Spirocyclic hydantoin derivatives having adamts-4 inhibitory activity and uses thereof

Abstract

The present invention relates to novel spirohydantoin derivatives having metalloprotease ADAMTS-4 inhibitory activity and uses thereof. The spirohydantoin derivatives described in the present invention are useful for the prevention or treatment of diseases caused by liver damage, such as fatty liver, liver cirrhosis, and the like.

Description

Technical Field

[0001] This invention relates to novel spirocyclic hydantoin derivatives with ADAMTS-4 inhibitory activity against metalloproteinases, and their use in the prevention or treatment of liver fibrosis.

[0002] The research for this invention was completed with the support of the Polam Hospital (04-2023-0032). Background Technology

[0003] Fatty liver disease is a liver injury caused by the abnormal accumulation of fat in hepatocytes. Further progression of fatty liver disease can lead to steatohepatitis (including liver fibrosis), cirrhosis, or hepatocellular carcinoma. The causes of fatty liver disease are broadly classified into alcoholic and non-alcoholic types. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and its incidence continues to rise due to nutritional excess caused by high-fat and high-carbohydrate intake. The accumulation of triglycerides in the liver and hepatocyte damage directly related to NAFLD are the result of an imbalance in hepatic lipid uptake / synthesis and release / oxidation caused by changes in local factors and systemic factors such as insulin resistance.

[0004] Currently, among chronic diseases in China, hepatitis, cirrhosis, and liver cancer have the highest incidence rates, ranking alongside circulatory system diseases, and account for a significant proportion of disease-related deaths. Persistent liver tissue damage caused by viral infections or long-term alcohol consumption can progress to cirrhosis or liver cancer. There remains an urgent need to develop drugs that can alleviate liver tissue damage and ultimately be used to treat liver diseases.

[0005] Liver fibrosis is part of the body's adaptive response to chronic liver diseases (such as hepatitis). It refers to the state in which damaged liver tissue cannot be repaired into normal hepatocytes, but instead transforms into fibrous tissue mainly composed of collagen. Although liver fibrosis is an adaptive response that occurs during tissue damage repair, the decline in liver function is inevitable because the liver is replaced by fibrous tissue that cannot perform its inherent functions such as metabolism and bile secretion. If liver fibrosis continues to recur, it can progress to cirrhosis and even death, thus necessitating the development of appropriate therapeutic drugs. Since the pathogenesis of liver fibrosis is not fully understood, in-depth research is urgently needed on novel mechanisms of action and corresponding inhibitory therapeutic drugs. Summary of the Invention

[0006] The problem the invention aims to solve One object of the present invention is to provide novel spirocyclic hydantoin derivatives, isomers thereof, or pharmaceutically acceptable salts thereof that have inhibitory activity against the metalloproteinase ADAMTS-4.

[0007] Another object of the present invention is to provide a composition comprising the above-described spirocyclic hydantoin derivative, its isomer, or a salt thereof.

[0008] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described spirocyclic hydantoin derivative, its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier for the prevention or treatment of liver fibrosis.

[0009] means for solving problems To achieve the above objectives, the present invention provides compounds of the following formula, isomers thereof, or pharmaceutically acceptable salts thereof:

Chemical Formula 1

[0010] Furthermore, the present invention provides compositions comprising compounds of the above-described chemical formula 1, their isomers, or salts thereof.

[0011] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of the above-described chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the prevention or treatment of liver fibrosis.

[0012] Invention Effects The compounds of Formula 1 of this invention, their isomers, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against liver fibrosis by inhibiting the metalloproteinase ADAMTS-4, and are therefore effective in preventing or treating liver fibrosis diseases such as cirrhosis and fatty liver disease (e.g., NASH). Attached Figure Description

[0013] Figure 1 A graph illustrating the TR-FRET assay results of the compound inhibiting ADAMTS-4 activity according to an embodiment of the present invention.

[0014] Figure 2 To illustrate the results of blood drug concentration measurements over time after administering control group, positive control group AGG523, and a compound according to an embodiment of the present invention to mice.

[0015] Figure 3 To demonstrate the experimental results evaluating the inhibitory effect of AGG523 on CCl4-induced liver fibrosis.

[0016] Figure 4To demonstrate the experimental results evaluating the inhibitory effect of a compound according to an embodiment of the present invention on CCl4-induced liver fibrosis.

[0017] Figure 5 To demonstrate the experimental results of MTT assay and evaluation of TGFβ-induced stellate cell activation indicators after treating LX2 cells with AGG523 and a compound according to an embodiment of the present invention. Detailed Implementation

[0018] The present invention will now be described in more detail.

[0019] In this invention, unless otherwise specified, the term "halogen" refers to F, Cl, Br, or I.

[0020] The term "hydroxyl group" refers to the -OH group.

[0021] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Specifically, C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. In one embodiment, the alkyl group may optionally be substituted with one or more substituents, such as 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, and other hydrocarbon groups.

[0022] The term "alkylene" refers to a divalent group derived from an alkyl group. For example, it can be (-CH2-)n (n is 1 to 24), including but not limited to -CH2-, -CH2CH2-, and -CH2CH2CH2-. For example, "C1-C3 alkylene" refers to an alkylene having 1 to 3 carbon atoms.

[0023] The term "alkoxy" refers to the chemical formula "-O-alkyl". The alkoxy group may optionally be substituted with one or more substituents. For example, "C1-C6 alkoxy" includes, but is not limited to, methoxy, ethoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, sec-pentoxy, neopentoxy, hexoxy, etc. In one embodiment, the alkoxy group may optionally be substituted with one or more substituents, for example, by one to three halogens, hydroxyl groups, C1-C6 alkyl groups, and other hydrocarbon groups.

[0024] The term "cycloalkyl" refers to a hydrocarbon having one or more saturated rings or one or more non-aromatic rings, wherein the non-aromatic rings may have a degree of unsaturation. Unless otherwise defined, a cycloalkyl group can be monocyclic or polycyclic. In this case, the polycyclic group can be one of a fused, bridged, or spiro ring. For example, "3- to 14-membered cycloalkyl" refers to a cycloalkyl group containing 3 to 14 carbon atoms constituting the rings. Specifically, 3- to 14-membered cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptyl, adamantyl, etc. In one embodiment, the cycloalkyl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms in each ring of the cycloalkyl group may be substituted with substituents.

[0025] The term "cycloalkyl" refers to a hydrocarbon having one or more saturated rings or one or more non-aromatic rings, wherein the non-aromatic rings may have a degree of unsaturation. Unless otherwise defined, a cycloalkyl group can be monocyclic or polycyclic. In this case, the polycyclic group can be one of a fused, bridged, or spiro ring. For example, "3- to 14-membered cycloalkyl" refers to a cycloalkyl group containing 3 to 14 carbon atoms constituting the rings. Specifically, 3- to 14-membered cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptyl, adamantyl, etc. In one embodiment, the cycloalkyl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms in each ring of the cycloalkyl group may be substituted with substituents.

[0026] The term "aryl" refers to an aromatic hydrocarbon. Unless otherwise defined, an aryl group can be monocyclic or polycyclic. For example, aryl groups include phenyl, naphthyl, indenyl, and biaryl groups. In one embodiment of the invention, a C6-C10 aryl group refers to an aromatic ring containing 6 to 10 carbon atoms. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms in each ring of the aryl group may be substituted with substituents.

[0027] The term "heteroaryl" refers to an aromatic heterocycle containing one to four heteroatoms selected from N, O, and S. Unless otherwise defined, a heteroaryl can be monocyclic or polycyclic. For example, "5- to 10-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocycle containing one to four heteroatoms selected from N, O, and S, or a bicyclic ring formed by fusion of the heteroaryl ring with a benzene ring or other heteroaryl rings. In one embodiment, the 0, 1, 2, 3, or 4 atoms in each ring of the heteroaryl may be substituted with substituents. Examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophene, furanyl, pyrrole, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, azaindolyl, indololinyl, benzothiophene, benzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalolinyl, purine, furanylpyridinyl, and similar groups.

[0028] The term "heterocyclyl" refers to a saturated or partially unsaturated ring containing one to four heteroatoms selected from N, O, and S in addition to a carbon atom. Unless otherwise defined, a heterocyclyl group can be monocyclic or polycyclic. For example, "4- to 10-membered heterocyclyl group" refers to a 4-, 5-, or 6-membered aliphatic heterocycle, or a bicyclic ring formed by fusion of the said heterocyclyl group ring with a benzene ring or other heterocyclyl group ring. In one embodiment, the 0, 1, 2, 3, or 4 atoms in each ring of the heterocyclyl group may be substituted with substituents. For example, heterocyclic groups include, but are not limited to, azirrobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, dioxopentyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholin-4-yl, azirrohepyl, diazirrohepyl, homopiperazinyl, oxazahepyl, indolyl, isoindolyl, dihydroindolyl, dioxoisoindololinyl, dihydrofuranyl, dihydroimidazolinyl, dihydrooxazolyl, dihydrobenzodioxane, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxane, or benzodioxane, etc.

[0029] The term "substitution" refers to the process of replacing a hydrogen atom in a molecule with a substituent, without exceeding a specified valence, in order to form a chemically stable compound. For example, "group A is substituted by substituent B" means that the hydrogen atoms bonded to the carbon atoms or other atoms that make up the skeleton of group A are replaced by substituent B, thereby forming a covalent bond between group A and substituent B.

[0030] The term "substituent" refers to another group that is combined with the parent nucleus group. There can be one or more substituents. When multiple substituents are present, they can be the same or different. When both the parent nucleus group and the substituents are hydrocarbon groups, the number of carbon atoms in the parent nucleus does not include the number of carbon atoms in the substituents. For example, butyl (-C4H9) with a methoxy (-O-CH3) substituent is classified as a C4 alkyl group substituted with a C1 alkoxy group.

[0031] The term "isomer" refers to multiple stereoisomers. Embodiments of the present invention may generate multiple stereoisomers during the preparation process. Unless otherwise specified, all stereoisomers that may be generated during the reaction may be included.

[0032] In the embodiments of the present invention, the following abbreviations are used throughout: "Ac" represents acetyl, "AcO" or "OAc" represents acetoxy, "ACN" represents acetonitrile, "aq" represents aqueous, "BOC", "Boc" or "boc" represents N-tert-butyloxycarbonyl, "Bn" represents benzyl, "Bu" represents butyl, "nBu" represents n-butyl, "tBu" represents tert-butyl, "Cbz" represents benzyloxycarbonyl, "DCC" represents N,N′-dicyclohexylcarbodiimide, "D "CM" represents chloromethane (CH2Cl2), "DEA" represents diethylamine, "TEA" or "Et3N" represents triethylamine, "DIPEA" represents diisopropylethylamine, "DMF" represents N,N-dimethylformamide, "DMSO" represents dimethyl sulfoxide, "EDC" represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "EDTA" represents ethylenediaminetetraacetic acid, "Et" represents ethyl, "EtOAc" represents ethyl acetate, and "EtOH" represents... Ethanol, "HATU" represents (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), "HOAc" or "AcOH" represents acetic acid, "IPA" represents isopropanol, "LAH" represents lithium aluminum hydride, "mCPBA" represents m-chloroperoxybenzoic acid, "Me" represents methyl, "MeOH" represents methanol, "MS" represents mass spectrometry, "MTBE" represents methyl tert-butyl ether, and "NHS" represents... N-chlorosuccinimide, "Ph" indicates phenyl, "PyBOP" indicates benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, "TFA" indicates trifluoroacetic acid, "THF" indicates tetrahydrofuran, "TLC" indicates thin-layer chromatography, "Rf" indicates retention fraction, "rt" indicates retention time, "rt" indicates room temperature, "h" indicates hour, "min" indicates minute, "s" indicates second, "equiv." indicates equivalent, and "sat." indicates saturation.

[0033] This invention provides compounds of Formula 1, their isomers, or pharmaceutically acceptable salts thereof:

Chemical Formula 1

[0034] In one embodiment, in the compound of chemical formula 1, R 3 It is hydrogen or C1-C6 alkyl, or R 3 With R 6 A ring can be formed by linking C1-C3 alkylene groups (e.g., methylene groups).

[0035] In one embodiment, in the compound of chemical formula 1, R 5 It is hydrogen or C1-C6 alkyl, or R 3 With R 5 A ring can be formed by linking C1-C3 alkylene groups (e.g., methylene (-CH2-)).

[0036] In one embodiment, in the compound of chemical formula 1, R 7 It can be C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, or piperazineyl. The C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, and piperazineyl are each independently unsubstituted, or can be substituted with 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups (e.g., -CF3) or C1-C6 alkoxy groups (e.g., -OCF3 or -OCHF2) substituted with 1 to 3 halogens or hydroxyl groups, but are not limited thereto.

[0037] In one embodiment, in the compound of chemical formula 1, R 8 It can be hydrogen, phenyl, C 3-8 Cycloalkyl (e.g., cyclohexyl, cyclopentenyl), furanyl, thiophene, pyrazolyl, pyridyl, indene, benzofuranyl, benzothiophene, or morpholinyl. The phenyl, C 3-8Cycloalkyl, furanyl, thiophene, pyrazolyl, pyridyl, indene, benzofuranyl, benzothiophene, and morpholinyl are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 Aryl (where p is an integer from 1 to 5) (e.g., -O-benzyl), or C1-C6 alkyl (e.g., -CF3), C1-C6 alkoxy (e.g., -OCF3 or -OCHF2), or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced, but not limited to these.

[0038] In one embodiment, in the compound of chemical formula 1, R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl groups, such as 4-10 membered heterocyclic groups, can be piperazine groups, C 6-10 The aryl group can be phenyl, but is not limited to it. The C group mentioned therein... 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups or C1-C6 alkoxy groups, but is not limited thereto.

[0039] Specifically, the R 9 For example, it can be... , , or .

[0040] In another embodiment of the present invention, the compound of chemical formula 1 may be a compound of chemical formula 2 as follows: [Chemical Formula 2] In the above formula, R 1 It can be hydrogen, halogen, or allyl; R 2 and R 4 One is hydrogen, and the other is... or ; R 3 It is hydrogen or C1-C6 alkyl, or R 3 With R 6 It can form a ring through the linkage of C1-C3 alkylene groups; R 5 and R 6 It is hydrogen; L represents -CO-, -SO2-, or -CONH-; R 7 C1-C6 alkyl, C 6-10 Aryl, -CH2-C 6-10Aryl, C 3-14 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic, wherein the C1-C6 alkyl, C 6-10 Aryl, C 3-14 The cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups or C1-C6 alkoxy groups substituted by 1-3 halogens or hydroxyl groups. R 8 For hydrogen, C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl or 4-10-membered heterocyclic, wherein the C 6-10 The aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 aryl (where p is an integer from 1 to 5), or C1-C6 alkyl, C1-C6 alkoxy, or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced; R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl, wherein the C 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; m is an integer from 0 to 5, and when m is 0, it is a single key; The heteroaryl group is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S.

[0041] In one embodiment, in the compound of chemical formula 2, R 3 It is hydrogen or C1-C6 alkyl, or R 3 With R 6 A ring can be formed by linking C1-C3 alkylene groups (e.g., methylene (-CH2-)).

[0042] In one embodiment, in the compound of chemical formula 2, R 7It can be C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, or piperazineyl. The C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, and piperazineyl are each independently unsubstituted, or can be substituted with 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups (e.g., -CF3) or C1-C6 alkoxy groups (e.g., -OCF3 or -OCHF2) substituted with 1 to 3 halogens or hydroxyl groups, but are not limited thereto.

[0043] In one embodiment, in the compound of chemical formula 2, R 8 It can be hydrogen, phenyl, C 3-8 Cycloalkyl (e.g., cyclohexyl, cyclopentenyl), furanyl, thiophene, pyrazolyl, pyridyl, indene, benzofuranyl, benzothiophene, or morpholinyl. The phenyl, C 3-8 Cycloalkyl, furanyl, thiophene, pyrazolyl, pyridyl, indene, benzofuranyl, benzothiophene, and morpholinyl are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 Aryl (where p is an integer from 1 to 5) (e.g., -O-benzyl), or C1-C6 alkyl (e.g., -CF3), C1-C6 alkoxy (e.g., -OCF3 or -OCHF2), or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced, but not limited to these.

[0044] In one embodiment, in the compound of chemical formula 2, R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl groups, such as 4-10 membered heterocyclic groups, can be piperazines, C 6-10 The aryl group can be phenyl, but is not limited to it. The C group mentioned therein... 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups or C1-C6 alkoxy groups, but is not limited thereto.

[0045] Specifically, the R 9 For example, it can be... or .

[0046] Specific examples of compounds of chemical formula 2 described in this invention are as follows, but are not limited thereto: (1) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran-2-sulfonamide; (2) N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; (3) 4-Cyclohexyl-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; (4) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (5) N-((3-allyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (6) 4'-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; (7) 4'-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; (8) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide; (9) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; (10) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; (11) 2'-(benzyloxy)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (12) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; (13) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; (14) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-4-yl)benzenesulfonamide; (15) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-3-yl)benzenesulfonamide; (16) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(6-methoxypyridin-3-yl)benzenesulfonamide; (17) 4-(2,6-dimethoxypyridin-3-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; (18) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(1-methyl-1H-pyrazol-5-yl)benzenesulfonamide; (19) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide; (20) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(furan-2-yl)benzenesulfonamide; (21) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(thiophen-2-yl)benzenesulfonamide; (22) 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; (23) 4-(benzo[b]thiophen-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)benzenesulfonamide; (24) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-morpholinobenzenesulfonamide; (25) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-3-sulfonamide; (26) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4,5-trifluorobenzenesulfonamide; (27) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3,4-trifluorobenzenesulfonamide; (28) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; (29) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; (30) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,4',5-trifluoro-[1,1'-biphenyl]-4-sulfonamide; (31) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2-methyl-[1,1'-biphenyl]-4-sulfonamide; (32) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2-methoxy-[1,1'-biphenyl]-4-sulfonamide; (33) 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methoxybenzenesulfonamide; (34) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide; (35) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide; (36) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-2-sulfonamide; (37) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-3-sulfonamide; (38) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,5-difluoro-4-morpholinobenzenesulfonamide; (39) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3-difluoro-4-morpholinobenzenesulfonamide; (40) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-fluoropyridine-3-sulfonamide; (41) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-fluoropyridine-3-sulfonamide; (42) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-methylpyridine-3-sulfonamide; (43) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methylpyridine-3-sulfonamide; (44) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide; (45) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)pyridine-sulfonamide; (46) 1-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)isoquinoline-4-sulfonamide; (47) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)furan-2-sulfonamide; (48) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)thiophene-2-sulfonamide; (49) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)thiazole-5-sulfonamide; (50) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide; (51) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methoxy-1H-indole-2-carboxamide; (52) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-methoxy-1H-indole-2-carboxamide; (53) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; (54) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-difluoro-1H-indole-2-carboxamide; (55) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)-1H-indole-2-carboxamide; (56) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methylbenzofuran-2-carboxamide; (57) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-carboxamide; (58) 4-(cyclopent-1-en-1-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide; (59) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(hydroxymethyl)-1H-indole-2-carboxamide; (60) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-hydroxy-1H-indole-2-carboxamide; (61) 5-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran-2-carboxamide; (62) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide; (63) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-ethoxy-1H-indole-2-carboxamide; (64) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(trifluoromethoxy)-1H-indole-2-carboxamide; (65) 4-(difluoromethoxy)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide; (66) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-7-fluoro-4-methoxy-1H-indole-2-carboxamide; (67) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-fluoro-4-methoxy-1H-indole-2-carboxamide; (68) 5-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; (69) 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; (70) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,7-dimethoxy-1H-indole-2-carboxamide; (71) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-dimethoxy-1H-indole-2-carboxamide; (72) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,5-dimethoxy-1H-indole-2-carboxamide; (73) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methyl-2-(4-(trifluoromethyl)benzyl)butyramide; (74) 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-(trifluoromethyl)phenyl)urea; (75) 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-fluorophenyl)urea; (76) 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-fluorobenzyl)urea; (77) 1-((1r,3r,5r,7r)-adamantane-2-yl)-3-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)urea; (78) 2-(benzofuran-2-ylsulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (79) 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (80) 2-((4-(benzofuran-2-yl)phenyl)sulfonyl)-2,6,8-triazadispiro[3.0.45.34]dodecane-7,9-dione; (81) 2-((5-(4-fluorophenyl)pyridin-2-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (82) 2-((5-(benzofuran-2-yl)pyridin-2-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (83) 2-((6-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (84) 2-((6-(benzofuran-2-yl)pyridin-3-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; (85) 2-(5-(trifluoromethyl)benzofuran-2-carbonyl)-2,6,8-triazadispiro[3.0.45.34]dodecane-7,9-dione; (86) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (87) 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)benzenesulfonamide; (88) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide; (89) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-2-sulfonamide; (90) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide; (91) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-3-sulfonamide; (92) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorobenzofuran-2-yl)pyridine-3-sulfonamide; (93) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-fluorobenzofuran-2-yl)pyridine-3-sulfonamide; (94) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; (95) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(6-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; (96) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(3-methylbenzofuran-2-yl)pyridine-3-sulfonamide; (97) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methylbenzofuran-2-yl)pyridine-3-sulfonamide; (98) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyrimidine-5-sulfonamide; (99) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-fluoropyridine-3-sulfonamide; (100) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-fluoropyridine-3-sulfonamide; (101) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-methylpyridine-3-sulfonamide; (102) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-methylpyridine-3-sulfonamide; (103) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide; (104) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide; (105) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)furan-2-sulfonamide; (106) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiophene-2-sulfonamide; (107) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiazole-5-sulfonamide; (108) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1H-imidazol-5-sulfonamide; (109) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1H-imidazol-5-sulfonamide; (110) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide; (111) 6-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; (112) 6-((S)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; (122) 4-(4,4-difluorocyclohexyl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)benzenesulfonamide; (123) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (124) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (125) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (126) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; (127) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3',4',5'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; (128) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',3',4'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; (129) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(5-fluoropyridin-2-yl)benzenesulfonamide; (130) 4-(2,6-difluoropyridin-3-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; (131) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide; (132) N-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-carboxamide; (133) 2-(2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)-N-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetamide; (134) 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)piperidine-1-sulfonamide; (135) 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)piperidine-1-sulfonamide; (136) 3-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)azacyclobutane-1-sulfonamide; (137) 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylpyridine-3-sulfonamide; (138) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylpyridine-2-sulfonamide; (139) N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(1H-inden-2-yl)pyridine-3-sulfonamide; (140) 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-4-methylthiazolyl-5-sulfonamide; and (141) 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylthiophene-2-sulfonamide.

[0047] In another embodiment of the present invention, the compound of chemical formula 1 may be a compound of chemical formula 3 as follows:

Chemical Formula 3

[0048] In one embodiment, in the compound of chemical formula 3, R 5 It is hydrogen or C1-C6 alkyl, or R 3 With R 5 A ring can be formed by linking C1-C3 alkylene groups (e.g., methylene (-CH2-)).

[0049] In one embodiment, in the compound of chemical formula 3, R 7 It may be phenyl, benzofuranyl, or indoleyl. The phenyl, benzofuranyl, and indoleyl groups are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups (e.g., -CF3) or C1-C6 alkoxy groups (e.g., -OCF3 or -OCHF2) substituted by 1 to 3 halogens or hydroxyl groups, but are not limited thereto.

[0050] In one embodiment, in the compound of chemical formula 3, R 8 It may be hydrogen or phenyl. The phenyl group is independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1 to 3 halogens or hydroxyl groups, but is not limited thereto.

[0051] In one embodiment, in the compound of chemical formula 3, R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl groups, such as 4-10 membered heterocyclic groups, can be piperazine groups, C 6-10 The aryl group can be phenyl, but is not limited to it. The C group mentioned therein... 6-10 The aryl group is unsubstituted, or may be substituted with 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups. Specifically, the R... 9 For example, it can be... , , or However, it is not limited to this.

[0052] Specific examples of the compounds of chemical formula 3 described in this invention are as follows, but are not limited thereto: (113) N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; (114) N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4-methoxy-1H-indole-2-carboxamide; (115) 5-Chloro-N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)benzofuran-2-carboxamide; (116) 8-(4-(3,5-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (117) 8-(4-(3,4-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (118) (S)-8-(4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (119) (S)-8-(4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (120) 1-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; and (121) 1-((S)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; This invention includes pharmaceutically acceptable salts of the above-described compounds.

[0053] The pharmaceutically acceptable salt should have low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. For example, the pharmaceutically acceptable salt can be an acid addition salt formed from a pharmaceutically acceptable free acid.

[0054] The free acid can be an inorganic acid or an organic acid. The inorganic acid can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, etc., and the organic acid can be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, pyric acid, aspartic acid, glutamic acid, etc.

[0055] The acid addition salt can be prepared by conventional methods, such as dissolving the compound of Formula 1 in an excess of aqueous acid solution and then precipitating the salt using an organic solvent miscible with water (e.g., methanol, ethanol, acetone or acetonitrile).

[0056] In addition, the pharmaceutically acceptable salt may be an alkali metal salt (such as sodium salt) or an alkaline earth metal salt (such as potassium salt).

[0057] The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound of Formula 1 in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate.

[0058] Furthermore, the compounds of the present invention may contain a chiral carbon center and thus may exist as R or S isomers, racemic compounds, single enantiomers or mixtures thereof, single diastereomers or mixtures thereof, all of which are stereoisomers and mixtures thereof within the scope of the present invention.

[0059] Furthermore, the compounds of the present invention may include hydrates and solvates of the compound of Formula 1. The hydrates and solvates may be prepared using known methods, and are preferably non-toxic and water-soluble. Particularly preferably, the hydrates and solvates may be in the form of 1 to 5 water molecules and an alcoholic solvent (especially ethanol, etc.) molecule, respectively.

[0060] Furthermore, the present invention provides a method for preparing the above-mentioned compounds.

[0061] Specifically, the compound of chemical formula 1 can be prepared by the method shown in the reaction formula below, but is not limited to such methods. In particular, those skilled in the art will fully understand that the compound of chemical formula 1 of the present invention can be prepared by various methods using well-known techniques in the art.

[0062] The following reaction formulas illustrate the preparation method of representative compounds of the present invention according to the preparation steps. Many other compounds of the present invention can also be prepared by changing the reagents and solvents used in the following preparation steps or by changing the reaction order.

[0063] General experimental procedures The compounds of the present invention can be synthesized by the following reaction formula 1.

[0064] According to one embodiment, the compounds of the present invention can be synthesized using spirocyclic hydantoin compounds as starting materials. For example, the starting material can be 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1). For instance, the starting material (SM-1) can be reacted with sulfonyl chloride (R2-SO2Cl) to form a sulfonamide bond, thereby synthesizing the target spirocyclic hydantoin derivative. As another example, the starting material (SM-1) can be reacted with a carboxylic acid (R2-COOH) to form an amide bond, thereby synthesizing the target spirocyclic hydantoin derivative. As yet another example, the starting material (SM-1) can be reacted with an isocyanate (R2-N=C=O) to form a urea bond, thereby synthesizing the target spirocyclic hydantoin derivative.

[0065]

Reaction Formula 1

[0066] All starting materials and reagents were commercially available and used directly without additional purification. Reactions sensitive to air and humidity were performed under nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck), and thin-layer chromatography (TLC) was performed using 0.25 mm silica gel plates (Merck). 1 H and 13C{ 1 ¹H NMR spectra were recorded in chloroform (CDCl₃), deuterated methanol (CD₃OD), or deuterated dimethyl sulfoxide (DMSO-d₆) solutions on a Bruker 600 MHz spectrometer. ¹H NMR data were recorded in order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet and / or multiplet resonances), proton number, and coupling constant (J) in Hertz (Hz). High-resolution mass spectrometry (HRMS) was recorded on a JEOL JMS-700 (EI).

[0067] The preparation method of the compounds of the present invention will be described in more detail in the following examples.

[0068] The compounds of Formula 1, their isomers, or pharmaceutically acceptable salts thereof have been confirmed to inhibit the metalloproteinase ADAMTS-4. Therefore, the compounds or pharmaceutical compositions containing them are effective in treating diseases caused by ADAMTS-4 expression, such as cirrhosis, fatty liver disease, and other liver fibrosis. As used herein, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread, and recurrence of the disease by applying the compounds or pharmaceutical compositions of the present invention; "treatment" refers to all actions that improve or bring about beneficial changes in the symptoms of the disease by applying the compounds or pharmaceutical compositions of the present invention.

[0069] The present invention provides the use of the compound of the stated chemical formula 1, its isomers or pharmaceutically acceptable salts thereof for the inhibition of ADAMTS-4.

[0070] The present invention provides the use of the compound of the stated chemical formula 1, its isomers or pharmaceutically acceptable salts thereof for the prevention or treatment of diseases (e.g., liver fibrosis) associated with ADAMTS-4 activity.

[0071] This invention provides the use of the compound of Formula 1, its isomers or pharmaceutically acceptable salts thereof for the preparation of medicaments for the prevention or treatment of diseases associated with ADAMTS-4 activity (e.g., liver fibrosis).

[0072] This invention provides the use of the compound of Formula 1, its isomers or pharmaceutically acceptable salts thereof for the preparation of a medicament for inhibiting ADAMTS-4.

[0073] Furthermore, the present invention provides a method for preventing or treating diseases associated with ADAMTS-4 activity (such as liver fibrosis), the method comprising administering a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need.

[0074] Furthermore, the present invention provides a method for inhibiting ADAMTS-4, the method comprising administering to an individual who requires inhibition of ADAMTS-4 a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0075] The diseases associated with ADAMTS-4 activity may be liver fibrosis diseases, such as cirrhosis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

[0076] The pharmaceutical composition of the present invention can inhibit ADAMTS-4. The term "inhibition" as used herein refers to the inhibition of any stage of gene transcription, mRNA processing, translation, translocation, and maturation, or the inhibition of protein-protein binding, protein activation, or signal transduction thereby.

[0077] In addition to the active ingredient, the pharmaceutical composition of the present invention may also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is a substance commonly used in formulation, including but not limited to lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Furthermore, in addition to the above components, it may further contain lubricants, humectants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0078] The pharmaceutical compositions of the present invention can be administered orally or via the non-enteric route (e.g., intravenous, subcutaneous, intraperitoneal, or local administration) according to the intended method. The dosage may vary depending on the patient’s condition and weight, disease severity, drug formulation, route of administration, and time of administration, and may be appropriately selected by those skilled in the art.

[0079] The pharmaceutical compositions of the present invention are administered in pharmaceutically effective amounts. In this invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment. The effective dose level can be determined based on factors such as the type and severity of the patient's disease, the activity of the drug, the patient's sensitivity to the drug, the timing of administration, the route of administration and excretion rate, the duration of treatment, concurrent medications, and other factors well known in the medical field.

[0080] The pharmaceutical compositions of this invention can be administered as a single therapeutic agent, or in combination with other therapeutic agents, or sequentially or simultaneously with existing therapeutic agents, and can be administered once or multiple times. Taking all of the above factors into account, it is crucial to administer the minimum dose that achieves the greatest effect without side effects, which can be readily determined by those skilled in the art.

[0081] Specifically, the effective dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the patient's age, sex, condition, weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and combination therapy. Generally, it is administered daily or every other day at a dose of 0.001 to 150 mg per kilogram of body weight, preferably 0.01 to 100 mg, or divided into 1 to 3 doses daily. However, the dosage may be increased or decreased depending on factors such as route of administration, severity of obesity, sex, weight, and age. Therefore, the above dosage does not limit the scope of the present invention in any way.

[0082] Furthermore, the present invention provides a method for the prevention, regulation, or treatment of liver fibrosis, including the step of administering the pharmaceutical composition to an individual. In this invention, "individual" refers to a person requiring disease treatment, and more specifically, to humans or non-human primates, mice, dogs, cats, horses, cattle, and other mammals.

[0083] The present invention will now be described in more detail through examples and experimental cases. However, the examples and experimental cases described below are merely illustrative of the present invention, and the scope of the present invention is not limited to the examples and experimental cases described below.

[0084]

Example

[0085]

Reaction 2

[0086] Step a: Synthesis of sulfonamide compound (1) (compound 1, intermediate 4 or intermediate 25) Sulfonyl chloride (1.5 equivalents) was added to a THF / DMF (1:1) solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (starting material 1, SM-1) (1.0 equivalents), followed by triethylamine (3.0 equivalents). The reaction mixture was stirred for 12–16 hours. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give the target compound.

[0087] N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-iodobenzenesulfonamide (intermediate 4) (Yield 90%, white solid). 1 H NMR (600 MHz, CD3OD) δ 7.78-7.69 (m, 4H), 2.88(dd, J = 12.7, 8.0 Hz, 1H), 2.73 (dd, J= 12.7, 7.1 Hz, 1H), 2.46-2.35 (m,1H), 2.25-2.13 (m, 1H), 2.04-1.91 (m, 1H), 1.87-1.71 (m, 3H), 1.44-1.33 (m,1H). 13 C{ 1 H} NMR (150 MHz, CD3OD) δ 180.5, 159.1, 140.6, 133.5, 129.9, 128.2,71.8, 48.4, 44.0, 39.1, 30.1, 23.3. 3-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide (intermediate 25) (Yield 34%, white solid). (Yield 34%, white solid).

[0088] Step a': Synthesis of sulfonamide compound (2) (compound 26, compound 27, intermediates 28 to 32, intermediates 34 to 35 or intermediates 40 to 49) Sulfonyl chloride (1.5 equivalents) was added to a THF / DMF (1:1) solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1) (1.0 equivalents), followed by triethylamine (3.0 equivalents). The reaction mixture was stirred overnight. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give the target compound.

[0089] 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-fluorobenzenesulfonamide (Intermediate 28) (Yield 51%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.84 (dd, J = 9.8, 1.9 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.62 (dd,J = 8.4, 1.8 Hz, 1H), 2.79 (dd, J = 12.6, 5.9 Hz, 1H), 2.72(dd, J = 12.6, 8.9 Hz, 1H), 2.29-2.20 (m, 1H), 2.02-1.95 (m, 1H), 1.91-1.84(m, 1H), 1.74-1.64 (m, 2H), 1.64-1.54 (m, 1H), 1.36-1.27 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.4, 158.4 (d, J = 258.4 Hz), 156.8, 131.5, 128.7 (d, J = 3.8 Hz), 128.0 (d, J = 14.5 Hz), 127.6 (d, J = 9.1 Hz), 121.2 (d, J =24.7 Hz), 70.0, 46.6, 43.0, 38.2, 29.3, 22.5. 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-fluorobenzenesulfonamide (Intermediate 29) (Yield 53%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.09 (s, 1H), 7.97 (dd, J = 8.3, 6.8 Hz, 1H), 7.81 (dd, J = 6.8, 5.1 Hz, 1H), 7.69(dd, J = 8.2, 2.1 Hz, 1H), 7.53 (dd, J= 8.3, 1.7 Hz, 1H), 2.75-2.67 (m, 1H),2.63-2.56 (m, 1H), 2.28-2.20 (m, 1H), 2.03-1.94 (m, 1H), 1.88-1.79 (m, 1H),1.75-1.65 (m, 2H), 1.64-1.55 (m, 1H), 1.33-1.25 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.1, 158.1 (d, J = 249.1 Hz), 156.4, 141.4 (d, J = 5.8 Hz), 134.8, 124.1 (d, J = 3.8 Hz), 114.9 (d, J = 24.8 Hz), 113.2 (d, J = 20.8 Hz),69.5, 46.1, 42.6, 37.9, 28.7, 22.0. 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,5-difluorobenzenesulfonamide (Intermediate 30) (55% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.03 (dd, J = 9.0, 5.3 Hz, 1H), 7.68 (dd, J = 7.5, 5.9Hz, 1H), 2.83 (dd, J = 12.7, 6.2 Hz, 1H), 2.76 (dd, J = 12.7, 8.6 Hz, 1H),2.29-2.20 (m, 1H), 2.02-1.94 (m, 1H), 1.91-1.84 (m, 1H), 1.74-1.64 (m, 2H),1.62-1.55 (m, 1H), 1.35-1.27 (m, 1H). 13C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 177.9,156.4, 154.9 (dd, J = 64.0, 3.0 Hz), 153.3 (dd, J = 73.1, 2.8 Hz), 128.9 (dd, J = 17.1, 5.6 Hz), 122.7 (d, J = 27.1 Hz), 116.7 (d, J = 27.4 Hz), 114.1 (dd, J = 23.5, 9.8 Hz), 69.5, 46.1, 42.6, 37.8, 28.8, 22.0. 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methylbenzenesulfonamide (Intermediate 31) (75% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.09(s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 2.3, 0.9 Hz, 1H), 7.65 (t, J = 5.9 Hz, 1H), 7.51-7.47 (m, 1H), 2.70-2.63 (m, 1H), 2.59-2.53 (m, 1H), 2.42(s, 3H), 2.27-2.20 (m, 1H), 2.03-1.95 (m, 1H), 1.89-1.81 (m, 1H), 1.73-1.65 (m, 2H), 1.63-1.53 ​​(m, 1H), 1.34-1.26 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6)δ 178.1, 156.4, 139.3, 138.8, 133.0, 128.8, 128.7, 125.8, 69.5, 46.1, 42.7,37.8, 28.8, 22.5, 22.0. 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methoxybenzenesulfonamide (Intermediate 32) (Yield 44%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.09(s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 6.8, 5.1 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.2, 2.0 Hz, 1H), 3.91 (s, 3H), 2.73-2.65 (m,1H), 2.60-2.52 (m, 1H), 2.27-2.17 (m, 1H), 2.04-1.92 (m, 1H), 1.90-1.79 (m,1H), 1.74-1.65 (m, 2H), 1.63-1.55 (m, 1H), 1.33-1.24 (m, 1H). 13 C{ 1 H} NMR (150MHz, DMSO- d 6 ) δ 178.1, 156.4, 155.7, 140.5, 133.7, 119.9, 115.4, 110.1, 69.6,56.6, 46.1, 42.7, 37.8, 28.7, 22.1. 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-2-sulfonamide (intermediate 34) (Yield 44%, white solid). 1 H NMR (600 MHz, DMSO- d 6) δ 10.60 (s, 1H), 8.88 (dd, J = 2.3, 0.7 Hz, 1H), 8.33 (dd, J = 8.4, 2.3 Hz, 1H), 8.12 (s, 1H), 7.95(s, 1H), 7.84 (dd, J = 8.3, 0.7 Hz, 1H), 2.89-2.77 (m, 2H), 2.27-2.19 (m,1H), 2.02-1.94 (m, 1H), 1.92-1.85 (m, 1H), 1.75-1.66 (m, 2H), 1.63-1.55 (m,1H), 1.39-1.29 (m,1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.0, 156.4, 150.8,141.3, 123.6, 123.4, 69.6, 46.4, 43.2, 37.7, 28.9, 22.1. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-3-sulfonamide (intermediate 35) (50% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.74 (dd, J = 2.6, 0.7 Hz, 1H), 8.16 (dd, J = 8.4, 2.6 Hz, 1H), 8.11-8.07 (m, 1H),7.93 (t, J = 5.8 Hz, 1H), 7.77 (dd, J = 8.4, 0.8 Hz, 1H), 2.79-2.72 (m, 1H),2.66-2.61 (m, 1H), 2.28-2.20 (m, 1H), 2.02-1.94 (m, 1H), 1.87-1.78 (m, 1H),1.74-1.65 (m, 2H), 1.64-1.55 (m, 1H), 1.33-1.24 (m, 1H). 13C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.1, 156.4, 153.7, 147.8, 138.1, 135.8, 125.2, 69.5, 46.1, 42.6,37.9, 28.7, 22.0. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-fluoropyridine-3-sulfonamide (intermediate 40) (72% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.59 (s, 1H), 8.28 (t, J = 8.6 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 2.85 (dd, J =12.7, 6.3 Hz, 1H), 2.77 (dd, J = 12.7, 8.5 Hz, 1H), 2.28-2.19 (m, 1H), 2.01-1.94 (m, 1H), 1.91-1.82 (m, 1H), 1.75-1.64 (m, 2H), 1.64-1.55 (m, 1H), 1.36-1.26 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 177.9, 157.4, 156.4, 150.8 (d, J = 13.6 Hz), 144.0, 123.3 (d, J = 5.2 Hz), 122.7 (d, J = 28.4 Hz), 69.5, 46.1, 42.6, 37.9, 28.8, 22.0. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-fluoropyridine-3-sulfonamide (Intermediate 41) (65% yield, white solid).

[0090] 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.59 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.23 ​​(dd, J = 7.8, 2.0 Hz, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 2.80 (dd, J =12.6, 7.7 Hz, 1H), 2.69 (dd, J = 12.6, 7.4 Hz, 1H), 2.32-2.20 (m, 1H), 2.04-1.96 (m, 1H), 1.90-1.80 (m, 1H), 1.75-1.66 (m, 2H), 1.65-1.54 (m, 1H), 1.35-1.26 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.08, 156.46, 153.83 (d, J =263.6 Hz), 142.85 (d, J = 5.9 Hz), 141.35 (d, J = 19.2 Hz), 137.47, 123.85 (d, J = 21.1 Hz), 69.44, 46.07, 42.57, 37.98, 28.61, 21.99. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-methylpyridine-3-sulfonamide (intermediate 42) (80% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.59 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.56 (d, J= 8.3 Hz, 1H), 2.75 (dd, J =12.7, 6.1 Hz, 1H), 2.71 (s, 3H), 2.66 (dd, J = 12.7, 8.7 Hz, 1H), 2.29-2.16(m, 1H), 2.01-1.92 (m, 1H), 1.90-1.80 (m, 1H), 1.74-1.63 (m, 2H), 1.62-1.52(m, 1H), 1.32-1.20 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 177.9, 157.6,156.4, 151.9, 140.0, 134.4, 122.2, 69.5, 46.0, 42.5, 37.8, 28.9, 23.1, 22.0. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methylpyridine-3-sulfonamide (intermediate 43) (78% yield, white solid).

[0091] 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide (intermediate 44) (Yield 48%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.58 (s, 1H), 8.96 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 2.90-2.83 (m, 1H), 2.84-2.77 (m, 1H), 2.33-2.24 (m, 1H), 2.01-1.95 (m, 1H), 1.90-1.83 (m, 1H), 1.74-1.65 (m, 2H), 1.64-1.57 (m, 1H), 1.38-1.28 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 178.0,156.4, 155.1, 150.8, 137.0 (q, J = 34.9 Hz), 133.5, 123.5-123.1 (m), 121.0(d, J = 275.8 Hz), 69.5, 46.1, 42.9, 38.0, 28.8, 22.1. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (intermediate 45) (Yield 52%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.99 (d, J = 2.3 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 2.81 (dd, J = 12.7, 8.0 Hz, 1H), 2.70 (dd, J = 12.6, 7.0 Hz, 1H), 2.29-2.20(m, 1H), 2.02-1.95 (m, 1H), 1.85-1.79 (m, 1H), 1.73-1.65 (m, 2H), 1.65-1.56(m, 1H), 1.32-1.24 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.1, 156.5,150.8, 150.6, 136.1 (q, J = 4.9 Hz), 135.9, 124.3 (q, J = 33.5 Hz), 121.7 (d, J = 273.1 Hz), 69.4, 46.1, 42.5, 38.1, 28.6, 22.0. 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methylpyridine-3-sulfonamide (intermediate 46) (Yield 67%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.59 (s, 1H), 8.70 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.47-8.42 (m, 1H), 8.34 (t, J = 5.7 Hz, 1H), 8.09 (ddd, J = 8.5, 7.0, 1.3 Hz, 1H), 8.07 (s, 1H), 7.96 (ddd, J = 8.3,7.0, 1.1 Hz, 1H), 2.84-2.75 (m, 1H), 2.68 (ddd, J = 12.6, 9.0, 5.5 Hz, 1H),2.26-2.17 (m, 1H), 1.98-1.89 (m, 1H), 1.78-1.68 (m, 1H), 1.68-1.57 (m, 2H),1.56-1.43 (m, 1H), 1.22-1.13 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.0,156.4, 155.6, 142.4, 133.5, 132.1, 130.3, 130.3, 126.9, 126.2, 124.8, 69.5,46.1, 42.6, 37.8, 28.8, 22.1. 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)furan-2-sulfonamide (Intermediate 47) 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)thiophene-2-sulfonamide (intermediate 48) 2-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)thiazole-5-sulfonamide (intermediate 49) Step b: Synthesis of compounds 2 to 11, 13 to 23, 25, 28 to 37, or 40 to 49 Add appropriate amounts of boric acid (1.5 equivalents), Pd(PPh3)4 (10 mol%), and NaHCO3 aqueous solution (2.0 M, 2.0 equivalents) to a 1,4-dioxane solution of the sulfonamide intermediate (1.0 equivalents) synthesized according to step a or a'. Then, degas the mixture by purging with nitrogen for 15 minutes, followed by heating at 120°C for 1 hour in an ultrasonic reactor. Filter the reaction mixture through a diatomaceous earth (Celite) mat, dilute the filtrate with aqueous NH4Cl solution, and extract with EtOAc. Wash the organic layer with water and brine, and dry with MgSO4. Evaporate the solvent under reduced pressure. Purify the residue by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%).

[0092] Example 1-1. Synthesis of N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide (compound 12) Reagents and conditions: a) sulfonyl chloride (R2-SO2Cl), triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 hours; b) boric acid (R3-B(OH)2), Pd(PPh3)4, 2.0 M sodium bicarbonate (NaHCO3) aqueous solution, 1,4-dioxane, 120℃, 1 hour; c) hydrogen, Pd / C catalyst, methanol, room temperature, 2 hours.

[0093] The following reactions were carried out after steps a and b of Example 1.

[0094] (Step c) A methanol solution of 2'-(benzyloxy)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide (compound 11) (20 mg, 0.038 mmol) and 10% Pd / C catalyst (2.4 mg, 60 mol%) was placed in a hydrogen atmosphere. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate, filtered through a diatomaceous earth (Celite) pad, and then concentrated under reduced pressure. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compound 12 (16 mg, 95%) as a white solid.

[0095] Examples 1-2. Synthesis of N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-4-(6-methoxypyridin-3-yl)benzenesulfonamide (compound 24) Reagents and conditions: a) Sulfonyl chloride (R2-SO2Cl), triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 hours; d) Pd2(dba)3,2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (Xphos), sodium tert-butoxide (NaO) t Bu), 1,4-dioxane, 120℃, 1 hour.

[0096] The following reaction is carried out after step a in Example 1.

[0097] (Step d) Add Pd2(dba)3 (10 mg, 10 mol%), XPhos (9.4 mg, 0.01 mmol), morpholine (14 μL, 0.17 mmol), and NaO to a 1,4-dioxane solution of sulfonamide intermediate (intermediate 4, Int 4) (50 mg, 0.11 mmol). t Bu (21 mg, 0.22 mmol). The mixture was then degassed by purging with nitrogen for 15 minutes and heated in an ultrasonic reactor at 120 °C for 1 hour. The reaction mixture was filtered through a diatomaceous earth (Celite) pad, the filtrate was diluted with aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compound 24.

[0098] Examples 1-3. Synthesis of (Compound 38) and (Compound 39) Reagents and conditions: a') sulfonyl chloride (R2-SO2Cl), triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 hours; e) morpholine, N,N-diisopropylethylamine (i-Pr2Net), DMSO, 130℃, 30 minutes.

[0099] The following reaction is performed after step a' in Example 1.

[0100] (Step e) Morpholine (1.2 equivalents) was added to a DMSO solution (1.0 equivalent) of compound 26 or compound 27, followed by N,N-diisopropylethylamine (i-Pr2NEt) (3.0 equivalents). The reaction mixture was heated in an ultrasonic reactor at 130°C for 30 minutes. The reaction was quenched with a saturated aqueous solution of NH4Cl, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compound 38 or compound 39.

[0101] Compounds 1 to 49 and 122 to 131, as shown in Table 1 below, were prepared using the method described in Example 1 above.

[0102] Table 1 Example 2. Synthesis of N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide (compound 50)

Reaction Formula 3

[0103] Step a: Synthesis of intermediate 50-1 (Int 50-1) CuBr (77 mg, 0.54 mmol) was added to DMF solution, followed by the addition of 1,1'-bi-2-naphthol (0.15 mmol) and stirring for 10 minutes. Then, under a nitrogen atmosphere, 1-Boc-piperazine (1 g, 5.37 mmol), K3PO4 (2.29 g, 10.7 mmol), and 1-fluoro-4-iodobenzene (0.62 mL, 5.37 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 18 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 and filtered through a diatomaceous earth (Celite) mat. The organic extracts were combined, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography on silica gel (EtOAc / n-hexane = 1:10) to give tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylic acid ester (Intermediate 50-1, Int 50-1) (230 mg, 15% yield).

[0104] 1 H NMR (600 MHz, CD3OD) δ 6.97 (d, J = 6.5 Hz, 4H), 3.56 (t, J = 5.1Hz, 4H), 3.03 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H). 13 C{ 1H} NMR (150 MHz, CD3OD)δ 159.0 (d, J = 238.3 Hz), 156.4, 149.5 (d, J = 2.1 Hz), 119.9 (d, J = 7.7Hz), 116.4 (d, J = 22.3 Hz), 81.4, 51.6, 28.7. Step b: Synthesis of intermediate 50-2 (Int 50-2) tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylic acid ester (Int 50-1) (230 mg, 0.82 mmol) was added to a 1,4-dioxane solution (5 mL) in 4.0 M hydrochloric acid. The reaction was stirred at room temperature for 1 hour and monitored by TLC until complete. The solvent was removed under reduced pressure. The reaction mixture was filtered, washed with triethylamine, and dried under vacuum to give 1-(4-fluorophenyl)piperazine hydrochloride (intermediate 50-2, Int 50-2) (148 mg, 97% yield).

[0105] 1 H NMR (600 MHz, CD3OD) δ 7.47 (dd, J = 9.1, 4.3 Hz, 2H), 7.20 (t, J =8.7 Hz, 2H), 3.69 (dd, J = 6.9, 3.6 Hz, 4H), 3.62 (dd, J = 6.6, 3.7 Hz, 4H). 13 C{ 1 H} NMR (150 MHz, CD3OD) δ 161.8 (d, J = 244.5 Hz), 143.8, 122. 5 (d, J =8.4 Hz), 117.6 (d, J = 23.3 Hz), 50.8, 43.8. Step c: Synthesis of arylpiperazine sulfonyl chloride (i) A solution of intermediate 50-2 (Int 50-2) (230 mg, 0.82 mmol) and triethylamine (Et3N) (mL, mmol) in CH2Cl2 (mL) was cooled to 0 °C, and chlorosulfonic acid (mL, mmol) was carefully added dropwise. The reaction was stirred at room temperature for 24 hours, and the solvent was removed under reduced pressure. The reaction mixture was filtered, washed with diethyl ether (Et2O), and dried under vacuum to give a crude mixture, which was used directly for the next step of the reaction without further purification.

[0106] (ii) PCl5 (mg, mmol) was added in portions to the benzene solution of the above intermediate, and the mixture was stirred at room temperature for 3 hours. After extraction with EtOAc, the organic layer was partially washed with saturated NH4Cl aqueous solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (EtOAc / n-hexane = 1:5) to give 4-(4-fluorophenyl)piperazine-1-sulfonyl chloride (Int 50-3) (75 mg, yield 64%).

[0107] 1 H NMR (600 MHz, CD3OD) δ 7.08-7.00 (m, 4H), 3.50 (s, 4H), 3.33 (s, 4H). 13 C{ 1 H} NMR (150 MHz, CD3OD) δ 160.3, 158.7, 148.1, 120.5 (d, J = 7.9Hz), 116.6 (d, J = 22.3 Hz), 50.5, 49.1. Step d: Synthesis of arylpiperazine sulfonamide derivatives To a THF / DMF (1:1 v / v, 2.0 mL) solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1), 4-(4-fluorophenyl)-piperazine-1-sulfonyl chloride (Int 50-3) (55 mg, 0.20 mmol) was added, followed by triethylamine (Et3N) (0.07 mL, 0.49 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2 and dried to give N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide (compound 50) (37 mg, 52%) in the form of a white solid.

[0108] 1 H NMR (600 MHz, DMSO- d 6) δ 10.63 (s, 1H), 8.16 (s, 1H), 7.43-7.22 (m,1H), 7.06 (t, J = 8.9 Hz, 2H), 6.98 (dd, J = 9.2, 4.7 Hz, 2H), 3.16-3.09 (m,8H), 2.85-2.76 (m, 2H), 2.32-2.23 (m, 1H), 2.03-1.92 (m, 2H), 1.78-1.67 (m,2H), 1.67-1.59 (m, 1H), 1.46-1.37 (m, 1H). HRMS (EI) m / z: [M] + Calculated value C 18 H 24 FN5O4S 425.1533; Measured value 425.1528. Example 3. Synthesis of amide derivatives (compounds 51 to 72)

Reaction 4

[0109] Step a: Amide bond formation (compounds 51 to 58, compounds 61 to 72, intermediate 59) A solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1) (1.0 equivalent) in DMF was supplemented with carboxylic acid (1.5 equivalent) and PyBOP (1.1 equivalent), followed by N,N-diisopropylethylamine (4.0 equivalent). The reaction mixture was stirred for 12–16 hours. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give compounds 51–58, compounds 61–72, and intermediate 59.

[0110] 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide (Intermediate 59, IM-59) (Yield 61%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 11.94 (d, J = 2.3 Hz,1H), 10.57 (s, 1H), 8.57 (t, J = 5.5 Hz, 1H), 8.24 (s, 1H), 7.43 (dt, J =8.2, 0.9 Hz, 1H), 7.26 (dd, J = 7.5, 0.8 Hz, 1H), 7.15-7.07 (m, 2H), 3.30-3.24 (m, 1H), 3.24-3.16 (m, 1H), 3.04-2.98 (m, 1H), 2.06-2.00 (m, 1H), 1.97-1.91 (m, 1H), 1.80-1.70 (m, 2H), 1.69-1.61 (m, 1H), 1.53-1.44 (m, 1H). 13 C{ 1 H NMR (150 MHz, DMSO- d 6) δ 178.2, 160.5, 156.5, 136.6, 132.4, 127.7, 124.3,122.3, 114.4, 111.9, 102.1, 69.8, 46.3, 45.9, 45.8, 37.7, 28.8, 25.9, 25.9,22.0. Example 3-1. Synthesis of N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(hydroxymethyl)-1H-indole-2-carboxamide (compound 59) Reagents and conditions: a) Carboxylic acid (R2-COOH), PyBOP, N,N-diisopropylethylamine (i-Pr2Net), DMF, room temperature, 12 hours; b) (tributyltin)methanol, Pd(PPh3)4, DMF, 120℃, sealed tube, 24 hours.

[0111] The following reaction is carried out after step a in Example 3.

[0112] (Step b) To a DMF (3.0 mL) solution of 4-bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide (intermediate 59) (20 mg, 0.049 mmol) and Pd(PPh3)4 (5.7 mg, 0.0049 mmol), (tributyltin)methanol (20.6 mg, 0.064 mmol). The mixture was then degassed with nitrogen for 15 minutes, and the reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was filtered through a diatomaceous earth (Celite) mat, the filtrate was diluted with an aqueous solution of NH4Cl, and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(hydroxymethyl)-1H-indole-2-carboxamide (compound 59).

[0113] Example 3-2. Synthesis of N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-hydroxy-1H-indole-2-carboxamide (compound 60) Reagents and conditions: a) Carboxylic acid (R2-COOH), PyBOP, N,N-diisopropylethylamine (i-Pr2Net), DMF, room temperature, 12 hours; c) BBr3, CH2Cl2, -78℃, 1 hour.

[0114] The following reaction is carried out after step a in Example 3.

[0115] (Step c) To a CH2Cl2 solution (2.0 mL) of N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide (compound 53) (10 mg, 0.028 mmol), BBr3 (0.03 mL, 1.0 M CH2Cl2 solution) was added at -78 °C. After stirring for 1 hour, the reaction mixture was diluted with CH2Cl2, washed with NH4Cl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compound 60.

[0116] Compounds 51 to 72, as shown in Table 2 below, were prepared using the method described in Example 3 above.

[0117] Table 2 Example 4. Synthesis of urea derivatives (compounds 74 to 77) [Reaction Formula 5] Reagents and conditions: (a) Isocyanate (R2-N=C=O), triethylamine (Et3N), THF, room temperature, 12 hours.

[0118] An appropriate amount of isocyanate (1.0 equivalent) was added to a THF solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1) (1.0 equivalent), followed by triethylamine (3.0 equivalent). The reaction mixture was stirred for 16 hours. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give compounds 74 to 77.

[0119] Compounds 74 to 77, as shown in Table 3 below, were prepared using the method described in Example 4 above.

[0120] Table 3 Example 5. Synthesis of 2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione derivatives (compounds 78 to 84)

Reaction Formula 6

[0121] Step a: Synthesis of compound 78, intermediate 79, intermediate 82 and intermediate 84 Sulfonyl chloride (1.5 equivalents) was added to a THF / DMF (1:1) solution of 2,6,8-triazabisspiro[3.0.45.34]dodecane-7,9-dione (starting material 2, SM-2) (1.0 equivalents), followed by triethylamine (3.0 equivalents). The reaction mixture was stirred for 12–16 hours. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give compounds 78, intermediate 79, intermediate 82, and intermediate 84.

[0122] 2-((4-iodophenyl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione (intermediate 79) (67% yield, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.70 (s, 1H), 8.12-7.98 (m, 3H), 7.53 (d, J = 8.6 Hz, 2H), 3.66 (dd, J = 26.5, 8.6 Hz, 2H), 3.42(dd, J= 26.5, 8.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.75-1.69 (m, 1H), 1.67-1.60(m, 1H), 1.59-1.52 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 176.4, 156.2,138.4, 133.0, 129.6, 102.4, 69.9, 57.4, 55.5, 45.1, 35.4, 33.4, 19.3. 2-((5-bromopyridin-2-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione (intermediate 82) (Yield 38%, white solid). (Yield 38%, white solid).

[0123] 2-((6-chloropyridin-3-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione (intermediate 84) (Yield 48%, white solid).

[0124] Step b: Synthesis of compounds 79 to 84 To a 1,4-dioxane solution of the intermediates (intermediates 79, 82, or 84) (1.0 equivalent), appropriate amounts of boric acid (1.5 equivalent), Pd(PPh3)4 (10 mol%), and NaHCO3 aqueous solution (2.0 M, 2.0 equivalent) were added. The mixture was then degassed by nitrogen purging for 15 minutes and heated in an ultrasonic reactor at 120°C for 1 hour. The reaction mixture was filtered through a diatomaceous earth (Celite) mat, the filtrate was diluted with an aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compounds 79 to 84.

[0125] Compounds 78 to 84, as shown in Table 4 below, were prepared using the method described in Example 5 above.

[0126] Table 4 Example 6. Synthesis of 7-aminomethylspirocyclohydantoin derivatives (compounds 86 to 109 and 137 to 141)

Reaction Formula 7

[0127] Step a: Synthesis of intermediates 86 to 109 Sulfonyl chloride (1.5 equivalents) was added to a THF / DMF (1:1) solution of 7-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (starting material 3, SM-3) (1.0 equivalents), followed by triethylamine (3.0 equivalents). The reaction mixture was stirred overnight. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to give intermediates 86 to 109.

[0128] 4-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)benzenesulfonamide (intermediate 86) (Yield 83%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.56 (d, J = 16.9 Hz, 1H), 8.15 (d, J = 64.8 Hz, 1H), 8.01-7.96 (m, 2H), 7.77 (dt, J = 21.4, 6.1Hz, 1H), 7.54 (dd, J = 8.6, 1.0 Hz, 2H), 2.77-2.67 (m, 2H), 2.29-2.11 (m,1H), 2.10-1.91 (m, 1H), 1.90-1.66 (m, 3H), 1.66-1.55 (m, 1H), 1.42-1.32 (m,1H).13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 179.0 (d, J = 70.9 Hz), 156.2, 140.2 (d, J = 9.1 Hz), 138.1, 128.2 (d, J = 3.3 Hz), 100.3 (d, J = 3.3 Hz), 68.0 (d, J = 85.2 Hz), 46.7 (d, J = 44.2 Hz), 40.8 (d, J = 99.5 Hz), 38.6 (d, J = 39.7Hz), 36.4 (d, J = 43.6 Hz), 28.7 (d, J = 97.5 Hz). 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-2-sulfonamide (intermediate 89) (Yield 46%, white solid).

[0129] 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-3-sulfonamide (intermediate 91) (76% yield, white solid).

[0130] 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-3-sulfonamide (intermediate 98) (Yield 12%, white solid).

[0131] 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-fluoropyridine-3-sulfonamide (Intermediate 99) (Yield 12%, white solid). 1H NMR (600 MHz, CD3OD) δ 8.36-8.30 (m, 1H), 7.55(dd, J = 8.0, 2.1 Hz, 1H), 3.07-2.96 (m, 2H), 2.41-2.29 (m, 1H), 2.27-2.12(m, 1H), 2.09-1.90 (m, 2H), 1.88-1.73 (m, 2H), 1.59-1.46 (m, 1H). 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-fluoropyridine-3-sulfonamide (Intermediate 100) (Yield 23%, white solid). 1 H NMR (600 MHz, CD3OD) δ 8.65 (d, J = 2.0 Hz, 1H), 8.12 (dt, J = 7.6, 2.2 Hz, 1H), 3.03-2.91 (m, 2H), 2.40-2.29 (m, 1H), 2.26-2.13 (m, 1H), 2.10-1.91 (m, 2H), 1.90-1.75 (m, 2H), 1.61-1.44 (m, 1H). 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-methylpyridine-3-sulfonamide (Intermediate 101) (Yield 30%, white solid). 1 H NMR (600 MHz, CD3OD) δ 8.21 (dd, J = 8.3, 1.8Hz, 1H), 7.45 (dt, J = 8.3, 0.8 Hz, 1H), 2.97-2.89 (m, 2H), 2.79 (s, 3H), 2.39-2.27 (m, 1H), 2.24-2.09 (m, 1H), 2.07-1.88 (m, 2H), 1.86-1.71 (m, 2H),1.55-1.40 (m, 1H). 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-methylpyridine-3-sulfonamide (intermediate 102) (Yield 41%, white solid). 1 H NMR (600 MHz, CD3OD) δ 8.61 (dd, J = 2.5, 0.8Hz, 1H), 8.14-8.10 (m, 1H), 2.98-2.89 (m, 2H), 2.47 (s, 3H), 2.39-2.27 (m,1H), 2.26-2.10 (m, 1H), 2.09-1.90 (m, 2H), 1.89-1.74 (m, 2H), 1.59-1.43 (m,1H). 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide (intermediate 103) (Yield 11%, white solid). 1 H NMR (600 MHz, CD3OD) δ 9.07 (s, 1H), 8.00 (s,1H), 3.10-3.01 (m, 2H), 2.42-2.31 (m, 1H), 2.30-2.13 (m, 1H), 2.11-1.91 (m,2H), 1.90-1.75 (m, 2H), 1.60-1.44 (m, 1H). 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (intermediate 104) (Yield 11%, white solid). 1 H NMR (600 MHz, CD3OD) δ 9.01 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H), 3.03-2.91 (m, 2H), 2.42-2.28 (m, 1H), 2.27-2.12 (m, 1H), 2.10-1.90 (m, 2H), 1.89-1.76 (m, 2H), 1.59-1.41 (m, 1H). 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)furan-2-sulfonamide (intermediate 105) (Yield 21%, white solid). 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.56 (d, J = 14.7 Hz,1H), 8.24 (br s, 1H), 8.16 (d, J = 62.4 Hz, 1H), 7.13 (t, J = 3.6 Hz, 1H), 6.83 (t, J = 3.4 Hz, 1H), 2.92-2.79 (m, 2H), 2.30-2.12 (m, 1H), 2.10-1.92 (m,1H), 1.90-1.68 (m, 3H), 1.68-1.56 (m, 1H), 1.43-1.33 (m, 1H). 13 C{ 1 H} NMR (150MHz, DMSO- d 6 ) δ 179.0 (d, J = 67.5 Hz), 156.2, 150.5, 126.3, 117.8, 113.6,68.0 (d, J = 80.8 Hz), 46.6 (d, J = 40.4 Hz), 40.8 (d, J = 102.6 Hz), 38.6(d, J = 40.5 Hz), 36.4 (d, J = 43.7 Hz), 28.7 (d, J = 91.5 Hz). 5-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiophene-2-sulfonamide (intermediate 106) (Yield 37%, white solid).

[0132] 2-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiazole-5-sulfonamide (intermediate 107) (Yield 13%, white solid).

[0133] 2-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1H-imidazol-5-sulfonamide (intermediate 108) (Yield 22%, white solid).

[0134] 2-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1H-imidazol-5-sulfonamide (intermediate 109) (Yield 52%, white solid).

[0135] Step b: Synthesis of compounds 86 to 109 To a 1,4-dioxane solution of the intermediate (1.0 equivalent), boric acid (1.5 equivalent), Pd(PPh3)4 (10 mol%), and an aqueous solution of NaHCO3 (2.0 M, 2.0 equivalent) were added. The mixture was then degassed by purging with nitrogen for 15 minutes and heated in an ultrasonic reactor at 120°C for 1 hour. The reaction mixture was filtered through a diatomaceous earth (Celite) mat, and the filtrate was diluted with an aqueous solution of NH4Cl and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to obtain the target compound.

[0136] Compounds 86 to 109 and 137 to 141, as shown in Table 5 below, were prepared using the method described in Example 6 above.

[0137] Table 5 [Reaction 8] Separation of stereoisomers of compound 91 [Conditions for chiral separation] The four stereoisomers of compound 91 were separated using a preparative chiral SFC column (stationary phase: Chiralpak Daicel OD-10, 25 x 250 mm, 10 μm; mobile phase: CO2, MeOH + 0.05% Et2NH).

[0138] Example 7. Synthesis of other spirocyclic hydantoin derivatives (compounds 85, 110, 114 to 115) [Reaction Formula 9] Reagents and conditions: (a) Carboxylic acid (R2-COOH), PyBOP, N,N-diisopropylethylamine ( i -Pr2Net), DMF, room temperature, 12 hours.

[0139] Carboxylic acid (1.5 equivalents) and PyBOP (1.1 equivalents) were added to a DMF solution of starting materials 2 to 4 (SM-2 to SM-4) (1.0 equivalents), followed by N,N-diisopropylethylamine (4.0 equivalents). The reaction mixture was stirred for 12–16 hours. The reaction was quenched with a saturated aqueous NH4Cl solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was filtered, washed with CH2Cl2, and dried to obtain the target compound.

[0140] Compounds 85, 110, 114 to 115, as shown in Table 6 below, were prepared using the method described in Example 7 above.

[0141] Table 6 Example 8. Synthesis of arylpiperazine derivatives

Reaction Formula 10

[0142] Step a: Synthesis of intermediates 116 to 118 Add aryl iodide (1.1 equivalent), Pd2(dba)3 (10 mol%), Johnphos (0.1 equivalent), and NaO to a toluene solution of 1-Boc-piperazine or 1-Boc-3-methylpiperazine (1.0 equivalent). tBu (1.5 equivalents). The mixture was then degassed by purging with nitrogen for 15 minutes, and the reaction mixture was refluxed overnight at 110°C. The reaction mixture was filtered through a diatomaceous earth (Celite) mat, the filtrate was diluted with an aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure under vacuum. The residue was analyzed by rapid chromatography using silica gel (EtOAc / n Purification with hexane (1:10) yielded a yellow solid intermediate.

[0143] tert-Butyl 4-(3,5-difluorophenyl)piperazine-1-carboxylate (intermediate 116) (Yield 53%, yellow solid). 1 H NMR (600 MHz, CDCl3) δ 6.37 (dd, J = 10.6, 2.2Hz, 2H), 6.30-6.25 (m, 1H), 3.56 (t, J = 5.3 Hz, 4H), 3.15 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H). 13 C{ 1 H} NMR (150 MHz, CDCl3) δ 164.9 (d, J = 15.6 Hz), 163.3 (d, J = 15.6 Hz), 154.7, 153.1 (t, J = 12.0 Hz), 98.8-98.5 (m), 94.8(t, J = 26.0 Hz), 80.3, 48.4, 28.5. tert-butyl 4-(3,4-difluorophenyl)piperazine-1-carboxylate (intermediate 117) (Yield 64%, yellow solid). 1 H NMR (600 MHz, CDCl3) δ 7.08-7.02 (m, 1H), 6.74(ddd, J = 13.1, 7.2, 3.2 Hz, 1H), 6.67-6.60 (m, 1H), 3.58 (t, J= 5.2 Hz, 4H), 3.06 (s, 4H), 1.48 (s, 9H). 13 C{ 1 H} NMR (150 MHz, CDCl3) δ 154.7, 151.5(d, J = 13.7 Hz), 149.9 (d, J = 13.7 Hz), 117.5 (d, J = 17.6 Hz), 112.5,106.3 (d, J = 20.8 Hz), 80.3, 50.1, 28.5. tert-Butyl(S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carboxylate (Intermediate 118) (Yield 41%, yellow solid). 1 H NMR (600 MHz, CDCl3) δ 6.41-6.22 (m, 3H), 4.28-4.05 (m, 1H), 4.05-3.78 (m, 2H), 3.35-3.15 (m, 2H), 3.13-3.02 (m, 2H), 1.48(s, 9H), 1.07 (d, J = 6.7 Hz, 3H). tert-Butyl(S)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carboxylate (intermediate 119) (Yield 30%, yellow solid). 1 H NMR (600 MHz, CDCl3) δ 7.11-7.00 (m, 1H), 6.76-6.52 (m, 2H), 4.08-3.80 (m, 1H), 3.76-3.56 (m, 2H), 3.48-3.31 (m, 1H), 3.29-2.94 (m, 3H), 1.48 (s, 9H), 0.97 (s, 3H). Step b: Synthesis of intermediates 116a to 118a A solution of 1,4-dioxane in 4.0 M hydrochloric acid was added to a suitable amount of toluene solution of intermediates (intermediates 116 to 119) (1.0 equivalent). After stirring for 1 to 3 hours, the reaction mixture was diluted with CH2Cl2. The solvent was evaporated under vacuum. The residue was filtered through Et2O to give intermediates 116a to 119a.

[0144] 1-(3,5-Difluorophenyl)piperazine hydrochloride (intermediate 116a) (Yield 86%, white solid). 1 H NMR (600 MHz, CD3OD) δ 6.67-6.60 (m, 2H), 6.45-6.38 (m, 1H), 3.50-3.46 (m, 4H), 3.38-3.34 (m, 4H). 13 C{ 1 H} NMR (150 MHz, CD3OD) δ 166.3 (d, J = 15.7 Hz), 164.7 (d, J = 16.0 Hz), 153.8 (t, J = 12.5Hz), 100.1 (d, J = 6.6 Hz), 99.9 (d, J = 6.9 Hz), 96.0 (t, J = 26.4 Hz), 46.6, 44.4. 1-(3,4-Difluorophenyl)piperazine hydrochloride (intermediate 117a) (Yield 98%, white solid). 1 H NMR (600 MHz, CD3OD) δ 7.21-7.15 (m, 1H), 7.04-6.99 (m, 1H), 6.86-6.82 (m, 1H), 3.45-3.37 (m, 8H). (S)-1-(3,5-difluorophenyl)-2-methylpiperazine hydrochloride (intermediate 118a) (89% yield, white solid). Synthesized using the same method as intermediate 116a.

[0145] (S)-1-(3,4-difluorophenyl)-2-methylpiperazine hydrochloride (intermediate 119a) (99% yield, white solid). Synthesized using the same method as intermediate 116a.

[0146] Step c: Synthesis of arylpiperazine derivatives (compounds 111 to 112, compounds 116 to 121)

Reaction Formula 11

[0147] The arylpiperazine intermediates (Int 116a to 119a) were reacted with starting material 5 (SM-5), starting material 6 (SM-6), or starting material 7 (SM-7) to synthesize compounds 111 to 112 and compounds 116 to 121.

[0148] Using the method described in Example 8 above, compounds 111 to 112 and compounds 116 to 121, as shown in Table 7 below, were prepared.

[0149] Table 7 Example 9. Synthesis of compounds 132 and 133

Reaction Formula 12

[0150] General operating procedures for amide coupling (intermediates 120 and 121) PyBOP (1.1 equivalents), HOBt (1.1 equivalents), and i-Pr₂EtN (3.0 equivalents) were added to a carboxylic acid (1.0 equivalent) solution in DMF, followed by the addition of an appropriate amount of amine (1.2 equivalents). The reaction mixture was stirred for 12 hours. The mixture was quenched with saturated NH₄Cl aqueous solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H₂O = 10% / 90% → 100% / 0%) to give the target compounds (intermediates 120 and 121).

[0151] Intermediate 120 N-(4-bromobenzyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-carboxamide (75% yield, white solid) 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.54 (s, 1H), 8.22 (t, J = 6.0 Hz, 1H),8.03 (s, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 4.27 (dd, J = 15.4, 6.2 Hz, 1H), 4.12 (dd, J = 15.4, 5.7 Hz, 1H), 2.94 (dd, J = 10.2, 8.3Hz, 1H), 2.05-1.89 (m, 3H), 1.82 (td, J = 9.2, 7.3, 4.1 Hz, 1H), 1.78-1.70(m, 1H), 1.72-1.65 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.0, 169.8,156.5, 139.0, 131.0, 129.3, 119.5, 70.0, 52.4, 41.5, 37.0, 27.0, 22.5. Intermediate 121 N-(4-bromophenyl)-2-(2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)acetamide (22% yield, white solid) 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.56 (s, 1H), 10.12 (s, 1H), 7.95 (s,1H), 7.54 (d, J = 8.9 Hz, 2H), 7.45 (d, J= 8.8 Hz, 2H), 2.42-2.33 (m, 2H), 2.23 (dd, J = 14.4, 10.4 Hz, 1H), 2.03-1.96 (m, 1H), 1.94-1.87 (m, 1H), 1.82-1.66 (m, 3H), 1.61-1.52 (m, 1H). 13 C{ 1 H} NMR (150 MHz, DMSO- d 6 ) δ 178.0,170.0, 156.4, 138.6, 131.5, 121.0, 114.6, 70.0, 44.7, 36.2, 35.1, 29.5, 21.4. General operating procedures for Pd(0)-catalyzed cross-coupling (compounds 132 and 133) To the intermediates (Int 120, Int 121) in 1,4-dioxane (1.0 equivalent), (4-fluorophenyl)boronic acid (1.2 equivalent), Pd(PPh3)4 (10 mol%), and an aqueous solution of NaHCO3 (2.0 M, 2.0 equivalent) were added. The mixture was then degassed by purging with N2 for 15 min. The reaction mixture was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was diluted with an aqueous solution of NH4Cl and extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by RP column chromatography (Sfär C18 Duo; MeOH / H2O = 10% / 90% → 100% / 0%) to give compounds 132 and 133.

[0152] Table 8 Example 10. Synthesis of compounds 134 to 136

Reaction Formula 13

[0153] Intermediate 122 or 123 (1.0 equivalent) was added to a solution of SM-1 or SM-3 (1.0 equivalent) in DMA, followed by Et3N (3.0 equivalent). The reaction mixture was stirred at room temperature for 12–16 hours. The mixture was quenched with saturated NH4Cl aqueous solution, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (EtOAc / n-hexane / MeOH = 1:1:0.1) to give compounds 134 to 136.

[0154] Table 9

Experimental Example

[0155] 0.5 μg of recombinant human ADAMTS-4 protein was added to each well of a 96-well black opaque plate. 100 nM each of the control group (DMSO only), the positive control group AGG523 (Cas No.: 920289-29-8), and the 6-aminomethylspirocyclohydantoin derivative synthesized in this invention were added to each well, and the reaction was carried out at 37°C for 15 minutes. Afterwards, 25 μM of fluorescently labeled ADAMTS-4 substrate was added to each well, and fluorescence was continuously measured every 5 minutes at 340 nm (excitation wavelength) and 420 nm (emission wavelength) for 1 hour.

[0156] Figure 1 The fluorescence changes of some test drugs over one hour are shown. Figure 1 As shown, after adding the compound described in this invention, the measured fluorescence value was low because the binding of ADAMTS-4 protein to the substrate was inhibited.

[0157] Furthermore, Table 10 below shows the inhibition rate (%) of the compounds of the present invention against ADAMTS-4 activity at a concentration of 100 nM. In Table 10 below, compounds 73-1 and 73-2 represent isomer-1 and isomer-2 of compound 73, respectively.

[0158] Table 10 Furthermore, in the ADAMTS-4 activity inhibition experiment described above, the half maximal inhibitory concentration (IC50) of each embodiment was determined. 50 The values ​​are shown in Table 11 below. 50 The IC50 value represents the concentration required for a specific substance to inhibit the function of a biological process or component by 50%. 50 The lower the value, the less ADAMTS-4 activity can be inhibited with a smaller dosage.

[0159] Table 11 Experimental Example 2. Dynamic Evaluation of Drugs The ADAMTS-4 IC, which was confirmed in Experimental Example 1, 50 Compounds with lower values ​​were evaluated using pharmacokinetics (PK).

[0160] First, AGG523 at 10 mg / kg was administered intravenously or orally to fasted mice. Blood samples were collected from the orbital vein at 3, 7, 15, 30, 1, 2, 4, 8, and 24 hours post-administration. The collected blood was centrifuged for 5 minutes to separate the plasma, and the blood drug concentration was determined using HPLC / MS / MS. Compounds 4 and 53 of this invention were also tested using the same method described above.

[0161] Experimental results are as follows Figure 2 As shown, AGG523 reaches its peak drug concentration (C) within minutes of administration. max The compound exhibits an abnormal pattern and a high clearance rate (CL), suggesting that the drug is easily metabolized or excreted, thus requiring high concentrations to achieve sufficient pharmacological effects. However, compound 4 of this invention, when administered orally, shows a high peak blood concentration and a relatively short time (t) to reach that concentration. max The time interval is 1 hour, and the PK distribution curve is normal.

[0162] Experimental Example 3. Evaluation of the inhibitory effect of AGG523 administration on CCl4-induced liver fibrosis. (1) AGG523 administration and induction of liver fibrosis Eight-week-old C57BL6J mice were orally administered AGG523 100 mg / kg twice daily, and intraperitoneally injected with 1 ml / kg CCl4 twice weekly for a total of 4 weeks to induce liver fibrosis.

[0163] (2) Preparation of liver tissue sections After drug administration, mice underwent laparotomy, and a portion of the left lobe of the liver was harvested, fixed in formalin, and then embedded in paraffin to form a paraffin block. The paraffin block was sliced ​​to obtain paraffin sections, which were then dewaxed with xylene and hydrated with distilled water to prepare liver tissue sections.

[0164] (3) Masson's trichrome staining of liver tissue Weigert iron hematoxylin solution was added to the liver tissue sections, and the reaction was allowed to proceed for 10 minutes to stain the cell nuclei. Then, Biebrich scarlet-acid fusion solution was added, and the reaction was allowed to proceed for 15 minutes to stain the cytoplasm, muscle, and other acidic tissues. The stained liver tissue sections were washed with distilled water, and then collagen was stained with aniline blue for 5 minutes, followed by washing with 1% acetic acid. This staining process will be referred to below as "Masson's trichrome staining."

[0165] The degree of fibrosis was evaluated using the above method, and the results are as follows: Figure 3 As shown, in tissues with CCl4-induced liver fibrosis, the group not given AGG523 ( Figure 3 The image labeled CCl4) and the image of the AGG523 group ( Figure 3 No significant difference in the degree of fibrosis was observed among the stained images labeled AGG523, therefore it is believed that AGG523 failed to improve the degree of fibrosis.

[0166] (4) Analysis of αSMA by Western blotting After harvesting a portion of liver tissue, proteins were extracted using RIPA lysis buffer, and 20 μg of protein was electrophoresed on an SDS-PAGE gel. Proteins migrating downwards in the gel were transferred to an NC (nitrocellulose) membrane, and non-specific bands were removed with 5% skimmil. After washing the membrane with PBST, it was incubated overnight at 4°C with alpha smooth muscle actin (αSMA), an indicator of stellate cell activation, or an internal control GAPDH antibody. After washing with PBST, the membrane was reacted with mouse HRP antibody at room temperature for 1 hour, and protein luminescence was measured using a luminol reaction. This process will be referred to as Western blotting.

[0167] The results of confirming the αSMA, an indicator of stellate cell activation, by Western blotting are as follows: Figure 3As shown, no significant decrease in stellate cell activation indicators was observed in the AGG523-treated group. This is attributed to the poor PK properties of AGG523, which prevented it from exhibiting an inhibitory effect on liver fibrosis.

[0168] Experimental Example 4. Evaluation of the inhibitory effect of compound 4 on liver fibrosis. Eight-week-old C57BL6J mice were orally administered compound 4 at a dose of 100 mg / kg twice daily, and intraperitoneally injected with 1 ml / kg CCl4 twice weekly for four weeks to induce liver fibrosis. After the administration was completed, liver tissue was harvested from the mice, and the degree of fibrosis was evaluated using Masson's trichrome staining. Western blotting was used to confirm the stellate cell activation marker αSMA in a portion of the liver tissue. The experimental results are shown in… Figure 4 .

[0169] like Figure 4 As shown, in the compound 4 administration group, αSMA expression was reduced, and the degree of fibrosis scoring was significantly decreased. Based on the above experimental results, it was confirmed that compound 4, an ADAMTS-4 inhibitor with relatively good PK, has an inhibitory effect on liver fibrosis.

[0170] Experimental Example 5. Inhibition of TGFβ-induced stellate cell activation markers by ADAMTS-4 inhibitor treatment Human astrological cell line LX2 cells were loaded at 5 × 10 4 The culture medium was inoculated into 96-well plates, and after 18 hours, it was replaced with serum-free medium. AGG523 and compounds 4 and 53 of this invention were treated at concentrations of 2, 5, 10, 20, 30, 50, and 100 μM for a total of 24 hours. After removing the supernatant, 1 mg / ml of 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was added, and the reaction was carried out at 37°C for 2 hours. After removing the supernatant, DMSO was added and reacted for 15 minutes. The absorbance was measured at 540 nm to evaluate the drug toxicity. The results showed that AGG523 and compound 4 of this invention did not exhibit drug toxicity except at the 100 μM concentration treatment, while compound 53 of this invention did not exhibit drug toxicity at all tested concentrations, including 100 μM.

[0171] In addition, 3×10 5 LX2 cells were seeded in 6-well plates. After 18 hours, each drug was pretreated for 1 hour at concentrations that did not show toxicity, followed by reaction with TGFβ for 24 hours. After the reaction, stellate cell activation markers were confirmed by Western blotting. The results are shown in... Figure 5 .according to Figure 5AGG523 and compounds 4 and 53 of the present invention in vitro ( in ex vitro Under the same conditions, it also reduced the stellate cell activation indicators (Col1a1, αSMA, PAI-1) by inhibiting ADAMTS-4.

[0172] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will understand that other specific forms can be readily derived without altering the technical concept or essential features of the invention. Therefore, the embodiments described above should be understood in all respects as illustrative and not limiting.

Claims

1. Compounds of Formula 1, their isomers, or pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above formula, R 1 It can be hydrogen, halogen, or allyl. R 2 and R 4 One is hydrogen, and the other is... or ; R 3 It is hydrogen or C1-C6 alkyl, or R 3 With R 6 A ring can be formed by linking C1-C3 alkylene groups; R 5 It is hydrogen or C1-C6 alkyl, or R 3 With R 5 A ring can be formed by linking C1-C3 alkylene groups; R 6 It is hydrogen; L represents -CO-, -SO2-, or -CONH-; R 7 C1-C6 alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 3-14 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic, wherein the C1-C6 alkyl, C 6-10 Aryl, C 3-14 The cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups or C1-C6 alkoxy groups substituted by 1-3 halogens or hydroxyl groups. R 8 For hydrogen, C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl or 4-10-membered heterocyclic, wherein the C 6-10 The aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 aryl (where p is an integer from 1 to 5), or C1-C6 alkyl, C1-C6 alkoxy, or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced; R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl, wherein the C 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; n is 0 or 1; m is an integer from 0 to 5, and when m is 0, it is a single key; The heteroaryl group is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S.

2. The compound according to claim 1, wherein the compound of chemical formula 1 is a compound of chemical formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above formula, R 1 It can be hydrogen, halogen, or allyl. R 2 and R 4 One is hydrogen, and the other is... or ; R 3 It is hydrogen or C1-C6 alkyl, or R 3 With R 6 A ring can be formed by linking C1-C3 alkylene groups; R 5 and R 6 It is hydrogen; L represents -CO-, -SO2-, or -CONH-; R 7 C1-C6 alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 3-14 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic, wherein the C1-C6 alkyl, C 6-10 Aryl, C 3-14 The cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl groups or C1-C6 alkoxy groups substituted by 1-3 halogens or hydroxyl groups. R 8 For hydrogen, C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl or 4-10-membered heterocyclic, wherein the C 6-10 The aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclic groups are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 aryl (where p is an integer from 1 to 5), or C1-C6 alkyl, C1-C6 alkoxy, or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced; R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl, wherein the C 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; m is an integer from 0 to 5, and when m is 0, it is a single key; The heteroaryl group is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S.

3. The compound according to claim 2, R 7 It is a C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, or piperazineyl, wherein the C1-C6 alkyl, phenyl, benzyl, azacyclobutyl, adamantyl, furanyl, thiophene, imidazolyl, thiazolyl, pyridinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl, and piperazineyl are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1 to 3 halogens or hydroxyl groups; R 8 For hydrogen, phenyl, C 3-8 Cycloalkyl, furan, thiophene, pyrazole, furanyl, thiophene, pyrazolyl, pyridyl, indole, benzofuranyl, benzothiopheneyl or morpholinyl, wherein the phenyl, C 3-8 Cycloalkyl, furanyl, thiophene, pyrazolyl, pyridyl, indene, benzofuranyl, benzothiophene, and morpholinyl are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or -O-(CH2)pC groups. 6-10 aryl (where p is an integer from 1 to 5), or C1-C6 alkyl, C1-C6 alkoxy, or -O-(CH2)pC substituted with 1 to 3 halogens or hydroxyl groups. 6-10 Aryl groups are replaced; R 9 It is a piperazine phenyl compound, wherein the phenyl group is unsubstituted or may be substituted with 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups or C1-C6 alkoxy groups, its isomers or pharmaceutically acceptable salts thereof.

4. The compound according to claim 2, wherein the compound is any one of the compounds selected from the group consisting of, isomers thereof, or pharmaceutically acceptable salts thereof: N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran-2-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; 4-Cyclohexyl-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-((3-allyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; 4'-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; 4'-Bromo-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-methyl-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; 2'-(benzyloxy)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-4-yl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-3-yl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(6-methoxypyridin-3-yl)benzenesulfonamide; 4-(2,6-dimethoxypyridin-3-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(1-methyl-1H-pyrazol-5-yl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(furan-2-yl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(thiophen-2-yl)benzenesulfonamide; 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)benzenesulfonamide; 4-(benzo[b]thiophen-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-morpholinobenzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4,5-trifluorobenzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3,4-trifluorobenzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,4',5-trifluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2-methyl-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2-methoxy-[1,1'-biphenyl]-4-sulfonamide; 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methoxybenzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-2-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,5-difluoro-4-morpholinobenzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3-difluoro-4-morpholinobenzenesulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-fluoropyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-fluoropyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-methylpyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methylpyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)pyridine-sulfonamide; 1-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)isoquinoline-4-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)furan-2-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)thiophene-2-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)thiazole-5-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-methoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-difluoro-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methylbenzofuran-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-carboxamide; 4-(cyclopent-1-en-1-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(hydroxymethyl)-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-hydroxy-1H-indole-2-carboxamide; 5-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-ethoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(trifluoromethoxy)-1H-indole-2-carboxamide; 4-(difluoromethoxy)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-7-fluoro-4-methoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-fluoro-4-methoxy-1H-indole-2-carboxamide; 5-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; 6-Chloro-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,7-dimethoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-dimethoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,5-dimethoxy-1H-indole-2-carboxamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methyl-2-(4-(trifluoromethyl)benzyl)butyramide; 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-(trifluoromethyl)phenyl)urea; 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-fluorophenyl)urea; 1-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-(4-fluorobenzyl)urea; 1-((1r,3r,5r,7r)-adamantane-2-yl)-3-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)urea; 2-(benzofuran-2-ylsulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-((4-(benzofuran-2-yl)phenyl)sulfonyl)-2,6,8-triazadispiro[3.0.45.34]dodecane-7,9-dione; 2-((5-(4-fluorophenyl)pyridin-2-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-((5-(benzofuran-2-yl)pyridin-2-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-((6-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-((6-(benzofuran-2-yl)pyridin-3-yl)sulfonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; 2-(5-(trifluoromethyl)benzofuran-2-carbonyl)-2,6,8-triazabispiro[3.0.45.34]dodecane-7,9-dione; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)pyridine-2-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorobenzofuran-2-yl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-fluorobenzofuran-2-yl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(6-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(3-methylbenzofuran-2-yl)pyridine-3-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methylbenzofuran-2-yl)pyridine-3-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)pyrimidine-5-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-fluoropyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-5-fluoropyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-2-methylpyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-5-methylpyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)furan-2-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)thiophene-2-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)thiazolyl-5-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1H-imidazol-5-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1H-imidazol-5-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide; 6-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; 6-((S)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; 4-(4,4-difluorocyclohexyl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3',4',5'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',3',4'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(5-fluoropyridin-2-yl)benzenesulfonamide; 4-(2,6-difluoropyridin-3-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide; N-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-carboxamide; 2-(2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)-N-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetamide; 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)piperidine-1-sulfonamide; 4-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)piperidine-1-sulfonamide; 3-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)azacyclobutane-1-sulfonamide; 6-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-4-methylpyridine-3-sulfonamide; 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylpyridine-2-sulfonamide; N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(1H-inden-2-yl)pyridine-3-sulfonamide; 2-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4,4]nonane-7-yl)methyl)-4-methylthiazolyl-5-sulfonamide; and 5-(benzofuran-2-yl)-N-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylthiophene-2-sulfonamide.

5. The compound according to claim 1, wherein the compound of chemical formula 1 is a compound of chemical formula 3, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 3】 In the above formula, R 1 It can be hydrogen, halogen, or allyl; R 2 and R 4 One is hydrogen, and the other is... or ; R 3 It is hydrogen; R 5 It is hydrogen or C1-C6 alkyl, or R 3 With R 5 A ring can be formed by linking C1-C3 alkylene groups; R 6 It is hydrogen; L represents -CO-, -SO2-, or -CONH-; R 7 C 6-10 Aryl or 5-10 heteroaryl, wherein the C 6-10 The aryl group and the 5-10 heteroaryl group are each independently unsubstituted, or may be substituted by 1-3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1-3 halogens or hydroxyl groups. R 8 It is hydrogen or C 6-10 Aryl, wherein the C 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1 to 3 halogens or hydroxyl groups; R 9 It is a 4-10 member heterocyclic group -C 6-10 Aryl, wherein the C 6-10 The aryl group is unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; m is an integer from 0 to 5, and when m is 0, it is a single key; The heteroaryl group is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the heterocyclic group is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S.

6. The compound according to claim 5, R 7 It is phenyl, benzofuranyl or indole, wherein the phenyl, benzofuranyl and indole are each independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1 to 3 halogens or hydroxyl groups. R 8 It is hydrogen or phenyl, wherein each of the phenyl groups is independently unsubstituted, or may be substituted by 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 alkyl or C1-C6 alkoxy groups substituted by 1 to 3 halogens or hydroxyl groups; R 9 It is a piperazine phenyl compound, wherein the phenyl group is unsubstituted or may be substituted with 1 to 3 halogens, hydroxyl groups, C1-C6 alkyl groups or C1-C6 alkoxy groups, its isomers or pharmaceutically acceptable salts thereof.

7. The compound according to claim 5, wherein the compound is any one of the compounds selected from the group consisting of, isomers thereof, or pharmaceutically acceptable salts thereof: N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4-methoxy-1H-indole-2-carboxamide; 5-Chloro-N-(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)benzofuran-2-carboxamide; 8-(4-(3,5-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 8-(4-(3,4-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (S)-8-(4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; (S)-8-(4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione; 1-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; and 1-((S)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione.

8. A composition comprising the compound, its isomer, or salt thereof according to any one of claims 1 to 7.

9. A pharmaceutical composition comprising the compound, isomer thereof, or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier according to any one of claims 1 to 7, for the prevention or treatment of liver fibrosis.

10. The pharmaceutical composition according to claim 9, wherein the liver fibrosis disease is cirrhosis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

11. A method for preventing or treating liver fibrosis, comprising administering to an individual a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7.

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