (1) an acid addition formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or an acid addition formed from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. (2) Salts formed when acidic protons present in the parent compound are substituted.

[0087] In this specification, the term "hydrate" means a compound bound with water, and is a broad concept encompassing inclusions in which there is no chemical bond between water and the compound.

[0088] In this specification, the term "solvent" means a higher-order compound formed between molecules or ions of a solute and molecules or ions of a solvent.

[0089] According to an implementation example of this disclosure, the compound represented by the chemical formula 1 is a novel active functional cosmetic raw material for the domestic cosmetics industry. As a novel compound derived from an amino acid structure, it can be a multifunctional novel compound that exhibits an inhibitory effect on compositions of MMP-1 (Collagenase) and / or MMP-2 & MMP-9 (Gelatinases) at low nanomolar concentrations (nM), such as below 500 nM, for example, in oral compositions or cosmetic compositions.

[0090] In one implementation example, the compound represented by chemical formula 1 can be any one of the following compounds:

[0091] N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide,

[0092] 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0093] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0094] N-hydroxy-1-(tris(methylbenzenesulfonyl)piperidine-2-carboxamide,

[0095] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide,

[0096] N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide,

[0097] N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide,

[0098] 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide,

[0099] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0100] 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0101] N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide,

[0102] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide,

[0103] N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)butyramide,

[0104] 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0105] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0106] N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide,

[0107] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0108] 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0109] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0110] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide,

[0111] 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0112] N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide,

[0113] N-hydroxy-4-methyl-2-(benzenesulfonamide)pentanamide and

[0114] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0115] In one implementation example, the compound represented by chemical formula 1 can be represented by any one of the following chemical formulas:

[0116]

[0117]

[0118] In one implementation example, the compound represented by the chemical formula 1 may be derived from amino acids.

[0119] For example, the compound represented by the chemical formula 1 can be derived from any of the following amino acids.

[0120]

[0121]

[0122] In another exemplary implementation of this disclosure, a composition is provided in which at least one compound represented by the chemical formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate is included as an active ingredient.

[0123] In one implementation example, the content of the compound represented by the chemical formula 1 can be from 0.01 μM to 100 mM, based on the overall volume of the composition.

[0124] For example, it can be above 0.01μM, above 0.05μM, above 0.1μM, above 1μM, above 10μM, above 100μM, above 0.5mM, above 1mM, above 1.5mM, above 2mM, above 2.5mM, above 10mM, or above 50mM, or below 100mM, below 50mM, below 10mM, below 8mM, below 6mM, below 4mM, below 1mM, below 100μM, below 10μM, below 1μM, below 0.1μM, or below 0.05μM.

[0125] For example, based on the overall composition volume, the content can be from 0.01 μM to 100 mM, preferably from 0.05 μM to 10 mM, and more preferably from 0.1 μM to 4 mM.

[0126] When the concentration is less than 0.01 μM, the effect may be minimal, and when it exceeds 100 mM, the high concentration may cause cytotoxicity problems.

[0127] In one implementation, the composition may be an MMP-1 activity inhibitor.

[0128] In one implementation, the composition may be an MMP-2 activity inhibitor.

[0129] The compositions comprising novel compounds disclosed herein can, in particular, be used to inhibit MMP-2 activity. MMP-2 is an enzyme that breaks down collagen IV in the basement membrane (Gelatinase), and is therefore effective on the skin. MMP-2 plays an important role, especially in the dermis, where it is crucial to maintain and protect collagen IV at healthy levels.

[0130] In one implementation, the composition may be an MMP-9 activity inhibitor.

[0131] In one embodiment, the composition may be a cosmetic composition comprising, as an active ingredient, at least one compound represented by the chemical formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0132] In one embodiment, the cosmetic composition may be in the form of a medium or matrix acceptable to cosmetics or dermatology. As a dosage form suitable for topical application, it can be provided as, for example, a solution, gel, solid, anhydrous paste, emulsion, suspension, microemulsion, microcapsule, microsphere, or ionic (liposome) and nonionic capsule dispersion, or in the form of cream, lotion, emulsion, powder, ointment, spray, or concealer stick. These compositions can be prepared according to conventional methods in the art.

[0133] The compositions according to this disclosure can also be used in the form of foam or further in the form of aerosol compositions containing compressed propellant.

[0134] The cosmetic composition according to this disclosure is not particularly limited in its dosage form, for example, it can be formulated as a gentle toner, astringent toner, nourishing toner, nourishing cream, massage cream, serum, eye cream, eye serum, cleansing cream, cleansing foam, makeup remover, makeup remover wipes containing the cosmetic composition, face mask, powder, body lotion, moisturizing cream, moisturizing oil, and moisturizing essence, etc.

[0135] When the dosage form of the cosmetic composition according to this disclosure is a cream, lotion, or gel, the carrier component may include animal fiber, plant fiber, wax, paraffin, starch, astragalus gum, cellulose derivatives, polyethylene glycol, organosilicon, bentonite, silica, talc, or zinc oxide, etc.

[0136] When the cosmetic composition according to this disclosure is in the form of powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as the carrier component. In particular, when sprayed, it may further contain propellants such as chlorofluorocarbons, propane / butane or dimethyl ether.

[0137] When the dosage form of the cosmetic composition according to this disclosure is a solution or emulsion, a solvent, solvator or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol oil, glyceryl fatty ester, polyethylene glycol or sorbitan fatty acid ester.

[0138] When the dosage form of the cosmetic composition according to this disclosure is a suspension, the carrier component may be water, ethanol or propylene glycol or other liquid diluents, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan ester or other suspending agents, microcrystalline cellulose, aluminum hydroxide, bentonite, agar or tragacanth gum, etc.

[0139] The cosmetic composition according to this disclosure may further include functional additives and ingredients included in general cosmetic compositions. The functional additives may include ingredients 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.

[0140] The cosmetic composition according to this disclosure is further formulated with the aforementioned functional additives, and includes ingredients typically found in cosmetic compositions. Examples of such formulation ingredients include oils, moisturizers, emollients, emulsifiers, organic and inorganic pigments, organic powders, UV absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, ethanol, pigments, fragrances, blood circulation enhancers, cooling agents, antiperspirants, purified water, etc.

[0141] In one embodiment, the composition may be an oral composition comprising, as an active ingredient, at least one compound represented by the chemical formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0142] The oral composition according to this disclosure can be in liquid or solid dosage form, and can be in the form of tablets, capsules, soft capsules, pills, granules, beverages (drinks), weight loss bars, chocolate, caramel, or biscuits, and its dosage form is not particularly limited. In addition to the active ingredient, the oral composition of this disclosure may also contain, as needed, appropriate amounts of excipients, sugars, flavorings, colorings, oils, proteins, etc.

[0143] In another exemplary implementation of this disclosure, a method for preparing a compound represented by the aforementioned chemical formula 1 is provided, the method comprising the step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with sulfonic acid, sulfonylhalide, sulfanilic acid, or sulfanilylhalide.

[0144] In one implementation, the sulfonylhalide can be a sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide.

[0145] In one implementation, the sulfanilyl halide may be sulfanilyl fluoride, sulfanilyl chloride, sulfanilyl bromide, or sulfanilyl iodide.

[0146] In one embodiment, the preparation method may further include the step of reacting the intermediate obtained by the reaction with hydroxylamine (free form) or hydroxylamine salt (salt form) to obtain the compound represented by chemical formula 1.

[0147] In one implementation example, the hydroxylamine salt may be hydroxylamine hydrochloride.

[0148] In one embodiment, the sulfonyl chloride may be selected from the group consisting of benzenesulfonyl chloride, 4-biphenylsulfonyl chloride, 4-butoxybenzene-1-sulfonyl chloride, 2-tris(benzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(1-adamantyl)benzenesulfonyl chloride, 4-n-propylbenzenesulfonyl chloride, and 4-acetylbenzenesulfonyl chloride, wherein the p-aminobenzenesulfonyl chloride may be N-acetyl-p-aminobenzenesulfonyl chloride.

[0149] In another exemplary implementation of this disclosure, a method for inhibiting MMP-1 activity is provided, the method comprising applying, in an effective amount, a composition comprising, as an active ingredient, a compound represented by the aforementioned Formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates to a subject in need.

[0150] In another exemplary implementation of this disclosure, a method for inhibiting MMP-2 activity is provided, the method comprising applying, in an effective amount, a composition comprising, as an active ingredient, a compound represented by the aforementioned Formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates to a subject in need.

[0151] In another exemplary implementation of this disclosure, a method for inhibiting MMP-9 activity is provided, the method comprising applying, in an effective amount, a composition comprising, as an active ingredient, a compound represented by the aforementioned Formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates to a subject in need.

[0152] In another exemplary implementation of this disclosure, use is provided for preparing compositions for inhibiting MMP-1 activity using a compound represented by the aforementioned chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates.

[0153] In another exemplary implementation of this disclosure, use is provided for preparing compositions for inhibiting MMP-2 activity using a compound represented by the aforementioned Chemical Formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates.

[0154] In another exemplary implementation of this disclosure, use is provided for preparing compositions for inhibiting MMP-9 activity using a compound represented by the aforementioned Chemical Formula 1, its isomers, pharmaceutically acceptable salts, hydrates, or solvates.

[0155] In another exemplary implementation of this disclosure, non-therapeutic use is provided for a compound represented by the aforementioned Formula 1, its isomers, pharmaceutically acceptable salts, hydrates, or solvates thereof for inhibiting MMP-1 activity.

[0156] In another exemplary implementation of this disclosure, non-therapeutic use is provided for inhibiting MMP-2 activity of a compound represented by the aforementioned Formula 1, its isomers, pharmaceutically acceptable salts, hydrates, or solvates.

[0157] In another exemplary implementation of this disclosure, non-therapeutic use is provided for a compound represented by the aforementioned Chemical Formula 1, its isomers, pharmaceutically acceptable salts, hydrates, or solvates thereof for inhibiting MMP-9 activity.

[0158] Specific example

[0159] Specific example 1: A compound represented by the following chemical formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate:

[0160] [Chemical Formula 1]

[0161]

[0162] In chemical formula 1,

[0163] X is represented by any one of the following chemical formulas 1-1 to 1-5.

[0164] [Chemical Formula 1-1]

[0165]

[0166] [Chemical Formula 1-2]

[0167]

[0168] [Chemical Formulas 1-3]

[0169]

[0170] [Chemical Formulas 1-4]

[0171]

[0172] [Chemical Formulas 1-5]

[0173]

[0174] In chemical formula 1-1,

[0175] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R1 atoms.

[0176] R1 is hydrogen, phenyl, C1-C4 alkoxy, C1-C3 alkyl, fluoro, adamantyl, acetamino, or hydroxyiminoethyl.

[0177] When there are two or three R1 groups, the R1 groups are identical to each other.

[0178] In chemical formulas 1-2,

[0179] Ar represents a phenyl group substituted with one R2 molecule.

[0180] R2 is a C1-C4 alkyl, C1-C4 alkoxy, adamantyl, acetyl, or acetamido.

[0181] In chemical formulas 1-3,

[0182] Ar represents a phenyl group substituted with 1 to 3 R3 radicals or an unsubstituted naphthalene group.

[0183] R3 is hydrogen or a C1-C4 alkyl group.

[0184] When there are two or three R3 groups, the R3 groups are all the same, and preferably R3 is a C1-C4 alkyl group.

[0185] In chemical formulas 1-4,

[0186] Ar is an unsubstituted or phenyl group substituted with 1 to 3 R4 groups.

[0187] R4 is hydrogen, phenyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0188] When there are two or three R4 groups, the R4 groups are identical to each other.

[0189] In chemical formulas 1-5,

[0190] Ar is a phenyl group substituted with 1 to 3 R5 radicals.

[0191] R5 is a C1-C4 alkyl group.

[0192] When there are two or three R5 groups, the R5 groups are identical to each other.

[0193] Specific Example 2: According to the compound described in Specific Example 1, the compound represented by the chemical formula 1 is any one of the following compounds:

[0194] N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide,

[0195] 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0196] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0197] N-hydroxy-1-(tris(methylbenzenesulfonyl)piperidine-2-carboxamide,

[0198] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide,

[0199] N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide,

[0200] N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide,

[0201] 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide,

[0202] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0203] 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0204] N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide,

[0205] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide,

[0206] N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)butyramide,

[0207] 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0208] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0209] N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide,

[0210] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0211] 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0212] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0213] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide,

[0214] 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0215] N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide,

[0216] N-hydroxy-4-methyl-2-(benzenesulfonamide)pentanamide and

[0217] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0218] Specific Example 3: According to Specific Example 1 or 2, the compound represented by Chemical Formula 1 is any one of the following compounds:

[0219] N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide,

[0220] 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0221] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0222] N-hydroxy-1-(tris(methylbenzenesulfonyl)piperidine-2-carboxamide,

[0223] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide,

[0224] N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide,

[0225] N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide,

[0226] 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide,

[0227] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0228] 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide,

[0229] N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide,

[0230] N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)butyramide,

[0231] 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0232] N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide,

[0233] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0234] 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0235] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide, N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide,

[0236] 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide,

[0237] N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide and

[0238] N-hydroxy-4-methyl-2-(benzenesulfonamide)pentanamide.

[0239] Specific Example 4: The compound according to any one of Specific Examples 1 to 3, wherein the compound represented by Chemical Formula 1 is any one of the following compounds:

[0240] 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide,

[0241] 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide,

[0242] 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide and

[0243] 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0244] Specific Example 5: The compound according to any one of Specific Examples 1 to 4, wherein the compound represented by the chemical formula 1 is derived from amino acids.

[0245] Specific Example 6: A cosmetic composition comprising, as an active ingredient, any one of Specific Examples 1 to 5, a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0246] Specific Example 7: According to the cosmetic composition of Specific Example 6, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates is from 0.01 μM to 100 mM based on the total volume of the composition.

[0247] Specific Example 8: An oral composition comprising, as an active ingredient, any one of Specific Examples 1 to 5, a compound represented by Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0248] Specific Example 9: According to the oral composition of Specific Example 8, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates is from 0.01 μM to 100 mM based on the total volume of the composition.

[0249] Specific Example 10: A composition for inhibiting MMP-1 activity, comprising, as an active ingredient, any one of Specific Examples 1 to 5, a compound represented by Chemical Formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0250] Specific Example 11: According to the MMP-1 activity inhibitory composition of Specific Example 10, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates is from 0.01 μM to 100 mM based on the total volume of the composition.

[0251] Specific Example 12: A composition for inhibiting MMP-2 activity, comprising, as an active ingredient, any one of Specific Examples 1 to 5, a compound represented by Chemical Formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0252] Specific Example 13: According to the MMP-2 activity inhibitory composition of Specific Example 12, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates is from 0.01 μM to 100 mM based on the total volume of the composition.

[0253] Specific Example 14: A composition for inhibiting MMP-9 activity, comprising, as an active ingredient, any one of Specific Examples 1 to 5, a compound represented by Formula 1, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0254] Specific Example 15: According to the MMP-9 activity inhibitory composition of Specific Example 14, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates or its solvates is from 0.01 μM to 100 mM based on the total volume of the composition.

[0255] Specific Example 16: A method for preparing a compound represented by Chemical Formula 1 according to any one of Specific Examples 1 to 5, the method comprising:

[0256] The step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilyl halide.

[0257] Specific Example 17: According to the preparation method described in Specific Example 16, the preparation method further includes the step of reacting the intermediate obtained by the reaction with free hydroxylamine or salt hydroxylamine salt to obtain the compound represented by Chemical Formula 1.

[0258] Specific Example 18: According to the preparation method described in Specific Example 16 or 17, the sulfonyl halide is sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide or sulfonyl iodide, and the p-aminobenzenesulfonyl halide is p-aminobenzenesulfonyl fluoride, p-aminobenzenesulfonyl chloride, p-aminobenzenesulfonyl bromide or p-aminobenzenesulfonyl iodide.

[0259] Specific Example 19: According to the preparation method of 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-tris(benzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(1-adamantyl)benzenesulfonyl chloride, 4-n-propylbenzenesulfonyl chloride, and 4-acetylbenzenesulfonyl chloride.

[0260] The p-aminobenzenesulfonyl chloride is N-acetyl-p-aminobenzenesulfonyl chloride.

[0261] Forms of implementation of the invention

[0262] The present disclosure will now be described in more detail through the following embodiments. However, the following embodiments are provided to help understand that the present disclosure is provided for illustrative purposes only, and its scope and extent are not limited thereto.

[0263] Example

[0264] Manufacturing example

[0265] As shown below, novel compounds were prepared, and the IUPAC names of 25 novel compounds are shown in Table 1 below.

[0266] [Table 1]

[0267]

[0268]

[0269] (1) Synthesis of T-01N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide

[0270] 1.69 g of pipecolinic acid was thoroughly stirred with 30 mL of THF, followed by the addition of 30 mL of 1 M Na₂CO₃. 2 mL of benzenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at the same temperature for 1 hour. After washing with 30 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 1.89 g of the intermediate 1-(benzenesulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0271] 1.89 g of 1-(benzenesulfonyl)piperidine-2-carboxylic acid was dissolved in 15 mL of THF along with 0.85 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.73 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.73 g of hydroxylamine hydrochloride and 1.46 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:2) to obtain 0.72 g of N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide.

[0272] 1 H-NMR (500MHz, DMSO-d6): δ10.62 (s, 1H), 8.79 (s, 1H), 7.78 (m, 2H), 7.66 (m, 1H), 7.57 (m, 2H), 4.34 (m, 1H), 3.63 (m, 1H), 3.47 (m, 1H), 1.78 (m, 1H), 1.55 (m, 1H) 1.45-1.40 (m, 3H), 1.17 (m, 1H)

[0273] (2) Synthesis of T-02 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide

[0274] 0.65 g of pipecolinic acid was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 0.78 g of the intermediate 1-([1,1'-biphenyl]-4-ylsulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0275] 0.7 g of 1-([1,1'-biphenyl]-4-ylsulfonyl)piperidine-2-carboxylic acid was dissolved in 20 mL of THF along with 0.25 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine dissolved in 10 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure 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.

[0276] 1 H-NMR (500MHz, DMSO-d6): δ10.67(s, 1H), 8.80(s, 1H), 7.87(m, 4H), 7.77(m, 2H), 7.52(m, 2H), 7.45(m, 1H ), 4.38(m, 1H), 3.66(m, 1H), 3.50(m, 1H), 1.81(m, 1H), 1.59(m, 1H), 1.47-1.43(m, 3H), 1.26-1.15(m, 1H)

[0277] (3) Synthesis of T-04 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide

[0278] 0.65 g of pipecolinic acid was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄ and concentration under reduced pressure to obtain 1.17 g of the intermediate 1-((4-butoxyphenyl)sulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0279] 1.17 g of 1-((4-butoxyphenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 0.42 mL of NMO (N-Methylmorpholine-N-oxide) in 30 mL of THF, and then stirred at 0 °C. 0.36 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.36 g of hydroxylamine hydrochloride and 0.72 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.37 g of 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide.

[0280] 1H-NMR (500MHz, DMSO-d6): δ10.61 (s, 1H), 8.77 (s, 1H), 7.67 (d, 2H, J=8.5Hz), 7.06 (d, 2H, J=9Hz), 4.30 (m, 1H), 4.0 5 (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)

[0281] (4) Synthesis of T-05N-hydroxy-1-(tris(methyl)sulfonyl)piperidine-2-carboxamide

[0282] 0.65 g of pipecolinic acid was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄ and concentration under reduced pressure to obtain 0.71 g of the intermediate 1-(mesitylenesulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0283] 0.69 g of 1-(tris(methyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 20 mL of THF along with 0.27 mL of NMO (N-methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.23 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.23 g of hydroxylamine hydrochloride and 0.46 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.14 g of N-hydroxy-1-(tris(benzenesulfonyl)piperidine-2-carboxamide).

[0284] 1 H-NMR (500MHz, DMSO-d6): δ10.48 (s, 1H), 8.86 (s, 1H), 7.05 (s, 2H), 3.69 (t, 1H, J=1 0.5Hz), 3.32 (s, 3H), 3.43 (s, 3H) 1.79 (m, 2H), 1.65-1.50 (m, 6H), 1.30-1.23 (m, 3H)

[0285] (5) Synthesis of T-08 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide

[0286] 0.83 g of phenylalanine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄ and concentration under reduced pressure to obtain 1.31 g of the intermediate ((4-(tert-butyl)phenyl)sulfonyl)phenylalanine). The intermediate was used directly in the next reaction without further purification.

[0287] 1.2 g of ((4-(tert-butyl)phenyl)sulfonyl)phenylalanine was dissolved in 20 mL of THF along 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 0.35 g of hydroxylamine hydrochloride and 0.69 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.38 g of 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide.

[0288] 1H-NMR (500MHz, DMSO-d6): δ10.61 (s, 1H), 8.88 (s, 1H), 8.13 (d, 1H, J=8.5Hz), 7.40 ( m, 4H), 7.12 (m, 3H), 7.00 (m, 2H), 3.71 (m, 1H), 2.76 (m, 1H), 2.55 (m, 1H), 1.26 (s, 9H)

[0289] (6) Synthesis of T-10N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide

[0290] 0.83 g of phenylalanine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄, and then concentration under reduced pressure to obtain 1 g of the intermediate (mesitylenesulfonyl)phenylalanine. The intermediate was used directly in the next reaction without further purification.

[0291] 1 g of mesitylsulfonyl phenylalanine was dissolved in 20 mL of THF along with 0.35 mL of NMO (N-methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.3 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.3 g of hydroxylamine hydrochloride and 0.6 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure 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)propionamide.

[0292] 1 H-NMR (500MHz, DMSO-d6): δ10.59 (s, 1H), 8.87 (s, 1H), 7.89 (d, 1H, J=9.5Hz), 7.07 (m, 3H), 6.95(m, 2H), 6.82(m, 2H), 3.67(m, 1H), 2.76(m, 1H), 2.60(m, 1H), 2.49(s, 6H), 2.26(s, 3H)

[0293] (7) Synthesis of T-11N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide

[0294] 0.83 g of phenylalanine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 1.36 g of 2-naphthalenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 hour. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with 100 mL of ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 1.2 g of the intermediate (naphthalen-2-ylsulfonyl)phenylalanine. The intermediate was used directly in the next reaction without further purification.

[0295] 1.1 g of (naphthalen-2-ylsulfonyl)phenylalanine was dissolved in 20 mL of THF along 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 for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction mixture was stored separately and then added dropwise to a solution containing 0.32 g of hydroxylamine hydrochloride and 0.65 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure to remove DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:2) to obtain 0.21 g of N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide.

[0296] 1H-NMR (500MHz, DMSO-d6): δ10.63 (s, 1H), 8.84 (s, 1H), 8.32 (d, 1H, J=9.5Hz), 8.19 (s, 1H), 8.19 (m, 2H), 7 .92 (d, 1H, J=9.5Hz), 7.65 (m, 2H), 7.56 (m, 1H), 7.28-7.00 (m, 5H), 3.84 (q, 1H), 2.78 (m, 1H), 2.59 (m, 1H)

[0297] (8) Synthesis of T-12 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide

[0298] 0.66 g of leucine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 1.52 g of biphenylsulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 hour. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄ and then concentration under reduced pressure to obtain 0.64 g of the intermediate ([1,1'-biphenyl]-4-ylsulfonyl)leucine. The intermediate was used directly in the next reaction without further purification.

[0299] 0.6 g of [1,1'-biphenyl]-4-ylsulfonyl)leucine was dissolved in 20 mL of THF along with 0.21 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.18 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 0.18 g of hydroxylamine hydrochloride and 0.36 mL of triethylamine dissolved in 10 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.34 g of 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide.

[0300] 1 H-NMR (500MHz, DMSO-d6): δ10.66 (s, 1H), 8.81 (s, 1H), 8.03 (d, 1H, J=6.0Hz), 7.83 (m, 4H), 7.73 (d, 2H, J=7.0Hz), 7 .51 (m, 2H), 7.43 (m, 1H), 3.59 (q, 1H), 1.41 (m, 1H), 1.33-1.21 (m, 2H), 0.75 (d, 3H, J=6.5Hz), 0.64 (d, 3H, J=7.0Hz)

[0301] (9) Synthesis of T-13 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide

[0302] 0.66 g of leucine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with 100 mL of ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 1.09 g of the intermediate ((4-(tert-Butyl)phenyl)sulfonyl)leucine. The intermediate was used directly in the next reaction without further purification.

[0303] 1.07 g of ((4-(tert-butyl)phenyl)sulfonyl)leucine was dissolved in 20 mL of THF along 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 for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.35 g of hydroxylamine hydrochloride and 0.7 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure 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.

[0304] 1 H-NMR (500MHz, DMSO-d6): δ10.64 (s, 1H), 8.83 (s, 1H), 7.88 (m, 1H), 7.70 (d, 2H, J=9.0Hz), 7.57 (d, 2H , J=8.5Hz), 3.49 (m, 1H), 1.32-1.24 (m, 11H), 1.12 (m, 1H), 0.69 (d, 3H, J=6.5Hz), 0.55 (d, 3H, J=6.5Hz)

[0305] (10) Synthesis of T-14 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide

[0306] 0.66 g of leucine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄, and then concentration under reduced pressure to obtain 1 g of the intermediate ((4-butoxyphenyl)sulfonyl)leucine. The intermediate was used directly in the next reaction without further purification.

[0307] 1 g of ((4-butoxyphenyl)sulfonyl)leucine was dissolved in 20 mL of THF along with 0.35 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.3 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.3 g of hydroxylamine hydrochloride and 0.6 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 40 mg of 2-((4-butoxyphenyl)sulfonamide)-N-hydroxy-4-methylpentanamide.

[0308] 1H-NMR (500MHz, DMSO-d6): δ10.61 (s, 1H), 8.77 (s, 1H), 7.76 (m, 1H), 7.67 (d, 2H, J=9.0Hz), 7.04 (d, 2H, J=8.5Hz), 4.04 (t, 2H, J=6.5Hz), 3 .50 (m, 1H), 1.70 (m, 2H), 1.45 (m, 3H), 1.27 (m, 1H), 1.19 (m, 1H), 0.93 (t, 3H, J = 7.0Hz), 0.77-0.72 (d, 3H, J = 6.5Hz), 0.63 (d, 3H, J = 6.0Hz)

[0309] (11) Synthesis of T-15N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide

[0310] 0.66 g of leucine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with 100 mL of ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 0.76 g of the intermediate (mesitylenesulfonyl)leucine. The intermediate was used directly in the next reaction without further purification.

[0311] 0.75 g of (tris(methyl)benzenesulfonyl)leucine was dissolved in 20 mL of THF along with 0.29 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.25 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.25 g of hydroxylamine hydrochloride and 0.5 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure 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.

[0312] 1 H-NMR (500MHz, DMSO-d6): δ10.51(s, 1H), 8.88(s, 1H), 7.77(m, 1H), 6.98(s, 2H), 3.45(m, 1H), 2.55(s, 3H ), 2.50 (s, 3H), 2.24 (s, 3H), 1.41 (m, 1H), 1.33-1.20 (m, 2H), 0.73 (d, 3H, J = 6.5Hz), 0.55 (d, 3H, J = 6.5Hz)

[0313] (12) Synthesis of T-18 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide

[0314] 0.59 g of valine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction was performed with 100 mL of ethyl acetate, followed by drying with MgSO₄ and concentration under reduced pressure to obtain 0.71 g of the intermediate ((4-(tert-Butyl)phenyl)sulfonyl)valine. The intermediate was used directly in the next reaction without further purification.

[0315] 0.7 g of ((4-(tert-butyl)phenyl)sulfonyl)valine was dissolved in 20 mL of THF along with 0.25 mL of NMO (N-methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.3 g of 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide.

[0316] 1 H-NMR (500MHz, DMSO-d6): δ10.50 (s, 1H), 8.80 (s, 1H), 7.81 (m, 1H), 7.68 (d, 2H, J=8.0Hz), 7.54 (d , 2H, J=8.0Hz), 3.27 (m, 1H), 1.75 (m, 1H), 1.29 (s, 9H), 0.73 (d, 3H, J=6.5Hz), 0.70 (d, 3H, J=6.5Hz)

[0317] (13) Synthesis of T-20N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamide)butyramide

[0318] 0.59 g of valine was thoroughly stirred with 20 mL of THF, followed by the addition of 11.5 mL of 1 M Na₂CO₃. 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. After two washes with 50 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with 100 mL of ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 0.53 g of the intermediate (mesitylenesulfonyl)valine. The intermediate was used directly in the next reaction without further purification.

[0319] 0.52 g of (tris(methyl)benzenesulfonyl)valine was dissolved in 20 mL of THF along with 0.25 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was stirred at 0 °C. 0.21 mL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution of 0.21 g of hydroxylamine hydrochloride and 0.42 mL of triethylamine dissolved in 20 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure 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)butyramide.

[0320] 1 H-NMR (500MHz, DMSO-d6): δ10.43 (s, 1H), 8.80 (s, 1H), 7.59 (d, 1H, J=9.5Hz), 6.98 (s , 2H), 3.18 (t, 1H, J=8.0Hz), 2.59-2.50 (m, 6H), 2.24 (s, 3H), 1.76 (m, 1H), 0.70 (m, 6H)

[0321] (14) Synthesis of T-21 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide

[0322] 500 mg of pipecolinic acid was thoroughly stirred with 8 mL of THF, followed by the addition of 9.6 mL of 1 M Na₂CO₃. 904 mg of 4-fluorobenzenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. After two washes with 20 mL of diethyl ether, 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. The intermediate was used directly in the next reaction without further purification.

[0323] 550 mg of 1-((4-fluorophenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF along with 0.23 mL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 0.2 g of hydroxylamine hydrochloride and 0.4 mL of triethylamine dissolved in 2 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 0.14 g of 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide.

[0324] 1 H-NMR (500MHz, DMSO-d6): δ10.63 (s, 1H), 8.76 (s, 1H), 7.82 (m, 2H), 7.42 (m, 2H), 4.32 (m , 1H), 3.62(m, 1H), 3.46(m, 1H), 1.80(m, 1H), 1.77(m, 1H), 1.51-1.39(m, 3H), 1.19(m, 1H)

[0325] (15) Synthesis of T-23 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide

[0326] 50 mg of pipecolinic acid was thoroughly stirred with 0.8 mL of THF, followed by the addition of 0.9 mL of 1 M Na₂CO₃. 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. After two washes with 2 mL of diethyl ether, 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)-adamantane-1-yl)phenyl)sulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0327] 50 mg of 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)piperidin-2-carboxylic acid was dissolved in 1 mL of THF along with 15 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 12.9 mg of hydroxylamine hydrochloride and 26 μL of triethylamine dissolved in 1 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH in DCM) to obtain 30 mg of 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide.

[0328] 1H-NMR (500MHz, DMSO-d6): δ10.61 (s, 1H), 8.81 (s, 1H), 7.70 (m, 2H), 7.55 (m, 2H), 4.33 (m, 1H), 3.59 (m, 1H), 3.45 (m, 1H), 2.07 (s, 3H), 1.89 (m, 7H), 1.77 (m, 7H), 1.52 (m, 1H), 1.43 (m, 2H), 1.19 (m, 1H)

[0329] (16) Synthesis of T-24N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide

[0330] 500 mg of pipecolinic acid was thoroughly stirred with 8 mL of THF, followed by the addition of 8.9 mL of 1 M Na₂CO₃. 831 μL of 4-n-Propylbenzenesulfonylchloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. After two washes with 10 mL of diethyl ether, 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. The intermediate was used directly in the next reaction without further purification.

[0331] 700 mg of 1-((4-propylphenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF along 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 234 mg of hydroxylamine hydrochloride and 470 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 0.16 g of N-hydroxy-1-((4-propylphenyl)sulfonyl)piperidine-2-carboxamide.

[0332] 1 H-NMR (500MHz, DMSO-d6): δ10.61 (s, 1H), 8.79 (s, 1H), 7.65 (m, 2H), 7.38 (m, 2H), 4.33 (m, 1H), 3.61 (m, 1H) ), 3.45 (m, 1H), 2.43 (t, 2H, J = 7.5Hz), 1.76 (m, 1H), 1.59-1.38 (m, 6H), 1.16 (m, 1H), 0.90 (t, 3H, J = 7.5Hz)

[0333] (17) Synthesis of T-25 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide

[0334] 500 mg of pipecolinic acid was thoroughly stirred with 8 mL of THF, followed by the addition of 8.9 mL of 1 M Na₂CO₃. 1.09 g of N-acetyl-p-aminobenzenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. After two washes with 10 mL of diethyl ether, 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. The intermediate was used directly in the next reaction without further purification.

[0335] 800 mg of 1-((4-acetamidophenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 6 mL of THF along with 296 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction mixture was stored separately and then added dropwise to a solution containing 256 mg of hydroxylamine hydrochloride and 512 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 0.18 g of 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide.

[0336] 1 H-NMR (500MHz, DMSO-d6): δ10.60 (s, 1H), 10.32 (s, 1H), 8.78 (s, 1H), 7.74 (m, 2H), 7.68 (m, 2H), 4.3 0 (m, 1H), 3.61 (m, 1H), 3.45 (m, 1H), 2.09 (s, 3H), 1.76 (m, 1H), 1.51 (m, 1H), 1.39 (m, 3H), 1.16 (m, 1H)

[0337] (18) Synthesis of T-28 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide

[0338] 500 mg of proline was thoroughly stirred with 9 mL of THF, followed by the addition of 10 mL of 1 M Na₂CO₃. 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. After two washes with 10 mL of diethyl ether, 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 860 mg of the intermediate ((4-(tert-Butyl)phenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0339] 700 mg of ((4-(tert-butyl)phenyl)sulfonyl)proline was dissolved in 5 mL of THF along 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 filtrate obtained after filtering the solids from the reaction mixture was stored separately and then added dropwise to a solution containing 234 mg of hydroxylamine hydrochloride and 470 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 546 mg of 1-((4-(tert-butyl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0340] 1 H-NMR (500MHz, DMSO-d6): δ10.66 (s, 1H), 8.94 (s, 1H), 7.78 (m, 2H), 7.64 (m, 2H), 3.91 (m, 1 H), 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)

[0341] (19) Synthesis of T-29 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide

[0342] 500 mg of proline was thoroughly stirred with 9 mL of THF, followed by the addition of 10 mL of 1 M Na₂CO₃. 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. After two washes with 10 mL of diethyl ether, 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 1.2 g of the intermediate ((4-butoxyphenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0343] 1 g of (4-butoxyphenyl)sulfonyl)proline was dissolved in 7 mL of THF along with 369 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 318 mg of hydroxylamine hydrochloride and 639 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 370 mg of 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0344] 1 H-NMR (500MHz, DMSO-d6): δ10.65 (s, 1H), 8.93 (s, 1H), 7.76 (m, 2H), 7.12 (m, 2H), 4.07 (t, 2H, J=6.5Hz), 3.88 (m, 1H), 3.39 (m, 1H), 3.11 (m, 1H), 1.83 (m, 1H), 1.74 (m, 3H), 1.63 (m, 1H), 1.45 (m, 3H), 0.94 (t, 3H, J=8.5Hz)

[0345] (20) Synthesis of T-32 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide

[0346] 50 mg of proline was thoroughly stirred with 0.9 mL of THF, followed by the addition of 1 mL of 1 M Na₂CO₃. 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. After two washes with 2 mL of diethyl ether, 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 171 mg of the intermediate ((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0347] 130 mg of ((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)proline was dissolved in 2 mL of THF along with 40 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction mixture was stored separately and then added dropwise to a solution containing 35 mg of hydroxylamine hydrochloride and 70 μL of triethylamine dissolved in 1 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH in DCM) to obtain 90 mg of 1-((4-((3r,5r,7r)-adamantane-1-yl)phenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0348] 1 H-NMR (500MHz, DMSO-d6): δ10.66 (s, 1H), 8.95 (s, 1H), 7.77 (m, 2H), 7.62 (m, 2H), 3.91 (m, 1H), 3 .39(m, 1H), 3.12(m, 1H), 2.15(s, 3H), 1.89-1.75(m, 13H), 1.65(m, 1H), 1.50(m, 1H), 1.16(m, 1H)

[0349] (21) Synthesis of T-33N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide

[0350] 500 mg of proline was thoroughly stirred with 9 mL of THF, followed by the addition of 10 mL of 1 M Na₂CO₃. 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. After two washes with 10 mL of diethyl ether, 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 1 g of the intermediate ((4-propylphenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0351] 900 mg of (4-propylphenyl)sulfonyl)proline was dissolved in 6 mL of THF along with 366 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 315 mg of hydroxylamine hydrochloride and 633 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH in DCM) to obtain 665 mg of N-hydroxy-1-((4-propylphenyl)sulfonyl)pyrrolidine-2-carboxamide.

[0352] 1 H-NMR (500MHz, DMSO-d6): δ10.66 (s, 1H), 8.94 (s, 1H), 7.76 (m, 2H), 7.46 (m, 2H), 3.90 (m, 1H), 3.38 (m, 1H), 3.14 (m, 1H), 2.66 (t, 2H, J=9Hz), 1.83 (m, 1H), 1.75 (m, 1H), 1.65 (m, 2H), 1.44 (m, 2H), 0.89 (t, 3H, J=7.5Hz)

[0353] (22) Synthesis of T-34 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide

[0354] 500 mg of proline was thoroughly stirred with 9 mL of THF, followed by the addition of 10 mL of 1 M Na₂CO₃. 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. After two washes with 10 mL of diethyl ether, 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 958 mg of the intermediate ((4-acetylphenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0355] 800 mg of (4-acetylphenyl)sulfonyl)proline was dissolved in 6 mL of THF along with 325 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 280 mg of hydroxylamine hydrochloride and 563 μL of triethylamine dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 110 mg of 1-((4-acetylphenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0356] 1 H-NMR (500MHz, DMSO-d6): δ10.72 (s, 1H), 8.97 (s, 1H), 8.15 (m, 2H), 7.97 (m, 2H), 3.95 (m, 1H), 3.43 (m, 1H), 3.13 (m, 1H), 2.65 (s, 3H), 1.86 (m, 1H), 1.72 (m, 2H), 1.48 (m, 1H)

[0357] (23) Synthesis of T-35N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide

[0358] 1 g of pipecolinic acid was thoroughly stirred with 16 mL of THF, followed by the addition of 17.8 mL of 1 M Na₂CO₃. 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. After two washes with 20 mL of diethyl ether, 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 intermediate 1-((4-(1-(hydroxyamino)ethyl)phenyl)sulfonyl)piperidine-2-carboxylic acid. The intermediate was used directly in the next reaction without further purification.

[0359] 1 g of 1-((4-(1-(hydroxyamino)ethyl)phenyl)sulfonyl)piperidine-2-carboxylic acid was dissolved in 10 mL of THF along with 388 μL of NMO (N-Methylmorpholine-N-oxide), and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 446 mg of hydroxylamine hydrochloride and 895 μL of triethylamine dissolved in 6 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 0.18 g of N-hydroxy-1-((4-(1-(hydroxyimino)ethyl)phenyl)sulfonyl)piperidine-2-carboxamide.

[0360] 1H-NMR (500MHz, DMSO-d6): δ11.55 (s, 1H), 10.63 (s, 1H), 8.79 (s, 1H), 7.82 (m, 2H), 7.75 (m, 2H), 4.3 5(m, 1H), 3.63(m, 1H), 3.47(m, 1H), 3.32(s, 3H), 1.74(m, 1H), 1.54(m, 1H), 1.45(m, 3H), 1.20(m, 1H)

[0361] (24) Synthesis of T-36N-hydroxy-4-methyl-2-(benzenesulfonamide)pentanamide

[0362] 500 mg of leucine was thoroughly stirred with 8 mL of THF, followed by the addition of 8.8 mL of 1 M Na₂CO₃. 584 μL of benzenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 hour. After two washes with 10 mL of diethyl ether, the pH of the aqueous layer was adjusted to pH 3 with 3 M HCl. Extraction with 20 mL of ethyl acetate followed by drying with MgSO₄ and then concentration under reduced pressure yielded 444 mg of the intermediate (phenylsulfonyl)leucine. The intermediate was used directly in the next reaction without further purification.

[0363] 400 mg of phenylsulfonyl leucine was dissolved in 178 μL of NMO (N-Methylmorpholine-N-oxide) in 5 mL of THF, and the mixture was stirred at 0 °C. 155 μL of ethyl chloroformate was slowly added dropwise, and the mixture was stirred for 30 minutes at the same temperature. The filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 154 mg of hydroxylamine hydrochloride and 308 μL of triethylamine dissolved in 2 mL of DMF. After stirring at room temperature for 30 minutes, the solution was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain 0.11 g of N-hydroxy-4-methyl-2-(benzenesulfonamide)pentanamide.

[0364] 1H-NMR (500MHz, DMSO-d6): δ10.65 (s, 1H), 8.81 (s, 1H), 8.00 (m, 1H), 7.77 (m, 2H), 7.57 (m, 1H), 7.5 5(m, 2H), 3.48(m, 1H), 1.43(m, 1H), 1.35-1.20(m, 2H), 0.72(d, 3H, J=6.5Hz), 0.60(d, 3H, J=7.0Hz)

[0365] (25) Synthesis of T-40 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide

[0366] 1 g of proline was thoroughly stirred with 18 mL of THF, followed by the addition of 20 mL of 1 M Na₂CO₃. 2.44 g of N-acetyl-p-aminobenzenesulfonyl chloride was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. After two washes with 20 mL of diethyl ether, 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 483 mg of the intermediate ((4-acetylaminophenyl)sulfonyl)proline. The intermediate was used directly in the next reaction without further purification.

[0367] 450 mg of ((4-acetaminophenyl)sulfonyl)proline was dissolved in 174 μL of NMO (N-Methylmorpholine-N-oxide) in 6 mL of THF, and the mixture was 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 filtrate obtained after filtering the solids from the reaction solution was stored separately and then added dropwise to a solution containing 200 mg of hydroxylamine hydrochloride and 401 μL of triethylamine dissolved in 1.5 mL of DMF. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to remove the DMF. Ethyl acetate and purified water were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The solid obtained after collecting the organic layer and concentrating it under reduced pressure was purified by column chromatography (5% MeOH DCM) to obtain 120 mg of 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

[0368] 1H-NMR (500MHz, DMSO-d6): δ10.64 (s, 1H), 10.38 (s, 1H), 8.91 (s, 1H), 7.79 (m, 4H), 3.9 0(m,1H),3.41(m,1H),3.11(m,1H),2.09(s,3H),1.82(m,1H),1.70(m,2H),1.42(m,1H)

[0369] Experimental Example

[0370] As shown below, the MMP blocking efficacy of the novel compound was experimentally confirmed.

[0371] 1. Experimental Design

[0372] Enzyme activity (%) at the same concentration was compared using treatments with 0.5 μM MMP-1 activity, 50 nM MMP-2 activity, and MMP-9 activity (n = 2). Here, enzyme activity (%) refers to the enzyme activity (%) of the experimental group when the untreated group is considered to have 100% enzyme activity.

[0373] 2. Evaluation of MMP activity

[0374] To assess the effect on the enzyme activity of the novel compound, colorimetric changes were measured using a kit sold by Abcam, following their experimental protocol. Enzyme activity was obtained by comparing absorbance per minute to the untreated group.

[0375] -MMP1 Inhibitor Screening Assay Kit (ab139443)

[0376] -MMP2 Inhibitor Screening Assay Kit (ab139446)

[0377] -MMP9 Inhibitor Screening Assay Kit (ab139448)

[0378] 3. Principle of MMP Activity Evaluation

[0379] If MMP activity increases, the substrate is decomposed, and the OD412 value increases. Therefore, the change in OD412 value (OD value) is measured every minute, and the value is calculated according to the enzyme activity calculation formula below. Here, OD412 refers to the optical density or absorbance at 412 nm.

[0380] -Thiopeptide (Ac-PLG-[2-mercapto-4-methyl-pentanoyl]-LG-OC2H5:Ac-PLG-[2-mercapto-4-methyl-pentanoyl]-LG-OC2H5) as a chromogenic substrate.

[0381] - The peptide bond at the MMP cleavage site is replaced by the thioester bond of the thiopeptide.

[0382] - Hydrolysis of this bond in MMP generates a thiol group, which reacts with DTNB [5,5'-dithiobis(2-nitrobenzoic acid), Ellman's reagent] to form 2-nitro-5-thiobenzoic acid, which can be determined by its absorbance at 412 nm. (ε = 13,600 M at pH 6.0 and above) -1 cm -1 )

[0383] <Formula for calculating enzyme activity>

[0384] Novel compound enzyme activity (%) = (V 新型化合物 / V 未处理组 )×100

[0385] V = Change in OD value per minute

[0386] The enzyme activity calculation formula can also be expressed as follows.

[0387] <Obstruction Effect Calculation Formula>

[0388] Inhibition effect of novel compound (%) = Enzyme activity in untreated group - Enzyme activity of novel compound

[0389] =100- Novel compound enzyme activity

[0390] 4. Experimental Results

[0391] The results of a comparative evaluation of single concentrations of 25 novel compounds targeting MMP enzyme activity and inhibition efficacy are shown in Table 2 (enzyme activity, in %) and Table 3 (inhibition activity, in %).

[0392] [Table 2]

[0393]

[0394]

[0395] [Table 3]

[0396]

[0397]

[0398] Tables 2 and 3 present three sets of experiments that differed from each other. For example, in the case of T-01, when MMP-1 was treated with 0.5 μM, the enzyme activity of MMP-1 remained at 34.2% (from 100%). In the case of MMP-2, when treated with 50 nM T-01, the enzyme activity was 81.6% (from 100%), and in the case of MMP-9, when treated with 50 nM T-01, the enzyme activity was 79.1% (from 100%).

[0399] The experimental results show that most MMP-2 and MMP-9 are hindered at the 50 nM level. In contrast, MMP-1 was found to show a hindering level at 0.5 uM, which is 10 times higher.

[0400] In addition, each compound inhibited the activity of each of the three enzymes, namely MMP-1, MMP-2, and MMP-9, to varying degrees. This can be presumed to be a result of the differences in binding between the structural characteristics of MMP-1, MMP-2, and MMP-9 and the compounds.

[0401] In other words, the reason for the difference in the inhibitory strength of T-01 to T-40 against MMPs is due to the slight difference in their structures. It has been confirmed that the binding capacity of enzymes differs according to their structures, and the inhibitory effect also differs accordingly.

[0402] Table 4 below shows the enzyme activity (%) when treated with high concentrations, under the conditions described below.

[0403] MMP-1 (%): T-05~20 at 10 μM, T-23~34 at 5 μM

[0404] MMP-2 (%): T-05~20 at 10 μM, T-23~34 at 0.5 μM

[0405] MMP-9 (%): T-05~20 not tested, T-23~34 at 0.5uM

[0406] [Table 4]

[0407] TM No. MMP-1 (%) MMP-2 (%) MMP-9 (%) Unprocessed group 100 100 100 T-05 91.7 84.2 Untested T-08 87.2 100 Untested T-10 100 84.5 Untested T-11 57.1 6.2 Untested T-13 100 28.1 Untested T-15 100 65.2 Untested T-18 100 100 Untested T-20 100 40.1 Untested T-23 100 100 100 T-25 85.8 61.7 79.4 T-28 100 100 100 T-32 100 92.4 88.1 T-33 73.9 73.7 77.8 T-34 41.8 62.2 69.9

[0408] Table 5 below shows the inhibition effect (%) when treated with high concentrations, under the conditions described below.

[0409] MMP-1 (%): T-05~20 at 10 μM, T-23~34 at 5 μM

[0410] MMP-2 (%): T-05~20 at 10 μM, T-23~34 at 5 μM

[0411] MMP-9 (%): T-05~20 not tested, T-23~34 at 5uM [Table 5]

[0412] TM No. MMP-1 (%) MMP-2 (%) MMP-9 (%) Unprocessed group 0.0 0.0 0.0 T-05 8.3 15.8 Untested T-08 12.8 0.0 Untested T-10 0.0 15.5 Untested T-11 42.9 93.8 Untested T-13 0.0 71.9 Untested T-15 0.0 34.8 Untested T-18 0.0 0.0 Untested T-20 0.0 59.9 Untested T-23 0.0 0.0 0.0 T-25 14.2 38.3 20.6 T-28 0.0 0.0 0.0 T-32 0.0 7.6 11.9 T-33 26.1 26.3 22.2 T-34 58.2 37.8 30.1

Claims

1. A compound, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate represented by the following chemical formula 1: [Chemical Formula 1] In chemical formula 1, X is represented by any one of the following chemical formulas 1-1 to 1-5. [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formulas 1-3] [Chemical Formulas 1-4] [Chemical Formulas 1-5] In chemical formula 1-1, Ar is an unsubstituted or phenyl group substituted with 1 to 3 R1 atoms. R1 is hydrogen, phenyl, C1-C4 alkoxy, C1-C3 alkyl, fluoro, adamantyl, acetamino, or hydroxyiminoethyl. When there is more than one R1 group, all R1 groups are identical to each other. In chemical formulas 1-2, Ar represents a phenyl group substituted with one R2 molecule. R2 is a C1-C4 alkyl, C1-C4 alkoxy, adamantyl, acetyl, or acetamido. In chemical formulas 1-3, Ar represents a phenyl group substituted with 1 to 3 R3 radicals or an unsubstituted naphthalene group. R3 is hydrogen or a C1-C4 alkyl group. When there is more than one R3 group, all R3 groups are the same as each other, and preferably R3 is a C1-C4 alkyl group. In chemical formulas 1-4, Ar is an unsubstituted or phenyl group substituted with 1 to 3 R4 groups. R4 is hydrogen, phenyl, C1-C4 alkyl, or C1-C4 alkoxy. When there is more than one R4 group, all R4 groups are identical to each other. In chemical formulas 1-5, Ar is a phenyl group substituted with 1 to 3 R5 radicals. R5 is a C1-C4 alkyl group. When there is more than one R5 group, all R5 groups are identical to each other.

2. The compound according to claim 1, wherein, The compound represented by the chemical formula 1 is any one of the following compounds: N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(tris(methylbenzenesulfonyl)piperidine-2-carboxamide, 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide, N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide, N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide, 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide, 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide, 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutanamide, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)butanamide, 1-((4-fluorophenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-((3r,5r,7r)-adamantane-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)-adamantane-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-(benzenesulfonamide)pentanamide, and 1-((4-acetamidophenyl)sulfonyl)-N-hydroxypyrrolidine-2-carboxamide.

3. The compound according to claim 1, wherein, The compound represented by chemical formula 1 is any one of the following compounds: N-hydroxy-1-(benzenesulfonyl)piperidine-2-carboxamide, 1-([1,1'-biphenyl]-4-ylsulfonyl)-N-hydroxypiperidine-2-carboxamide, 1-((4-butoxyphenyl)sulfonyl)-N-hydroxypiperidine-2-carboxamide, N-hydroxy-1-(tris(methylbenzenesulfonyl)piperidine-2-carboxamide, 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-phenylpropionamide, N-hydroxy-3-phenyl-2-((2,4,6-trimethylphenyl)sulfonamido)propionamide, N-hydroxy-2-(naphthalene-2-sulfonamido)-3-phenylpropionamide, 2-([1,1'-biphenyl]-4-sulfonamido)-N-hydroxy-4-methylpentanamide, 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-4-methylpentanamide, 2-((4-butoxyphenyl)sulfonamido)-N-hydroxy-4-methylpentanamide, N-hydroxy-4-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)pentanamide, N-hydroxy-3-methyl-2-((2,4,6-trimethylphenyl)sulfonamido)butyramide, 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)-adamantane-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-(benzenesulfonamide)pentanamide.

4. The compound according to claim 1, wherein, The compound represented by chemical formula 1 is any one of the following compounds: 2-((4-(tert-butyl)phenyl)sulfonamido)-N-hydroxy-3-methylbutyramide, 1-((4-((3r,5r,7r)-adamantane-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 chemical formula 1 is derived from amino acids.

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

7. The cosmetic composition according to claim 6, wherein, Based on the overall volume of the composition, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates is from 0.01 μM to 100 mM.

8. An oral composition comprising, as an active ingredient, any one of claims 1 to 5, a compound represented by chemical formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

9. The oral composition according to claim 8, wherein, Based on the overall volume of the composition, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates is from 0.01 μM to 100 mM.

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

11. The MMP-1 activity inhibitor composition according to claim 10, wherein, Based on the overall volume of the composition, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates is from 0.01 μM to 100 mM.

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

13. The MMP-2 activity inhibitor composition according to claim 12, wherein, Based on the overall volume of the composition, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates is from 0.01 μM to 100 mM.

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

15. The MMP-9 activity inhibitor composition according to claim 14, wherein, Based on the overall volume of the composition, the content of the compound represented by the chemical formula 1, its isomers, its pharmaceutically acceptable salts, its hydrates, or its solvates is from 0.01 μM to 100 mM.

16. A method for preparing a compound represented by chemical formula 1 according to any one of claims 1 to 5, the method comprising: The step of reacting an amino acid selected from pipecolinic acid, phenylalanine, leucine, valine, and proline with sulfonic acid, sulfonyl halide, sulfanilic acid, or sulfanilylhalide.

17. The preparation method according to claim 16, wherein, The preparation method further includes the step of reacting the intermediate obtained by the reaction with free hydroxylamine or salt hydroxylamine salt to obtain the compound represented by chemical formula 1.

18. The preparation method according to claim 16, wherein, The sulfonyl halide is a sulfonyl fluoride, sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide, and the p-aminobenzenesulfonyl halide is a p-aminobenzenesulfonyl fluoride, p-aminobenzenesulfonyl chloride, p-aminobenzenesulfonyl bromide, or p-aminobenzenesulfonyl iodide.

19. The preparation method according to claim 18, wherein, The sulfonyl chloride is selected from the group consisting of benzenesulfonyl chloride, 4-biphenylsulfonyl chloride, 4-butoxybenzene-1-sulfonyl chloride, 2-tris(benzenesulfonyl 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 p-aminobenzenesulfonyl chloride is N-acetyl-p-aminobenzenesulfonyl chloride.

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