Spiro-hydantoin derivative exhibiting adamts-4 inhibitory activity, and use thereof

Abstract

The present invention relates to a novel spiro-hydantoin derivative exhibiting metalloprotease ADAMTS-4 inhibitory activity, and a use thereof. The spiro-hydantoin derivative according to the present invention is useful for the prevention or treatment of diseases caused by liver injury such as a fatty liver and liver cirrhosis.

Description

[0001] Specification Title of the invention: Spiro-hydantoin derivatives having ADAMTS-4 inhibitory activity and their use Technical field The present invention relates to novel spiro-hydantoin derivatives having metalloprotease ADAMTS-4 inhibitory activity and their use for preventing or treating liver fibrosis. Research on the present invention was conducted with the support of Boramae Hospital (04-2023-0032). Background art Fatty liver disease is a disease that causes liver damage due to abnormal accumulation of fat in hepatocytes. If fatty liver disease progresses further, it progresses to steatohepatitis (including liver fibrosis), cirrhosis, or hepatocellular carcinoma. The causes of fatty liver disease are largely divided into alcoholic and non-alcoholic, and non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is continuously increasing in parallel with overnutrition related to high-fat and high-carbohydrate intake. Non-alcoholic fatty liver disease (NAFLD) is directly related to the accumulation of triglycerides in the liver and damage to hepatocytes, which results from an imbalance in lipid influx / synthesis and release / oxidation in the liver due to changes in local factors and systemic factors such as insulin resistance. Currently, among chronic diseases in Korea, hepatitis, cirrhosis, and liver cancer account for the highest proportion, along with circulatory system diseases, and they account for a large proportion of deaths due to disease. Continuous damage to liver tissue due to viral infection or alcohol consumption can develop into cirrhosis or liver cancer. There is still a need for the development of drugs that can reduce liver tissue damage and ultimately be used to treat liver diseases. Liver fibrosis is part of the biological adaptive response accompanying chronic liver diseases such as hepatitis, and refers to a state in which damaged liver tissue is transformed into fibrous tissue such as collagen rather than being restored to normal liver cells.Liver fibrosis is a biological response that occurs during the process of repairing tissue damage, but it inevitably leads to a decline in liver function because the liver is replaced by fibrous tissue that cannot perform its original functions, such as metabolism of biological substances and bile secretion. When liver fibrosis is continuously repeated, it can develop into cirrhosis and even lead to death, so the development of an appropriate treatment is necessary. Since the mechanism of liver fibrosis itself has not been clearly identified, there is a need for research into appropriate new mechanisms and therapeutic drugs that suppress it. Detailed Description of the Invention Technical Problem One object of the present invention is to provide a novel spiro-hydantoin derivative having metalloprotease ADAMTS-4 inhibitory activity, an isomer thereof, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a composition comprising the spiro-hydantoin derivative, an isomer thereof, or a salt thereof. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating liver fibrosis, comprising the spiro-hydantoin derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Technical Solution To achieve the above object, the present invention provides a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0002] [Chemical Formula 1] In the above formula,

[0003] R1 is hydrogen, halogen or allyl;

[0004] One of R2 and R4 is hydrogen, and the other is and; 3 3 6

[0005] R is hydrogen or C r C6 alkyl, or R and R are C r It can be connected to C3 alkylene to form a ring;

[0006] 5 Q 5

[0007] R is hydrogen or C r is C6 alkyl, or R and R are C r connected by C3 alkylene to form a ring;

[0008] 6

[0009] R is hydrogen;

[0010] L is -CO-, -SO2- or -CONH-; 7

[0011] R is C r C6 alkyl, C 6-10 aryl, -CH2-C 6-10 aryl, C3-i4 cycloalkyl, 5-10 member heteroaryl, or 4-10 member heterocyclic, wherein the C r C6 alkyl, C 6-10 aryl, C3-14 cycloalkyl, 5-10 member heteroaryl and 4-10 member heterocyclic are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r c6 alkoxy, or substituted with 1 to 3 halogens or hydroxy C r c6 alkyl or C r C6 alkoxy;

[0012] R 8 is hydrogen, C 6-10 aryl, C3-8 cycloalkyl, 5-10 member heteroaryl, or 4-10 member heterocyclic, wherein the C 6-10 aryl, 3-8 member cycloalkyl, 5-10 member heteroaryl, and 4-10 member heterocyclic are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy r C6 alkoxy, (wherein, day is an integer from 1 to 5) halogen or hydroxy substituted C r c6O alkyl, C r c6kJ alkoxy or 0V aryl;

[0013] Q

[0014] R is 4-10 membered heterocyclyl- C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C rC6 alkoxy may be substituted; n is 0 or 1; m is an integer from 0 to 5, and when m is 0, it is a simple bond; wherein the heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and , and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and . In addition, the present invention provides a composition comprising the compound of formula 1, an isomer thereof, or a salt thereof. In addition, the present invention provides a pharmaceutical composition for preventing or treating liver fibrosis disease, comprising the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Effect of the invention The compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention exhibits an activity of inhibiting liver fibrosis by inhibiting metalloprotease ADAMTS-4, and thus can be usefully used for the prevention or treatment of liver fibrosis diseases such as cirrhosis and steatohepatitis (e.g., NASH). Brief description of the drawings Fig. 1 is a graph showing the results of a TR-FRET assay experiment evaluating the inhibition of ADAMTS-4 activity by a compound according to an embodiment of the present invention. Fig. 2 shows the results of measuring blood drug concentrations over time after administering a control group, a positive control group AGG523, and a compound according to an embodiment of the present invention to mice. Fig. 3 shows the results of an experiment evaluating the inhibitory ability of AGG523 to inhibit CC14-induced liver fibrosis. Fig. 4 shows the results of an experiment evaluating the inhibitory ability of a compound according to an embodiment of the present invention to inhibit CC14-induced liver fibrosis. Figure 5 shows the results of an experiment evaluating the MTT assay and TGFp-induced activity index by treating LX2 cells with AGG523 and a compound according to an embodiment of the present invention. Embodiment for carrying out the invention The present invention will be described in more detail below. In the present invention, the term "halogen" means F, Cl, Br, or I unless otherwise stated.The term "hydroxy" refers to a - 0H group. The term "alkyl" refers to a linear or branched saturated hydrocarbon functional group. For example, "Ci- C6 alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. Specifically, Ci- C6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, .

[0015] 1-Methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3, 3-dimethylbutyl,

[0016] 2 - Including but not limited to ethylbutyl, etc. In one embodiment, the alkyl group can be substituted with one or more substituents, for example, 1 to 3 halogen, hydroxy, or Ci-C6 alkyl and other hydrocarbon groups. The term "alkylene" means a divalent radical derived from alkyl, exemplified by (- CH2- where Mn can be 1 to 24), and includes structures such as -CH2CH2- and - CH2CH2CH2-. For example, "Ci-C3 alkylene" means an alkylene group having 1 to 3 carbon atoms. The term "alkoxy" means a group of the formula '-O-alkyl', wherein the alkoxy group can be independently substituted with one or more substituents. For example, "Ci-C6alkoxy" includes, but is not limited to, methoxy, ethoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, sec-pentoxy, neopentoxy, hexyloxy, and the like. In one embodiment, the alkoxy group can be substituted with one or more substituents, for example, one to three halogen, hydroxy, or Ci-C6alkyl and other hydrocarbon groups. The term "cycloalkyl" means one or more saturated rings or one or more non-aromatic ring hydrocarbons, wherein the non-aromatic rings can have some degree of unsaturation. Unless defined otherwise, a cycloalkyl can be monocyclic or polycyclic. The polycyclics can be any of fused rings, bridged rings, or spiro. For example, “3 to 14 membered cycloalkyl” means a cycloalkyl having 3 to 14 ring-forming carbon atoms. Specifically, 3 to 14 membered cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,Cyclohexadienyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptyl, adamantyl, and the like. In one embodiment, the cycloalkyl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group can be substituted with a substituent. The term "cycloalkyl" means a hydrocarbon group having one or more saturated rings or one or more non-aromatic rings, wherein the non-aromatic rings may have some degree of unsaturation. Unless defined otherwise, a cycloalkyl can be monocyclic or polycyclic. The polycyclic rings can be any of fused rings, bridged rings, or spiro. For example, “3 to 14 membered cycloalkyl” means a cycloalkyl having 3 to 14 ring-forming carbon atoms. Specifically, 3 to 14 membered cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptyl, adamantyl, and the like. In one embodiment, a cycloalkyl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group can be substituted with a substituent. The term “aryl” refers to an aromatic ring hydrocarbon, and unless otherwise defined, an aryl may be single ring or multiple ring. For example, aryl may include phenyl, naphthyl, indenyl, etc., and biaryl. In one embodiment of the present invention, c6-Cioaryl refers to an aromatic ring having 6 to 10 carbon atoms. In one embodiment, 0, 1, 2, 3, 4,5 or 6 atoms may be substituted by substituents. The term “heteroaryl” means an aromatic ring containing 1 to 4 heteroatoms selected from N, 0, and . Unless otherwise defined, a heteroaryl may be monocyclic or polycyclic. For example, a “5 to 10 membered heteroaryl” is a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0, and , or a bicyclic ring in which the heteroaryl ring is fused to a benzene ring or another heteroaryl ring. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of monocyclic heteroaryls include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, azaindolinyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, purinyl, furopyridinyl and similar groups. The term “heterocyclyl” means a saturated or partially unsaturated ring containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from N, 0 and Unless otherwise defined, a heterocyclyl can be monocyclic or polycyclic. For example, “4 to 10 membered heterocyclyl” may be a 4-, 5-, or 6-membered aliphatic heterocycle, or a bicyclic ring in which the heterocyclyl ring is fused to a benzene ring or another heterocyclyl ring. In one embodiment,0, 1, 2, 3, or 4 atoms of each ring of the heterocyclyl group may be substituted with a substituent. For example, heterocyclyl can be azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isooxazolidinyl, thiazolidinyl, dioxolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, indolyl, isoindolyl, dihydroindolyl, dioxoisoindolinyl, dihydrofuryl, dihydroimidazolinyl, dihydrooxazolyl , dihydrobenzodioxynyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or benzodioxanyl, and the like, but are not limited thereto. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent so as to result in a chemically stable compound from such substitution without exceeding the valence on the designated atom. For example, "group A is replaced with substituent B" may mean that a hydrogen atom bonded to an atom such as carbon constituting the skeleton of group A is replaced by a substituent, so that group A and the substituent form a covalent bond. The term "substituent" is another group bonded to a group that is a parent nucleus, and there may be one or more substituents. When there are multiple substituents, each substituent may be the same or different. When both the parent nucleus and the substituent are hydrocarbon groups, the number of carbon atoms of the parent nucleus does not include the number of carbon atoms of the substituent. for example,A butyl group (- C4H9) having a methoxy group (- 0- CH3) as a substituent is classified as a C4 alkyl group substituted with a Ci alkoxy group. The term “isomer” refers to multiple stereoisomers. Embodiments of the present invention may produce multiple stereoisomers during the manufacturing process. If a specific stereoisomer is not indicated, all stereoisomers that may be produced during the reaction may be included. In the embodiments of the present invention, the following abbreviations are used throughout: "Ac" means acetyl, "AcO" or "OAc" means acetoxy, "ACN" means acetonitrile, "aq" means aqueous, "BOC", "Boc" or "boc" means #-tert-butoxycarbonyl, "Bn" means benzyl, "Bu" means butyl, "nBu" means normal-butyl, "tBu" means tert-butyl, "Cbz" means benzyloxycarbonyl, "DCC" means N,N'-dicyclohexyl carbodiimide, "DCM" means methylene chloride (CH2C12), "DEA" means diethylamine, "TEA" or "Et3N" means triethylamine, "DIPEA" means diisopropyl ethyl amine, "DMF" means N,N-dimethyl formamide, "DMSO" means dimethyl sulfoxide, "EDC" means 1-ethyl-3-(3-dimethylaminopropyl)carboxydiimide, "EDTA" means ethylenediaminetetraacetic acid, "Et" means ethyl, "EtOAc" means ethyl acetate, "EtOH" means ethanol, "HATU" means (1-[bis (dimethylamino)methylene]-1u 1,2,3 -triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HOAc" or "AcOH" means acetic acid, "IPA" means isopropyl alcohol, "LAH" means lithium aluminum hydride, "mCPBA" stands for meta-chloroperoxy-benzoic acid,"Me" means methyl, "MeOH" means methanol, "MS" means mass spectrometry, "MTBE" means methyl tert-butyl ether, "NHS" means N-chlorosuccinimide, "Ph" means phenyl, "PyBOP" means benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "TLC" means thin layer chromatography, "Rf" means retention fraction, "rt" means retention time, "r.t." means room temperature, "h" means hour, "min" means minute, "s" means second, "equiv." means equivalent, and "sat." means saturated. The present invention provides a compound of formula (1) below, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Formula 1], Wherein,

[0017] Ri is hydrogen, halogen or allyl;

[0018] XN only, R』 S

[0019] One of R2 and R4 is hydrogen and the other is R 6 Or '乂, R 9 And;

[0020] 3 3 6

[0021] R is hydrogen or C r C6 alkyl, or R and R are C r C3 alkylene is connected to form a ring;

[0022] 5 Q 5

[0023] R is hydrogen or C r C6 alkyl, or R and R are C r C3 alkylene is connected to form a ring;

[0024] 6

[0025] R is hydrogen;

[0026] L is -CO-, -SO2- or -CONH-;

[0027] 7

[0028] R is C r C6 alkyl, C 6-10 aryl, -CH2-C 6-10 aryl, C3-i4 cycloalkyl, 5-10 member heteroaryl, or 4-10 member heterocyclyl, wherein the C r C6 alkyl, C 6-10 aryl, C3-14 cycloalkyl, 5-10 member heteroaryl and 4-10 member heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r c6 alkoxy, or C r c6 alkyl or c r C6 alkoxy and may be substituted;

[0029] R 8 is hydrogen, C 6-10 aryl, C3-8 cycloalkyl, 5-10 member heteroaryl, or 4-10 member heterocyclyl, wherein the C 6-10 aryl, 3-8 member cycloalkyl, 5-10 member heteroaryl, and 4-10 member heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, alkoxy, -O-(CH2) p -C 6-10 aryl (wherein, day is an integer from 1 to 5) halogen or hydroxy-substituted c r c6 alkyl, C r C6 alkoxy also aryl and may be substituted; Q

[0030] R is 4-10 member heterocyclyl-C 6-10 aryl, wherein the C 6-10 aryl is unsubstituted or substituted with from 1 to 3 halogens, hydroxy, C rC6 alkyl or C r C6 alkoxy; n is 0 or 1; m is an integer from 0 to 5, and when m is 0, it is a simple bond; the heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0, and ne, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0, and ne. In one embodiment, in the compound of the above formula 1, R is hydrogen or C r C6 alkyl, or 3 6 or R and R are C r It can be connected to C3 alkylene (e.g., methylene) to form a ring. In one embodiment, in the compound of the above formula 1, R is hydrogen or C r C6Q 5 alkyl, or R and R are C r It can be connected to C3 alkylene (e.g., methylene (- CH2-)) to form a ring. As an embodiment, in the compound of the above formula 1, R 7 may be Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl or piperazinyl. At this time, Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl and piperazinyl are each independently unsubstituted or substituted with 1 to 3 halogen, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxy r C6 alkyl (e.g., - CF3) or c r c6alkoxy (e.g., -0CF3 or -0CHF2) can be substituted, but is not limited thereto. In one embodiment, in the compound of the above formula 1, R 8It may be hydrogen, phenyl, C3-8 cycloalkyl (e.g., cyclohexyl, cyclopentenyl), furanyl, thiophenyl, pyrazolyl, pyridinyl, indenyl, benzofuranyl, benzothiophenyl, or morpholinyl. At this time, the phenyl, C3-8 cycloalkyl, furanyl, thiophenyl, pyrazolyl, pyridinyl, indenyl, benzofuranyl, benzothiophenyl, and morpholinyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, -O-(CH2) p -C 6-10 aryl (wherein, 日 is an integer of 1 to 5) (e.g., -O-benzyl), or C substituted with 1 to 3 halogens or hydroxy r C6 alkyl (e.g., -CF3), C r C6 alkoxy (e.g., -OCF3•J or -OCHF2么) or -O-(CH2) n It may be substituted with p-C6U1丄0U aryl, and is not limited thereto. As an embodiment, in the compound of Formula 1, R is 4-10 member heterocyclyl-C6_ 10 aryl, for example, the 4-10 member heterocyclyl is piperazinyl, and C 6-10 aryl may be phenyl, and is not limited thereto. At this time, the c 6-10 aryl is unsubstituted or may be substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy, and is not limited thereto. In another embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 2 below:

[0031] [Formula 2] In the above formula,

[0032] Ri is hydrogen, halogen or allyl; and when JU 시〜 g尺 8 0 스〜 N' W H

[0033] One of R2 and O4 is hydrogen, and the other is R 6 or number R 9 and;

[0034] 3 3 6

[0035] R is hydrogen or C r C6 alkyl, or R and R are C r It can be connected to C3 alkylene to form a ring; 5 6

[0036] R and R are hydrogen;

[0037] L is -CO-, -S02-, or -CONH-; 7

[0038] R is C r C6 alkyl, C 6-10 Aryl, - CH2- C 6-10 Aryl, C3-i4 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C r C6 alkyl, C 6-10 Aryl, C3-14 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r c6alkoxy, or c substituted with 1 to 3 halogens or hydroxy r c6 alkyl or c r Can be substituted with C6 alkoxy;

[0039] R 8 Silver hydrogen, C 6-10 Aryl, C3-8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C 6-10 Aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydrides, (wherein p is an integer from 1 to 5), or C substituted with 1 to 3 halogens or hydroxylr 丄 C6O alkyl, C r 丄 C6kJ alkoxy or - 0-(CH2) p - C 6-1 丄0V aryl can be substituted with;

[0040] R is 4 - 10 member heterocyclyl - C 6-10 aryl, wherein the C 6-10 aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy can be substituted with; m is an integer from 0 to 5, and when m is 0, it is a single bond; the heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and, and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and. As an embodiment, in the compound of Formula 2, R is hydrogen or C r C63 6 alkyl, or R and R are C r C3 alkylene (e.g., methylene (- )) can be connected to form a ring. As an embodiment, in the compound of Formula 2, R 7 is Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl or piperazinyl. At this time, the Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl and piperazinyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C r C6 alkyl (e.g., - CF3) or c rcan be substituted with c6 alkoxy (such as, - 0CF3 or - 0CHF2), but is not limited thereto. As an example of an implementation, in the compound of Formula 2 above, R 8 can be hydrogen, phenyl, C3-8 cycloalkyl (such as, cyclohexyl, cyclopenthenyl), furanyl, thiophenyl, pyrazolyl, pyridinyl, indenyl, benzofuranyl, benzothiophenyl, or morpholinyl. At this time, the phenyl, C3-8 cycloalkyl, furanyl, thiophenyl, pyrazolyl, pyridinyl, indenyl, benzofuranyl, benzothiophenyl, and morpholinyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, - 0-(CH2) p - C 6-10 aryl (where, 日 is an integer of 1 to 5) (such as, - 0-benzyl), or C r C6 alkyl (such as, - CF3), C r C6 alkoxy (such as, - 0CF3•J or - 0CHF2么) or - 0-(CH2) n p- C6U1丄0U aryl, but is not limited thereto. As an example of an implementation, in the compound of Formula 2 above, R is 4- 10-member heterocyclyl-C6_ 10 aryl, and for example, the 4- 10-member heterocyclyl can be piperazine, and C 6-10 aryl can be phenyl, but is not limited thereto. At this time, the c 6-10 aryl is unsubstituted or can be substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy, but is not limited thereto.

[0041] Specifically, the above R is, for example Specific examples of the compound of Formula 2 according to the present invention are as follows, but are not limited thereto:

[0042] (1) #-((2, 4 -dioxo- 1,3 -diazaspiro[4.4]nonane- 6 -yl)methyl)benzofuran- 2-sulfonamide;

[0043] (2) #-((2, 4 -dioxo- 1,3 -diazaspiro[4.4]nonane- 6 -yl)methyl)-[1,1' -biphenyl]- 4 -sulfonamide;

[0044] (3) 4-Cyclohexyl- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)benzenesulfonamide;

[0045] (4) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)- 4'-fluoro-

[0046] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0047] (5)>((3-allyl- 2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6-yl)methyl)- 4'-fluoro-[ 1 , 1'-biphenyl]-4-sulfonamide

[0048] (6) 4'-chloro- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-

[0049] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0050] (7) 4' -Bromo- / V-((2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6-yl)methyl)-

[0051] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0052] (8) #-((2, 4 -dioxo- 1,3 -diazaspiro[4.4]nonane- 6 -yl)methyl)- 4'-methyl-[1,1' -biphenyl]- 4 -sulfonamide;

[0053] (9) #-((2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6-yl)methyl)- 4'-

[0054] (Trifluoromethyl)-[1, 1'-biphenyl]-4-sulfonamide;

[0055] (10) #-((2, 4 -dioxo- 1,3 -diazaspiro[4.4]nonane- 6 -yl)methyl)- 3'-

[0056] (Trifluoromethyl)-[1, 1'-biphenyl]-4-sulfonamide;

[0057] (11) 2'-(Benzyloxy)- / V-((2, 4 -dioxo- 1,3 -diazaspiro[4.4]nonan- 6-yl)methyl)- 4 ' -fluoro-[ 1 , 1' -biphenyl] -4 -sulfonamide;

[0058] (12) #-((2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6 -yl)methyl)- 4'-fluoro- 2 ' -(trifluoromethyl)-[1 , 1' -biphenyl]- 4 -sulfonamide;

[0059] (13) #-((2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6 -yl)methyl)- 4'-fluoro- 2' -(trifluoromethyl)-[1,1'-biphenyl]- 4 -sulfonamide; (14) #-((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(pyridin- 4 -yl)benzenesulfonamide;

[0060] (15)#-((2, 4-dioxo-1, 3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-3-yl)benzenesulfonamide;

[0061] (16) #-((2, 4 -dioxo- 1,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(6-methoxypyridin- 3 -yl)benzenesulfonamide;

[0062] (17) 4-(2, 6-dimethoxypyridin-3-yl)- / V-((2, 4-dioxo-1, 3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide;

[0063] (18) #-((2, 4 -dioxo- 1,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(1-methyl- 1opyrazol- 5 -yl)benzenesulfonamide;

[0064] (19) #-((2, 4 -dioxo- 1,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(1-methyl- 1opyrazol- 4 -yl)benzenesulfonamide;

[0065] (20) #-((2, 4 -dioxo- 1,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(furan- 2 -yl)benzenesulfonamide;

[0066] (21)#-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(thiophene-2-yl)benzenesulfonamide;

[0067] (22) 4-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)benzenesulfonamide;

[0068] (23) 4-(Benzo [b]thiophene- 2 -yl)-# -((2, 4 -dioxo- 1,3-diazaspiro [4.4]nonan- 6 -yl)methyl)benzenesulfonamide;

[0069] (24) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-morpholinobenzenesulfonamide;

[0070] (25) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro—[1,1'_biphenyl]_3—sulfonamide;

[0071] (26) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4,5-trifluorobenzenesulfonamide;

[0072] (27)#-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3,4-trifluorobenzenesulfonamide;

[0073] (28) #-((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6-yl)methyl)- 3,4'-difluoro- [1,1'-biphenyl]-4-sulfonamide;

[0074] (29) #-((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6 -yl)methyl)- 2,4'-difluoro- [1,1'-biphenyl]-4-sulfonamide;

[0075] (30) #-((2, 4 -dioxo- 1,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 2,4' ,5 - trifluoro- [ 1,1'-biphenyl ] -4 -sulfonamide ;

[0076] (31) #-((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6-yl)methyl)- 4'-fluoro- 2-methyl- [1,1'-biphenyl]- 4-sulfonamide; (32) #-((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6-yl)methyl)- 4'-fluoro- 2-methoxy- [1,1'-biphenyl]- 4-sulfonamide;

[0077] (33) 4-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-3-methoxybenzenesulfonamide;

[0078] (34) #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide;

[0079] (35) #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide;

[0080] (36) 5-(Benzofuran-2-yl)- / V-((2, 4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-2-sulfonamide;

[0081] (37)6-(Benzofuran-2-yl)- / V-((2, 4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-3-sulfonamide;

[0082] (38) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,5-difluoro-4-morpholinobenzenesulfonamide;

[0083] (39) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3-difluoro-4-morpholinobenzenesulfonamide;

[0084] (40)6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-2-fluoropyridine-3-sulfonamide;

[0085] (41)6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-5-fluoropyridine-3-sulfonamide;

[0086] (42)6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-2-methylpyridine-3-sulfonamide;

[0087] (43)6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-5-methylpyridine-3-sulfonamide;

[0088] (44) 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)- 4-(trifluoromethyl)pyridine-3-sulfonamide;

[0089] (45) 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)- 5-(trifluoromethyl)pyridine-sulfonamide;

[0090] (46) 1-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)isoquinoline-4-sulfonamide;

[0091] (47) 5-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)furan-2-sulfonamide;

[0092] (48) 5-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiophene-2-sulfonamide;

[0093] (49) 2-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiazole-5-sulfonamide; (50) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)- 4-(4-fluorophenyl)piperazine-1-sulfonamide;

[0094] (51) #-((2, 4 -dioxo- 1 , 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 5 -methoxy- 1-oindole- 2 -carboxamide;

[0095] (52) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-methoxy-1oindole-2-carboxamide;

[0096] (53) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1oindole-2-carboxamide;

[0097] (54) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-difluoro-1oindole-2-carboxamide;

[0098] (55) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-

[0099] (Trifluoromethyl)-1-oindole-2-carboxamide;

[0100] (56) #-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 3-methylbenzofuran- 2 -carboxamide;

[0101] (57) #-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- [1 , 1 ' -biphenyl ]- 4 -carboxamide;

[0102] (58) 4-(Cyclopent-1-en-1-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1-indole-2-carboxamide;

[0103] (59) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-

[0104] (Hydroxymethyl)-1-indole-2-carboxamide;

[0105] (60) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-hydroxy-1-indole-2-carboxamide;

[0106] (61) 5 -Chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)benzofuran-2-carboxamide;

[0107] (62) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-

[0108] (Trifluoromethyl)benzofuran-2-carboxamide;

[0109] (63) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-ethoxy-1oindole-2-carboxamide;

[0110] (64) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-

[0111] (Trifluoromethoxy)-1-oindole-2-carboxamide;

[0112] (65) 4-(Difluoromethoxy)->((2,4-dioxo-1,3-diazaspiro [4.4]nonane-6-yl)methyl)-1-indole-2-carboxamide;

[0113] (66) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-7-fluoro-4-methoxy-1-indole-2-carboxamide;

[0114] (67) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-fluoro-4-methoxy-1oindole-2-carboxamide; (68) 5-chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1oindole-2-carboxamide;

[0115] (69) 6-chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1-indole-2-carboxamide;

[0116] (70) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,7-dimethoxy-1-indole-2-carboxamide;

[0117] (71) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-dimethoxy-1oindole-2-carboxamide;

[0118] (72) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,5-dimethoxy-1-indole-2-carboxamide;

[0119] (73) >((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-3-methyl-2-(4-(trifluoromethyl)benzyl)butanamide;

[0120] (74) 1-((2, 4-dioxo- 1 ,3 -diazaspiro [4.4]nonan- 6 -yl)methyl)- 3-(4- (trifluoromethyl)phenyl)urea;

[0121] (75) 1-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonan- 6 -yl)methyl)- 3-(4-fluorophenyl)urea ;

[0122] (76) 1-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonan- 6 -yl)methyl)- 3-(4-fluorobenzyl)urea ;

[0123] (77) 1—((lr, 3r, 5r, 7r)—adamantane— 2 —yl)— 3—((2 , 4 -dioxo— 1 , 3 - diazaspiro [4.4]nonane- 6 -yl)methyl)urea ;

[0124] (78) 2-(Benzofuran-2-ylsulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0125] (79) 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0126] (80) 2-((4-(benzofuran-2-yl)phenyl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0127] (81) 2-((5-(4-fluorophenyl)pyridin-2-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0128] (82) 2-((5-(benzofuran-2-yl)pyridin-2-yl)sulfonyl)- 2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0129] (83) 2-((6-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0130] (84) 2-((6-(benzofuran-2-yl)pyridin-3-yl)sulfonyl)- 2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7,9 -dione ;

[0131] (85) 2-(5-(trifluoromethyl)benzofuran-2-carbonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4]dodecane- 7,9 -dione ; (86) #-((2, 4 -dioxo- 1 , 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 4 ' -fluoro— [ 1 , 1 ' _biphenyl ] —4 -sulfonamide ;

[0132] (87) 4-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)benzenesulfonamide;

[0133] (88) #-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 5-(4-fluorophenyl)pyridine- 2 -sulfonamide;

[0134] (89) 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-2-sulfonamide;

[0135] (90) #-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(4-fluorophenyl)pyridine- 3 -sulfonamide;

[0136] (91) 6-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-3-sulfonamide;

[0137] (92) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorobenzofuran-2-yl)pyridine-3-sulfonamide;

[0138] (93) #-((2, 4 -dioxo- 1 , 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(5-fluorobenzofuran- 2 -yl)pyridine- 3 -sulfonamide;

[0139] (94) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methoxybenzofuran-2-yl)pyridine-3-sulfonamide;

[0140] (95) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(6-methoxybenzofuran-2-yl)pyridine-3-sulfonamide;

[0141] (96) #-((2, 4 -dioxo- 1 ,3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(3-methylbenzofuran- 2 -yl)pyridine- 3 -sulfonamide;

[0142] (97) #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methylbenzofuran-2-yl)pyridine-3-sulfonamide;

[0143] (98) 2-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyrimidine-5-sulfonamide;

[0144] (99) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-fluoropyridine-3-sulfonamide;

[0145] (100) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-fluoropyridine-3-sulfonamide;

[0146] (101) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-methylpyridine-3-sulfonamide;

[0147] (102) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-methylpyridine-3-sulfonamide;

[0148] (103) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide; (104) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide;

[0149] (105) 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)furan-2-sulfonamide;

[0150] (106) 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiophene-2-sulfonamide;

[0151] (107) 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiazole-5-sulfonamide;

[0152] (108) 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-imidazole-5-sulfonamide;

[0153] (109) 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1-imidazole-5-sulfonamide;

[0154] (110) >((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 7-yl)methyl)- 5-

[0155] (Trifluoromethyl)benzofuran-2-carboxamide;

[0156] (111) 6-((5)-4-(3, 5 -difluorophenyl)- 3 -methylpiperazine-1-carbonyl)- 1,3- diazaspiro [4.4]nonane- 2,4 -dione;

[0157] (112) 6-((5)-4-(3, 4-difluorophenyl)- 3 -methylpiperazine-1-carbonyl)- 1,3- diazaspiro [4.4]nonane- 2,4 -dione;

[0158] (122) 4-(4,4-difluorocyclohexyl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)benzenesulfonamide;

[0159] (123) >((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6-yl)methyl)- 2'-fluoro-

[0160] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0161] (124) >((2 , 4 -dioxo- 1 , 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 3 ' -fluoro-

[0162] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0163] (125) >((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6-yl)methyl)- 3'-fluoro-

[0164] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0165] (126) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',4'-difluoro-[1,1'-biphenyl]-4-sulfonamide;

[0166] (127) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3',4',5'-trifluoro-[1,1'-biphenyl]-4-sulfonamide;

[0167] (128) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)- 2',3',4'-trifluoro-[1,1'-biphenyl]-4-sulfonamide;

[0168] (129) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(5-fluoropyridin-2-yl)benzenesulfonamide;

[0169] (130) 4-(2, 6-difluoropyridin- 3 -yl)->((2,4-dioxo- 1,3-diazaspiro [4.4]nonane- 6 -yl)methyl)benzenesulfonamide; (131) >((2,4-dioxo- 1,3-diazaspiro[4.4]nonane- 6 -yl)methyl)- 4'-fluoro- [ 1 , 1 '-biphenyl]- 4-carboxamide;

[0170] (132) >((4 ' -fluoro-[1 , 1 ' -biphenyl]- 4 -yl)methyl)-2 , 4 -dioxo- 1 , 3 - diazaspiro[4.4]nonane- 6 -carboxamide;

[0171] (133) 2-(2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)->(4'-fluoro-[1,1'-biphenyl]-4-yl)acetamide;

[0172] (134) 4-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)piperidine-1-sulfonamide;

[0173] (135) 4-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)piperidine-1-sulfonamide;

[0174] (136) 3-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)azetidine-1-sulfonamide;

[0175] (137) 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-4-methylpyridine-3-sulfonamide;

[0176] (138) 5-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-4-methylpyridine-2-sulfonamide;

[0177] (139) >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(1uindene-2-yl)pyridine-3-sulfonamide;

[0178] (140) 2-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylthiazole-5-sulfonamide; and

[0179] (141) 5-(benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-4-methylthiophene-2-sulfonamide. In another embodiment of the present invention, the compound of formula 1 may be a compound of formula 3 below:

[0180] [Chemical Formula 3] In the above formula,

[0181] Ri is hydrogen, halogen or allyl;

[0182] One of R2 and R4 is hydrogen, and the other is and ;

[0183] R is hydrogen; 5 Q 5

[0184] R is hydrogen or C r C6 alkyl, or R and R are c r It can be linked to C3 alkylene to form a ring;

[0185] 6

[0186] R is hydrogen;

[0187] L is -CO-, -S02- or -CONH-;

[0188] 7

[0189] R is C 6-10Aryl or 5-10 membered heteroaryl, wherein the above C 6-10 Aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxy r C6 alkyl or C r Can be substituted with C6 alkoxy;

[0190] R 8 is hydrogen or C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxy r C6 alkyl or C r Can be substituted with C6 alkoxy;

[0191] R is 4-10 membered heterocyclyl- C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy may be substituted; m is an integer from 0 to 5, and when m is 0, it is a simple bond; the heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and , and the heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and . In one embodiment, in the compound of the above formula 3, R is hydrogen or C r C6 alkyl, or R and R are C r C3 alkylene (e.g., methylene (- )) can be connected to form a ring. As an example, in the compound of the above chemical formula 3, R 7may be phenyl, benzofuranyl or indolyl. In this case, the phenyl, benzofuranyl and indolyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxy r C6 alkyl (e.g., - CFP or c r c6alkoxy (e.g., -OCF3 or -OCHF2) can be substituted, but is not limited thereto. In one embodiment, in the compound of the above formula 3, R 8 may be hydrogen or phenyl. In this case, the phenyl is independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or c substituted with 1 to 3 halogens or hydroxy r c6 alkyl or C r It can be substituted with C6 alkoxy, but is not limited thereto. In one embodiment, in the compound of the above formula 3, R is a 4-10 membered heterocyclyl-C 6-10 Aryl, for example, 4-10 membered heterocyclyl is piperazinyl, C 6-10 Aryl may be, but is not limited to, phenyl. In this case, the above c 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C can be substituted. Specifically, the R is, for example, Specific examples of the compound of formula 3 according to the present invention include, but are not limited to, the following:

[0192] (113) >(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4'-fluoro-

[0193] [ 1 , 1' -biphenyl] -4 -sulfonamide;

[0194] (114) >(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4-methoxy-1u-indole-2-carboxamide;

[0195] (115) 5 -Chloro- >(2,4-dioxo-1,3-diazaspiro [4.5]decane-8-yl)benzofuran-2-carboxamide;

[0196] (116) 8-(4-(3,5-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione;

[0197] (117) 8-(4-(3,4-difluorophenyl)piperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione;

[0198] (118) (S)-8-(4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione;

[0199] (119) (S)-8-(4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.5]decane-2,4-dione;

[0200] (120) l-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; and

[0201] (121) 1- ((S)-4- (3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; The present invention includes “pharmaceutically acceptable salts” of the above-described compounds. The pharmaceutically acceptable salts should have low toxicity to humans and should not have any adverse effects on the biological activity and physicochemical properties of the parent compound. For example, the pharmaceutically acceptable salts can be acid addition salts formed with pharmaceutically acceptable free acids. The above-mentioned acid may be an inorganic acid or an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, etc., and the organic acid may 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, embonic acid, aspartic acid, glutamic acid, etc. The above-mentioned acid addition salt may be prepared by a conventional method, for example, by dissolving the compound of the above-mentioned chemical formula 1 in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. In addition, the above-mentioned pharmaceutically acceptable salt may be an alkali metal salt (such as a sodium salt) or an alkaline earth metal salt (such as a potassium salt). The above alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound of the above chemical formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In addition, the compound of the present invention may have a chiral carbon center, and thus may exist in the form of R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures, and all such stereoisomers and mixtures thereof may fall within the scope of the present invention.In addition, the compound of the present invention may include a hydrate and a solvate of the compound of formula 1. The hydrate and solvate may be prepared using a known method, and are preferably non-toxic and water-soluble. In particular, the hydrate and solvate may be a compound in which 1 to 5 molecules of water and an alcoholic solvent (particularly, ethanol, etc.) are bound, respectively. In addition, the present invention provides a method for preparing the compounds. Specifically, the compound of formula 1 may be prepared by the method shown in the following reaction schemes, but is not limited to the method prepared by such a method. In particular, those skilled in the art will fully understand that the compound of formula 1 of the present invention may be prepared by various methods using well-known techniques in the art. The following reaction schemes show the preparation method of representative compounds according to the present invention step by step, and various compounds of the present invention may be prepared by changing the reagents and solvents used in the preparation steps below or by changing the reaction order. General Experimental Procedure The compound of the present invention can be synthesized by the following reaction scheme 1. According to one embodiment, the compound of the present invention can be synthesized using a spirohydantoin compound as a starting material. For example, the starting material can be 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1). In one example, the starting material (SM-1) can be reacted with sulfonyl chloride (R2- S02C1) to form a sulfonamide bond, thereby synthesizing the desired spirohydantoin derivative. In another example, the starting material (SM-1) can be reacted with carboxylic acid (R2- COOH) to form an amide bond, thereby synthesizing the desired spirohydantoin derivative. In yet another example, the starting material (SM-1) can be reacted with isocyanate (R2- N=C=O) to form a urea bond, thereby synthesizing the desired spirohydantoin derivative.

[0202] [Reaction Formula 1] The target compounds generated in the above reaction scheme can be separated and purified using conventional methods such as column chromatography and recrystallization. All starting materials and reagents were commercially available and used without additional purification. Air- and moisture-sensitive reactions were performed in a nitrogen environment. Flash column chromatography was performed using silica gel 60 (230-400mesh, Merck), and thin layer chromatography (Th i / VHayer chromatography; TLC) was performed using 0.25 mm silica gel plates (Merck). The p and ^cfH} NMR spectra were recorded on a Bruker 600 MHz spectrometer in solutions of chloroform (CDCh), deuterated methanol (CD3OD), or deuterated dimethyl sulfoxide (DMSO-⑦). The old NMR data were recorded in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and / or multiplet resonances, number of protons and coupling constant in Hertz (Hz) (7). High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-700 (EI). The preparation method for the compounds of the present invention will be described in more detail in the examples described below. Since the compound of the above formula 1, its isomer or its pharmaceutically acceptable salt has been confirmed to have an effect of inhibiting the metalloprotease ADAMTS-4, the compound or a pharmaceutical composition containing it can be usefully used for the treatment of diseases caused by the expression of ADAMTS-4, such as liver fibrosis diseases such as cirrhosis and steatohepatitis.The term "prevention" as used in the present invention means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering a compound or pharmaceutical composition according to the present invention, and "treatment" means any action that improves or beneficially changes the symptoms of the disease by administering a compound or pharmaceutical composition according to the present invention. The present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for inhibiting ADAMTS-4. The present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a disease associated with ADAMTS-4 activity, such as liver fibrosis. The present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disease associated with ADAMTS-4 activity, such as liver fibrosis. The present invention provides a use for the preparation of a drug for inhibiting ADAMTS-4 of a compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for preventing or treating a disease associated with ADAMTS-4 activity, such as a liver fibrosis disease, comprising administering to a subject in need thereof a compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting ADAMTS-4, comprising administering to a subject in need thereof a compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The disease associated with ADAMTS-4 activity may be a liver fibrosis disease, such as cirrhosis, alcoholic steatohepatitis, or nonalcoholic steatohepatitis (NASH). The pharmaceutical composition of the present invention can inhibit ADAMTS-4.The term "inhibition" used in the present invention means inhibition of any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of binding between proteins, activation of proteins, or signal transduction through them. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is one that is commonly used in formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. may be additionally included. The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage varies depending on the patient's condition and weight, the degree of the disease, the drug form, the administration route, and the time, but can be appropriately selected by a person skilled in the art. The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined depending on the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the administration time, the administration route, and the excretion rate, the treatment period, the concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses.Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitantly administered drugs, and generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, can be administered daily or every other day, or divided into 1 to 3 times a day. However, since the dosage may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way. In addition, the present invention provides a method for preventing, controlling or treating liver fibrosis disease, comprising a step of administering the pharmaceutical composition to a subject. In the present invention, the term "subject" refers to a subject requiring treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cows. Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, the following examples and experimental examples are intended to exemplify the present invention, and the scope of the present invention is not limited by the following examples and experimental examples.

[0203] [Example] Example 1. Synthesis of 6-aminomethyl spirohydantoin derivatives (Compounds 1 to 49 and 122 to 131) The compounds of the present invention can be prepared according to the following reaction scheme 1.

[0204] [Reaction Formula 2]

[0205] Reagents and conditions: a, a' ) sulfonyl chloride (R2- SO2CI), triethylamine (Et3N),

[0206] THF / DMF (1:1 v / v), room temperature, 12 h; b) boronic acid (RʹB(OH)2), Pd(PPh3)4, 2.0 M aqueous sodium hydrogen carbonate (NaHCO3), 1,4-dioxane, 120 °C, 1 h. Step a: Synthesis of sulfonamide compound (1) (Compound 1, Intermediate 4 or Intermediate 25)

[0207] To a solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (starting material 1, SM-1) (1.0 equivalent) in THF / DHF (1:1) was added sulfonyl chloride (1.5 equivalents), and triethylamine (3.0 equivalents) was added. The reaction mixture was stirred for 12 - 16 h. The reaction was terminated with saturated aqueous NH4Cl, washed with brine, and then the mixture was extracted with EtOAc. Then, the reaction mixture was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to obtain the compound. Thu ((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-iodobenzenesulfonamide (Intermediate 4)

[0208] 0

[0209] HN*< NH 0 ■心少 vXi ( 90% ’ white solid H W ( 600 MHz, CD3OD) δ 7.78 - 7.69 (m, ° O 1 4H), 2.88 (dd, J = 12.7, 8.0 Hz, 1H), 2.73 (dd, J = 12.7, 7.1

[0210] 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{ XH} NMR (150 MHz, CD3OD) 6 180.5, 159.1, 140.6, 133.5, 129.9, 128.2, 71.8, 48.4, 44.0, 39.1, 30.1, 23.3.

[0211] 3-Bromo-AH: (2, 4-dioxo-1, 3-diazaspiro[4.4]nonan-6-yl)methyl)benzenesulfonamide (Intermediate 25) Step a': Synthesis of sulfonamide compound (2) (compound 26, compound 27, intermediates 28 to 32, intermediates 34 to 35, or intermediates 40 to 49)

[0212] To a THF / DHF (1:1) solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione(SM-1) (1.0 eq.) was added sulfonyl chloride (1.5 eq.), followed by triethylamine (3.0 eq.). The reaction mixture was stirred overnight. The reaction was quenched with saturated NH4Cl aqueous solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to obtain the compound. Spiro[4.4]nonane-6-yl)methyl)-2- Solid). 41 NMR (600 MHz, DMSO-formed) 8 10.60

[0213] (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{ X H} NMR (150 MHz, DMSO-d6) 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.

[0214] 4-Bromo-αH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-3-fluorobenzenesulfonamide (Intermediate 29) Yield, white solid). 1H NMR (600 MHz, DMSO-d6) δ 10.60

[0215] (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{ X H} NMR (150 MHz, DMSO-d6) 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.

[0216] 4-Bromo-[[(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl]]-2,5-difluorobenzenesulfonamide (Intermediate 30) tR 2.0 (55% yield, white solid). 1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.03 (dd, J = 9.0, <>

[0217] 5.3 Hz, 1H), 7.68 (dd, J = 7.5, 5.9 Hz, 1H), 2.83 (dd, J = 12.7, 6.2 Hz, 1H), 2.76

[0218] (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). 13 C{ X H} NMR (150 MHz, DMSO-d6) δ 177.9, 156.4, 154.9 (dd, J = 64.0, 3.0 Hz), 153.3 (dd, J =

[0219] 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.

[0220] 4-Bromo-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-3-methylbenzenesulfonamide (Intermediate 31)

[0221] (75% yield, white solid). 1H NMR (600 MHz, DMSO-d6) δ 10.60

[0222] (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 好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). It should be noted that there seems to be a small error in the "J = 好8.3 Hz" in the original text which is likely a typo and is presented as is in the translation.13 C{4l} NMR (150 MHz, DMSO-d6) 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.

[0223] 4-Bromo-AH: (2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-3-methoxybenzenesulfonamide (Intermediate 32) (44% yield, white solid). X 1H NMR (600 MHz, DMSO-d6) δ 10.60

[0224] (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, 3.91 (s, 3H), 2.73 - 2.65 (m, 1H), 2.60 - 2.52 (m, 1H), 2.27 - 2.17

[0225] -1.92 (m, 1H), 1.90 - 1.79 (m, 1H), 1.74 - 1.65 (m, 2H), 1.63 - 1.55

[0226] -1.24 (m, 1H). 13 C{4l} NMR (150 MHz, DMSO-d6) δ 178.1, 156.4, 155.7, 133.7 119.9, 115.4, 110.1, 69.6, 56.6, 46.1, 42.7, 37.8, 28.7, 22.1. 5-Bromo-AH: (2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-2-sulfonamide (Intermediate 34) (44% yield, white solid). 141 NMR (600 MHz, DMSO-d6) δ

[0227] 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{ X H} NMR (150 MHz, DMSO-d6) 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.

[0228] 6-Chloro-4H-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-3-sulfonamide (Intermediate 35)

[0229] (50% yield, white solid). 1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.74 (dd, J =

[0230] 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

[0231] = 5.8 Hz, 1H), 7.77 (dd, J = 8.4, 0.8 Hz, 1H), 2.79 - 2.72 (m, 任1H), 2.66 - 2.61 (m,

[0232] 1H), 2.28 - 2.20 (m, 1H), 2.02 - 1.94 (m, 1H), 1.87 - 1.78 (m, 1H), 1.74 - 1.65 (m,

[0233] Note: In the original text, there seems to be a misspelling in "DMSO成" which should be "DMSO-d6". Also, in the translation of the NMR data, "任1H" in the original might be a mistake, I translated it as "1H" assuming it's just a single hydrogen signal. If there are specific requirements for these, please let me know.2H), 1.64 - 1.55 (m, 1H), 1.33 - 1.24 (m, 1H). 13 C{4l} NMR (150 MHz, DMSO-d6) 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.

[0234] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-2-fluoropyridine-3-sulfonamide (Intermediate 40)

[0235] (72% yield, white solid). 1H NMR (600 MHz, DMSO-d6) 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{4l} NMR (150 MHz, DMSO-d6) 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.

[0236] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-5-fluoropyridine-3-sulfonamide (Intermediate 41)

[0237] (65% yield, white solid). ¹H NMR (600 MHz, DMSO-d₆) 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

[0238] - 1.96 (m, 1H), 1.90 - 1.80 (m, 1H), 1.75 - 1.66 (m, 2H), 1.65 - 1.54 (m, 1H), 1.35

[0239] - 1.26 (m, 1H). 13 ¹³C{¹H} NMR (150 MHz, DMSO-d₆) 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.

[0240] 6-Chloro - N-(2,4-dioxo - 1,3-diazaspiro[4.4]nonan - 6 - yl)methyl)-2 - methylpyridine - 3 - sulfonamide (Intermediate 42)

[0241] (80% yield, white solid). \(^{1}H\) NMR (600 MHz, DMSO- \(d_{6}\)) \(\delta\) 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 \(^{13}C\) NMR (150 MHz, DMSO- \(d_{6}\)) \(\delta\) 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.

[0242] 6-Chloro-4-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-5-methylpyridine-3-sulfonamide (Intermediate 43) (yield, white solid).

[0243] 6-Chloro-4-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide (Intermediate 44)

[0244] (48% yield, white solid). \(^{1}H\) NMR (600 MHz, DMSO- \(d_{6}\)) \(\delta\) 10.58 (s, 1H), 8.96 (s, 1H),

[0245] 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{4l} 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.

[0246] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (Intermediate 45)

[0247] (52% yield, white solid). 41 NMR (600 MHz, DMSO-d6) 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{ X1H NMR (150 MHz, DMSO-d6) 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.

[0248] 6-Chloro-4H-3,1-benzoxazine-2,4(1H,3H)-dione, 6-[(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl]-5-methylpyridine-3-sulfonamide (Intermediate 46)

[0249] (67% yield, white solid). 1H NMR (600 MHz, DMSO-d6) 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

[0250] - 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

[0251] - 1.13 (m, 1H). 13 13C{1H} NMR (150 MHz, DMSO-d6) 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.

[0252] 5-Bromo-AH:((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)furan-2-sulfonamide (Intermediate 47)

[0253] 5-Bromo-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiophene-2-sulfonamide (Intermediate 48)

[0254] 2-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiazole-5-sulfonamide (Intermediate 49) Step b: To a solution of the sulfonamide intermediate (1.0 equivalent) synthesized according to Synthesis Step a or Step a' of Compounds 2 to 11, Compounds 13 to 23, Compound 25, Compounds 28 to 37 or Compounds 40 to 49 in 1,4-dioxane, appropriate boric acid (1.5 equivalents), Pd(PPh3)4 (10 mol%) and an aqueous NaHCO3 solution (2.0 M, 2.0 equivalents) were added. Then, the mixture was purged with nitrogen for 15 minutes to make it vacuum, and the reaction mixture was heated at 120 °C for 1 hour in an ultrasonic reactor. The reaction mixture was filtered through a Celite pad, 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 in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; MeOH / H2O = 10% / 90% - 100% / 0%). Example 1-1. Synthesis of Chuan-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4'-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide (Compound 12) Reagents and conditions: a) Sulfonyl chloride (R2-SO2Cl), triethylamine (Et3N),

[0255] THF / DMF (1:1 v / v), room temperature, 12 h; b) boronic acid (RʹB(0H)2), Pd(PPh3)4, 2.0 M aqueous sodium hydrogen carbonate (NaHC03), 1,4 - dioxane, 120 °C, 1 h; c) hydrogen, Pd / C catalyst, methanol, room temperature, 2 h. The following reactions were carried out subsequent to steps a and e of Example 1.

[0256] (Step C) A solution of 2ʹ-(benzyloxy)-N-((2,4 - dioxo - 1,3 - diazaspiro[4.4]nonan - 6 - yl)methyl)-4ʹ-fluoro-[1,1ʹ-biphenyl]-4 - sulfonamide (Compound 11) (20 mg, 0.038 mmol) and 10% Pd / C catalyst (2.4 mg, 60 mol%) in methanol was placed in a hydrogen atmosphere. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate, filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain Compound 12 (16 mg, 95%) as a white solid. Example 1 - 2. Synthesis of N-((2,4 - dioxo - 1,3 - diazaspiro[4.4]nonan - 6 - yl)methyl)-4-(6 - methoxypyridin - 3 - yl)benzenesulfonamide (Compound 24) Reagents and conditions: a) sulfonyl chloride (R2 - SO2CI), triethylamine (Et3N),

[0257] THF / DMF (1:1 v / v), room temperature, 12 h; d) Pd2(dba)3, 2 - dicyclohexylphosphino -

[0258] 2ʹ,4ʹ,6ʹ - triisopropylbiphenyl (Xphos), sodium tert - butoxide (NaOZBu),

[0259] 1,4 - dioxane, 120 °C, 1 h. The following reactions were carried out subsequent to step a of Example 1.

[0260] (Step d) To a 1,4-dioxane solution of sulfonamide intermediate (Intermediate 4, Int 4) (50 mg, 0.11 mmol) was added Pd2(dba)3 (10 mg, 10 mol%), XPhos (9.4 mg, 0.01 mmol), morpholine (14 u L, 0.17 mmol), and NaOZBu (21 mg, 0.22 mmol). The mixture was purged with nitrogen for 15 min to evacuate, and the reaction mixture was heated in an ultrasonic reactor at 120 °C for 1 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgS04. The solvent was evaporated under reduced pressure in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain compound 24. Example 1-3. (Compound 38) and (Compound 39) Reagents and conditions: a' ) sulfonyl chloride (R2- SO2CI), triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 h; e) morpholine, N,N-diisopropylethylamine ( / -

[0261] Pr2Net), DMSO, 130 °C, 30 min; The following reaction is the same as the step of Example 1 a' was carried out subsequently. (Step e) Morpholine (1.2 equivalents) was added to a DMSO solution of compound 26 or compound 27 (1.0 equivalent), and N, N-diisopropylethylamine ( / - Pr2Net) (3.0 equivalents) was added. The reaction mixture was heated in an ultrasonic reactor at 130 °C for 30 min. The reaction was quenched with a saturated aqueous solution of NH4C1, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by RP column chromatography (Sf ar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain compound 38 or compound 39. Using the method of Example 1 above, compounds 1 to 49 shown in Table 1 below and

[0262] 122 to 131 were manufactured.

[0263] [Table 1]

[0264]

[0265] Example 2. Synthesis of AK (2, 4-dioxo-1,3-diazaspiro [4.4]nonan-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide (Compound 50)

[0266] [Reaction Formula 3] Reagents and conditions: (a) 1-Fluoro-4-iodobenzene, CuBr, 1,1'-bi-2-naphthol, K3PO4, DMF, 80 °C, 18 h; (b) 4.0 M hydrochloric acid in 1,4-dioxane, room temperature, 1 h; (c) (i) chlorosulfonic acid, triethylamine (Et3N), CH2Cl2, room temperature; (ii) PCl5, benzene, room temperature, 12 h; (d) synthesis of starting material KSM-1), triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 h (synthesis of Int 50-1)

[0267] To a solution of CuBr (77 mg, 0.54 mmol) in DMF, 1,1'-bi-2-naphthol (0.15 mmol) was added and stirred for 10 min before adding 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) under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 18 h. After cooling to room temperature, the mixture was diluted with CH2Cl2 and filtered through a Celite pad. The combined organic extracts were dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / hexane = 1:10) to afford tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (intermediate 50-1, Int 50-1) (230 mg, 15%). 1H NMR (600 MHz, CD3OD) δ 6.97 (d, J = 6.5 Hz, 4H), 3.56 (t, J = 5.1 Hz, 4H), 3.03 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H). 13 C{ XH} NMR (150 MHz, CD3OD) 6 159.0 (d, J = 238.3 Hz), 156.4, 149.5 (d, J = 2.1 Hz), 119.9 (d, J = 7.7 Hz), 116.4 (d, J = 22.3 Hz), 81.4, 51.6, 28.7. ( Int 50- 2) Synthesis Fluorophenyl)piperazine-1-carboxylate (Int 50-1) (230 mg, 0.82 mmol) was added to a solution of 4.0 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction was stirred at room temperature for 1 h and monitored by TLC until completion. 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%).

[0268] 41 NMR (600 MHz, CD3OD) 8 7.47 (dd, J = 9.1, 4.3 Hz, 2H) , 7.20 (t, 7= 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{4l} NMR (150 MHz, CD3OD) 6 161.8 (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

[0269] (i) A CH2CI2 (mL) solution of intermediate 50-2 (Int 50-2) (230 mg, 0.82 mmol) and triethylamine (EtzN) (mL, mmol) was cooled to 0°C, and chlorosulfonic acid (mL, mmol) was carefully added dropwise. The reaction was stirred at room temperature for 24 h, and the solvent was removed under reduced pressure. The reaction mixture was filtered, washed with diethyl ether (Et20), and dried under vacuum to obtain a crude mixture, which was used in the next step without further purification.

[0270] (ii) PCI5 (mg, mmol) was added in portions to the benzene solution of the above intermediate, and stirred at room temperature for 3 hours. After extraction with EtOAc, the organic layer was partially washed with a saturated NH4C1 aqueous solution, dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc / zHfexane = 1:5) to obtain 4-(4-fluorophenyl)piperazine-1-sulfonyl chloride (Int 50-3) (75 mg, 64%).

[0271] 41 NMR (600 MHz, CD3OD) 8 7.08 - 7.00 (m, 4H) , 3.50 (s, 4H) , 3.33 (s, 4H) . 13 C{ X H} NMR (150 MHz, CD3OD) 6 160.3, 158.7, 148.1, 120. 5 (d, J = 7.9 Hz), 116.6 (d, J = 22.3 Hz), 50.5, 49.1. Step d: Synthesis of arylpiperazine sulfonamide derivatives

[0272] 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) was added 4-(4-fluorophenyl)-piperazine-1-sulfonyl chloride (Int 50-3) (55 mg, 0.20 mmol), followed by triethylamine (Et3N) (0.07 mL, 0.49 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHC03 solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2CI2 and dried to obtain >((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide (compound 50) (37 mg, 52%) as a white solid. Old NMR (600 MHz, DMSO-ds) 5 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 (El) m / z: [M] + Calculated value C18H24FN5O4S 425.1533; observed value 425.1528. Example 3. Synthesis of amide derivatives (Compounds 51 to 72) 311

[0273] 9

[0274] [Reaction Formula 4] 11 HHHz O ) ) ' 32 ( ( 28mnl..,,

[0275] SM-1 reagents and conditions: (a) carboxylic acid (R2-COOH), PyBOP, N,N-diisopropylethylamine ( / - Pr2Net), DMF, room temperature, 12 h; (b) (tributylstannyl)methanol, Pd(PPh3)4, DMF, 120 °C, sealed tube, 24 h; (c) BBr3, CH2CI2, -78 °C, 1 h. Step a: Amide bond formation (compounds 51 to 58, compounds 61 to 72, intermediate 59)

[0276] To a DMF solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1) (1.0 equiv.) was added carboxylic acid (1.5 equiv.) and PyBOP (1.1 equiv.), followed by N,N-diisopropylethylamine (4.0 equiv.). The reaction mixture was stirred for 12 to 16 h. The reaction was quenched with saturated NH4Cl aqueous solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to give compounds 51 to 58, compounds 61 to 72, and intermediate 59.

[0277] 4 -Bromo- AH: (2, 4 -dioxo- 1 , 3 -diazaspiro [4.4]nonane- 6 -yl)methyl) -1 min ■ Indole- 2-carboxamide (Intermediate 59, IM-59).

[0278] (61% yield, white solid). Old NMR (600 MHz, DMSO-formed) 8 11.94 (d, J = 10.57 (s, 1H), 8.57 (t, J = 5.5 Hz, 1H) , 8.24 (s, 1H) , 7.43 (dt, J = 1H), 7.26 (dd, J = 7.5, 0.8 Hz, 1H) , 7.15 - 7.07 (m, 2H) , 3.30 - 3.24

[0279] - 3.16 (m, 1H), 3.04 - 2.98 (m, 1H), 2.06 - 2.00 (m, 1H), 1.97 - 1.91

[0280] - 1.70 (m, 2H), 1.69 - 1.61 (m, 1H), 1.53 - 1.44 (m, 1H) . 13 C{ X H} NMR (150 MHz, DMSO-ds) 6 178.2, 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 #<(2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-(hydroxymethyl)-1-quindol-2-carboxamide; (Compound 59) Reagents and conditions: a) carboxylic acid (R2- COOH), PyBOP, N,N-diisopropylethylamine ( / - Pr2Net), DMF, room temperature, 12 h; b) (tributylstannyl)methanol, Pd(PPh3)4, DMF, 120 °C, sealed tube, 24 h. The following reaction was carried out subsequent to step a of Example 3.

[0281] (Step b) To a solution of 4-bromo- >((2,4-dioxo-1,3-diazaspiro [4.4]nonan- 6 -yl)methyl)- 1oindole- 2-carboxamide (intermediate 59) (20 mg, 0.049 mmol) and Pd(PPh3)4 (5.7 mg, 0.0049 mmol) in DMF (3.0 mL) was added (tributylstannyl)methanol (20.6 mg, 0.064 mmol). The mixture was then purged with nitrogen for 15 min to evacuate, and the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgS04, and the solvent was evaporated under reduced pressure in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain >((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-(hydroxymethyl)-1oindole-2-carboxamide (Compound 59). Example 3-2. Synthesis of ((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-hydroxy-1-way ■Indole-2-carboxamide (Compound 60) Reagents and conditions: a) carboxylic acid (R2- COOH), PyBOP, N,N-diisopropylethylamine ( / - Pr2Net), DMF, room temperature, 12 h; c) BBr3, CH2CI2, -78 °C, 1 h. The following reaction was carried out subsequent to step a of Example 3.

[0282] (Step c) A solution of ((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)-4-methoxy-1H-indole-2-carboxamide (Compound 53) (10 mg, 0.028 mmol) in CH2Cl2 (2.0 mL) was added with BBr3 (0.03 mL, 1.0 M CH2Cl2 solution) 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 (Sfar C18 Duo; MeOH / H2O 10% / 90% — 100% / 0%) to obtain Compound 60. Using the method of Example 3 above, Compounds 51 to 72 shown in Table 2 below were prepared.

[0283] [Table 2]

[0284] "Hr E : Past Example 4. Synthesis of Urea Derivatives (Compounds 74 to 77)

[0285] [Scheme 5] Reagents and Conditions: (a) Isocyanate (R2-N=C=O), triethylamine (Et3N), THF, room temperature, 12 hours.

[0286] To a THF solution of 6-(aminomethyl)-1,3-diazaspiro[4,4]nonane-2,4-dione (SM-1) (1.0 eq.), an appropriate isocyanate (1.0 eq.) was added, followed by triethylamine (3.0 eq.). The reaction mixture was stirred for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to obtain compounds 74 to 77. Compounds 74 to 77 shown in Table 3 below were prepared using the method of Example 4.

[0287] [Table 3] Example 5. 2, 6, 8 - Triazadispiro [3.0.4 5 .3 4 ]Synthesis of dodecane-7, 9-dione derivatives (compounds 78 to 84) [Reaction Scheme 6] Reagents and Triethylamine (Et3N), THF / DMF (1:1 v / v), room temperature, 12 h; (b) boronic acid (R『 B(0H)2), Pd (PPh3)4, 2.0 M sodium bicarbonate (NaHC03) aqueous solution, 1,4-dioxane, 120 °C, 1 h. Step a : Synthesis of compound 78, intermediate 79, intermediate 82 and intermediate 84

[0288] 2, 6, 8 - Triazadispiro [3.0.4 5 .3 4A solution of dodecane-7,9-dione (starting material 2, SM-2) (1.0 equivalent) in THF / DHF (1:1) was added with sulfonyl chloride (1.5 equivalents), and then triethylamine (3.0 equivalents) was added. The reaction mixture was stirred for 12 - 16 hours. The reaction was terminated with saturated aqueous NH4C1, washed with brine, and then the mixture was extracted with EtOAc. Subsequently, the reaction mixture was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2CI2, and dried to obtain compound 78, intermediate 79, intermediate 82, and intermediate 84.

[0289] 2-((4-Iodophenyl)sulfonyl)-2,6,8-triazadispiro[3.0.4 5 .3 4 Dodecane-7,9-dione (intermediate 79)

[0290] (67% yield, white solid). 1H NMR (600 MHz, DMSO-d6) 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 13C{1H} NMR (150 MHz, DMSO-d6) 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.

[0291] 2-((5-Bromopyridin-2-yl)sulfonyl)-2,6,8-triazadispiro[3.0.4 5 .3 4 Dodecane-

[0292] 7, 9 - Dion (Intermediate 82)

[0293] (38% yield, white solid).

[0294] 2-((6-chloropyridin-3-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]Dodecane-

[0295] 7, 9 - Dion (Intermediate 84)

[0296] (48% yield, white solid). Step b: Synthesis of compounds 79 to 84 To a 1,4-dioxane solution of the intermediate (intermediate 79, 82 or 84) (1.0 eq.) above was added the appropriate boronic acid (1.5 eq.), Pd(PPh3)4 (10 mol%) and NaHC03 aqueous solution (2.0 M, 2.0 eq.). The mixture was then purged with nitrogen for 15 min to evacuate, and the reaction mixture was heated in an ultrasonic reactor at 120 °C for 1 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with NH4Cl aqueous solution and extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgS04. The solvent was evaporated under reduced pressure in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain compounds 79 to 84. Using the method of Example 5, compounds 78 to 84 shown in Table 4 below were prepared.

[0297] [Table 4] Example 6.7 - Synthesis of aminomethyl spirohydantoin derivatives (compounds 86 to 109 and 137 to 141)

[0298] [Reaction Formula 7] Reagents and conditions: (a) Sulfonyl chloride (R2-SO2Cl), triethylamine (Et3N),

[0299] THF / DMF (1:1 v / v), room temperature, 12 h; (b) Boronic acid (R‘B(OH)2), Pd(PPh3)4, 2.0 M aqueous sodium hydrogen carbonate (NaHCO3), 1,4-dioxane, 120 °C, 1 h; Step a: Synthesis of intermediates 86 to 109

[0300] Sulfonyl chloride (1.5 equivalents) was added to a solution of 7-(aminomethyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (starting material 3, SM-3) (1.0 equivalent) in THF / DHF (1:1), and triethylamine (3.0 equivalents) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, washed with brine, and the mixture was extracted with EtOAc. Then, the reaction mixture was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to obtain intermediates 86 to 109. Spiro[4.4]nonan-7- (83% yield, white solid). 1H NMR (600 MHz, DMSO-d6) 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, 6.1 Hz, 1H), 7.54 (dd, J = 8.6, 1.0 Hz, 2H), 2.77 - 2.67 (m, 2H), 2.29 - 2.​​​1H NMR (150 MHz, DMSO-d6) 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 = 39.7 Hz), 36.4 (d, J = 43.6 Hz), 28.7 (d, J = 97.5 Hz). 3-Diazaspiro[4.4]nonan-7-yl)methyl)pyridin-2- (46% yield, white solid).

[0301] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)pyridine-3-sulfonamide (Intermediate 91)

[0302] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)pyridine-3-sulfonamide (Intermediate 98)

[0303] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-2-fluoropyridine-3-sulfonamide (Intermediate 99) 6 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). 6’2)21H•\ / ,,)

[0304] 6-Chloro-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-5-HHz)8-fluoropyridine-3-sulfonamide (Intermediate 100) O ( , m

[0305] 5

[0306] 2

[0307] [[ID=A12]]--

[0308] (23% yield, white solid). 1H 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).

[0309] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-2-methylpyridine-3-sulfonamide (Intermediate 101)

[0310] (30% yield, white solid). 1H NMR (600 MHz, CD3OD) δ 8.21 (dd, J = 8.3, 1.8 Hz, 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).

[0311] 6-Chloro-AH:(2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)methyl)-5-methylpyridine-3-sulfonamide (Intermediate 102) •

[0312] (41% yield, white solid). Old NMR (600 MHz, CD3OD) 6 8.61 (dd, J 8.14 - 8.10 (m, 1H), 2.98 - 2.89 (m, 2H), 2.47 (s, 3H), 2.39 - - 2.10 (m, 1H), 2.09 - 1.90 (m, 2H), 1.89 - 1.74 (m, 2H), 1.59 1.43

[0313] 6-Chloro-AH: (2, 4-dioxo-1, 3-diazaspiro[4.4]nonan-7-yl)methyl)-4-(trifluoromethyl)pyridine-3-sulfonamide (Intermediate 103). (11% yield, white solid). Old NMR (600 MHz, CD3OD) 6 9.07 (s, 1H) , 8.00 (s, 1H) ,

[0314] 3.10 - 3.01 (m, 2H), 2.42 - 2.31 (m, 1H), 2.30 - 2.13 (m, 1H), 2.11 - 1.91 (m, 2H),

[0315] 1.90 - 1.75 (m, 2H), 1.60 - 1.44 (m, 1H) .

[0316] 6-Chloro-AH: (2, 4-dioxo-1, 3-diazaspiro[4.4]nonan-7-yl)methyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (Intermediate 104). , , . Sulfonamide (Intermediate 107) Yield, white solid).

[0317] 2-Bromo-su((2, 4-dioxo-1, 3-diazaspiro[4.4]nonane-7-yl)methyl)-1-quinidazole-

[0318] 5-sulfonamide (intermediate 108) (22% yield, white solid).

[0319] 2 -chloro- Oxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1-imidazole-5-sulfonamide (Intermediate 109) Yield, white solid). Step b: Synthesis of compounds 86 to 109 To a 1,4-dioxane solution of the above intermediate (1.0 eq.), appropriate boronic acid (1.5 eq.), Pd(PPh3)4 (10 mol%) and NaHC03 aqueous solution (2.0 M, 2.0 eq.) were added. The mixture was then purged with nitrogen for 15 min to evacuate, and the reaction mixture was heated in an ultrasonic reactor at 120 °C for 1 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was diluted with NH4C1 aqueous solution and extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgS04. The solvent was evaporated under reduced pressure in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% — 100% / 0%) to obtain the compounds. Using the method of Example 6, compounds 86 to 109 and 137 to 141 shown in Table 5 below were prepared.

[0320] [Table 5]

[0321] [Reaction Scheme 8] Separation of stereoisomers of compound 91

[0322] [Chiral separation conditions] The four stereoisomers of compound 91 were separated using a preparative chiral SFC column (stationary phase: Chiralpak Daicel 0D-10, 25 x 250 mm, 10 um, mobile phase: C02, MeOH + 0.05% Et2NH). Example 7. Synthesis of other spirohydantoin derivatives (compounds 85, 110, 114 to 115)

[0323] [Reaction Formula 9]

[0324] SM-4 reagents and conditions: (a) Carboxylic acid (R2-COOH), PyBOP, N,N-diisopropylethylamine ( / - Pr2Net), DMF, room temperature, 12 h. To a DMF solution of starting materials 2 to 4 (SM-2 to SM-4) (1.0 eq.), carboxylic acid (1.5 eq.) and PyBOP (1.1 eq.) were added, and N,N-diisopropylethylamine (4.0 eq.) was added. The reaction mixture was stirred for 12 to 16 h. The reaction was quenched with saturated NH4Cl aqueous solution, washed with brine, and the mixture was extracted with EtOAc. The reaction mixture was then dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was filtered, washed with CH2Cl2, and dried to obtain the compound. Using the method of Example 7, compounds 85, 110, and 114 to 115 shown in Table 6 below were prepared.

[0325] [Table 6] Example 8. Synthesis of arylpiperazine derivatives

[0326] [Reaction Formula 1

[0327] R q =-F

[0328] R k = -H or -F

[0329] R s= -H or -F Reagents and conditions: (a) Aryl iodide, Pd2(dba)3, sodium tert-butoxide (NaO'Bu), (2-biphenyl)di-tert-butylphosphine (Johnphos), toluene, 110 °C, overnight; (b) 4.0 M hydrochloric acid in 1,4-dioxane, room temperature, 1-3 hours. Step a: Synthesis of intermediates 116-118

[0330] To a toluene solution of 1-Boc-piperazine or 1-Boc-3-methylpiperazine (1.0 equivalent), aryl iodide (1.1 equivalents), Pd2(dba)3 (10 mol%), Johnphos (0.1 equivalent) and NaO'Bu (1.5 equivalents) were added. Then, the mixture was purged with nitrogen for 15 minutes to make it vacuum, and the reaction mixture was refluxed at 110 °C overnight. The reaction mixture was filtered through a Celite pad, 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 in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / hexane = 1:10) to obtain the intermediate as a yellow solid. tert-Butyl 4-(3,5-difluorophenyl)piperazine-1-carboxylate (intermediate 116)

[0331] (53% yield, yellow solid). \(^{1}H\) NMR (600 MHz, \(CDCl_{3}\)) \(\delta\) 6.37 (dd, \(J = 10.6, 2.2\) Hz, 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, \(CDCl_{3}\)) \(\delta\) 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.

[0332] tert-Butyl 4-(3,4-difluorophenyl)piperazine-1-carboxylate (Intermediate 117)

[0333] (64% yield, yellow solid). \(^{1}H\) NMR (600 MHz, \(CDCl_{3}\)) \(\delta\) 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{ X \(^{13}C\{^{1}H\}\) NMR (150 MHz, \(CDCl_{3}\)) \(\delta\) 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.

[0334] (30% yield, yellow solid). Old NMR (600 MHz, CDCI3) 6 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 To a toluene solution of the appropriate intermediate (intermediates 116 to 119) (1.0 equivalent) was added a 4.0 M hydrochloric acid solution in 1,4-dioxane. After stirring for 1 to 3 hours, the reaction mixture was diluted with CH2CI2. The solvent was evaporated under reduced pressure in vacuo. The residue was filtered with Et2O to obtain intermediates 116a to 119a.

[0335] 1-(3, 5-difluorophenyl)piperazine hydrochloride (intermediate 116a) Old NMR (600 MHz, CD3OD) 6 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{ X H} NMR (150 MHz, CD3OD) 6 166.3 (d, J = 15.7 Hz), 164.7 (d, J = 16.0 Hz), 153.8 (t, J = 12.5 Hz), 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.

[0336] 1-(3, 4-difluorophenyl)piperazine hydrochloride (intermediate 117a) Old NMR (600 MHz, CD3OD) 6 7.21 - 7.15 (m, 1H), 7.04 - 6.99 (m, 1H), 6.86 - 6.82 (m, 1H), 3.45 - 3.37 (m, 8H).

[0337] (5)- 1-(3, 5 -difluorophenyl)- 2 -methylpiperazine hydrochloride (intermediate 118a) It was synthesized using the same method as intermediate 116a.

[0338] (5)-1-(3, 4-difluorophenyl)-2-methylpiperazine hydrochloride (intermediate 119a) It was synthesized in the same manner as intermediate 116a. Step c: Synthesis of arylpiperazine derivatives (compounds 111 to 112, compounds 116 to

[0339] 121)

[0340] Aryl piperazine intermediates, EDC, hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine ( / - Pr2Net), DMF, room temperature, overnight. Compounds 111 to 112 and compounds 116 to 121 were synthesized by reacting arylpiperazine intermediates (Int 116a to 119a) with starting material 5 (SM-5), starting material 6 (SM-6) or starting material 7 (SM-7). Using the method of Example 8, compounds 111 to 112 and compounds 116 to 121 shown in Table 7 below were prepared.

[0341] [Table 7] Example 9. Synthesis of compounds 132 and 133

[0342] [Reaction Formula 12] Reagents and conditions: (a) 4-bromobenzylamine, 4-bromoaniline, or 4'-fluoro-1,1'-biphenyl-4-carboxylic acid, PyBOP, HOBt, i-Pr2EtN, DMF, rt, 12 h; (b) (4-fluorophenyl)boronic acid, Pd(PPh3)4, 2.0 M NaHC03 in H20, 1,4-dioxane, microwave, 120 °C, 1 h. General procedure for amide coupling (Intermediates 120 and 121)

[0343] To a solution of carboxylic acid (1.0 equiv.) in DMF were added PyBOPd. 1 equiv.), HOBt (1 equiv.), / -Pr2EtN (3.0 equiv.), followed by the appropriate amine (1.2 equiv.). The reaction mixture was stirred for 12 h. The saturated aqueous NH4C1 solution was quenched, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; Me0H / H20 = 10% / 90% to 100% / 0%) to give compounds (intermediates 120 and 121). Intermediate 120 (4-bromobenzyl)-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-carboxamide (75%, white solid) Old NMR (600 MHz, DMSO-^) 6 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, 8.3 Hz, 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 CfH} NMR (150 MHz, DMSO-dA) 6 178.0, 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 (4-bromophenyl)-2-(2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)acetamide

[0344] (22%, white solid) Old NMR (600 MHz, DMSO-d6) 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 13C NMR (150 MHz, DMSO-d6) 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.

[0345] General procedure for Pd(0)-catalyzed cross-coupling (Compounds 132 and 133).

[0346] The intermediate in 1,4-dioxane (Int 120, Int 121) (1.0 equivalent) was added to (4-fluorophenyl)boronic acid (1.2 equivalents), Pd(PPh3)4 (10 mol%) and aqueous NaHCO3 solution (2.0 M, 2.0 equivalents). Then, the mixture was purged with Ar for 15 minutes to degas. The reaction mixture was heated at 120 °C for 1 hour in a microwave reactor. The reaction mixture was filtered through a Celite pad, and the filtrate was diluted with aqueous NH4Cl solution and then extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The solvent was evaporated under reduced pressure in vacuo. The residue was purified by RP column chromatography (Sfar C18 Duo; MeOH / H2O = 10% / 90% to 100% / 0%) to obtain Compounds 132 and 133.

[0347] [Table 8] Example 10. Synthesis of Compounds 134 to 136 Reagents and conditions: (a) Corresponding sulfonyl chloride, Et3N, DMA, 12 h, room temperature.

[0348] Intermediate 122 or 123 (1.0 eq.) was added to a solution of SM-1 or SM-3 (1.0 eq.) in DMA, followed by Et3N (3.0 eq.). The reaction mixture was stirred at room temperature for 12 to 16 h. The saturated aqueous NH4C1 solution was rapidly quenched, washed with brine, and extracted with EtOAc. The reaction mixture was then dried over anhydrous NH2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane / MeOH = 1:1:0.1) to give compounds 134 to 136.

[0349] [Table 9]

[0350] [Experimental Example] Experimental Example 1. Evaluation of ADAMTS-4 activity inhibition

[0351] To evaluate the inhibition of ADAMTS-4 activity by 6-aminomethyl spiro-hydantoin derivatives, TR-FRET (time resolved fluorescence energy transfer) analysis was performed. 0.5 μg of recombinant human ADAMTS-4 protein was added to each well of a 96-well 11 black opaque plate, and 100 nM of the control (DMSO only), positive control AGG523 (Cas No.: 920289-29-8), and 6-aminomethyl spiro-hydantoin derivatives synthesized in the examples of the present invention were added to each well, and the reaction was performed at 37 °C for 15 minutes. Afterwards, 25 μM of fluorescently labeled ADAMTS-4 substrate was added to each well, and the fluorescence was measured every 5 minutes at a wavelength of 340 nm (excitation) and 420 nm (emission) for 1 hour. Fluorescence changes of some of the tested drugs over 1 hour are shown in Fig. 1. As shown in Fig. 1, when the compound according to the present invention was added, it was confirmed that the measured fluorescence value was low due to inhibition of binding of ADAMTS-4 protein and substrate. In addition, the ADAMTS-4 activity inhibition rate (%) of the compound of the present invention at a concentration of 100 nM is shown in Table 10 below. In Table 10 below, compounds 73-1 and 73-2 represent isomer-1 and isomer-2 of compound 73.

[0352] [Table 1 In addition, in the ADAMTS-4 activity inhibition experiment described above, the half maximal inhibitory concentration (IC50) values ​​of each example were determined and shown in Table 11 below. IC50 is a value indicating the concentration required for a specific substance to inhibit a biological process or the function of a biological component by 50%, and the lower the IC5o value of a drug, the more likely it is to inhibit ADAMTS-4 activity in a small amount.

[0353] [Table 11]

[0354] Experimental Example 2. Pharmacokinetics evaluation Pharmacokinetics (Phamcokinets: PK) of compounds confirmed to have low IC5o values ​​for ADAMTS-4 in Experimental Example 1 were evaluated. First, 10 mg / kg of AGG523 was administered intravenously or orally to fasted mice. Orbital blood samples were collected at 3, 7, 15, 30, 1, 2, 4, 8, and 24 hours after administration. The collected blood was centrifuged for 5 minutes to separate the plasma, and the blood drug concentration was measured using HPLC / MS / MS. The experiment was conducted in the same manner as for compounds 4 and 53 according to the present invention. As a result of the experiment, as shown in Fig. 2, AGG523 showed the highest drug concentration (C) in just a few minutes after administration. m It showed an abnormal graph reaching a peak (ax), and the clearance (CL) was high, so it can be inferred that the drug should be administered at a high concentration to properly obtain the pharmacological effect because it is easily metabolized or excreted. On the other hand, compound 4 according to the present invention showed a normal PK distribution with a high peak blood concentration reached upon oral administration and a time to reach the peak concentration (tmax) of 1 hour. Experimental Example 3. Evaluation of the inhibitory ability of CC14-induced liver fibrosis by administration of AGG523

[0355] (1) AGG523 administration and induction of liver fibrosis

[0356] Liver fibrosis was induced in 8-week-old C57BL6J mice by oral administration of AGG523 at 100 mg / kg twice daily and intraperitoneal administration of 1 ml / kg of CCh twice weekly for a total of 4 weeks.

[0357] (2) Liver tissue section production After administration, the mouse was laparotomy, a portion of the left liver was incised, fixed with formalin, and a paraffin block was made. The paraffin block was cut to obtain a paraffin slide, and after deparaffinization using xylene to remove paraffin, liver tissue sections were made by hydrating with distilled water.

[0358] (3) Masson's trichrome staining of liver tissue Weigert's iron hematoxylin solution was added to the liver tissue section and reacted for 10 minutes to stain cell nuclei, then Biebrich scarlet-acid fusion solution was added and reacted for 15 minutes to stain the cytoplasm and acidic tissues such as muscle. The stained liver tissue section was washed with distilled water, collagen was stained with aniline blue for 5 minutes, and then washed with 1% acetic acid. The above-described staining process is referred to as 'Masson's trichrome staining' hereinafter. As a result of evaluating the fibrosis index through the above method, as shown in Fig. 3, there was no significant difference in the degree of fibrosis between the group that was not administered AGG523 (stained photo indicated as CCh in Fig. 3) and the group that was administered AGG523 (stained photo indicated as AGG523 in Fig. 3) in the tissue where liver fibrosis was induced by CCh, so it is thought that AGG523 does not improve the fibrosis index.

[0359] (4) aSMA analysis through Western blot After taking a portion of the liver tissue, proteins were extracted using RIPA lysis solution, and 20 μg of the proteins were electrophoresed on an SDS-page gel. The proteins that migrated down the gel were transferred to an NC (nitrocellulose) membrane, and non-specific bands were removed from the transferred membrane with 5% skim milk. After washing the membrane with PBST, it was reacted with a SMA (alpha smooth muscle actin), an indicator of stellate cell activation, or GAPDH antibody, a loading control, at 4 °C overnight. After washing with PBST, the mouse-HPR antibody was reacted for 1 hour at room temperature, and the luminescence of the protein was measured by luminol reaction. Hereinafter, the above-described process is referred to as Western blot. As shown in Figure 3, a Western blot analysis of aSMA, an indicator of stellate cell activation, revealed no significant decrease in the AGG523-administered group. This suggests that the ineffectiveness of AGG523 in inhibiting liver fibrosis may be due to its negative effects. Experimental Example 4. Evaluation of the inhibitory effect of compound 4 on liver fibrosis.

[0360] Compound 4 was orally administered twice a day at 100 mg / kg to 8-week-old C57BL6J mice, and at the same time, 1 ml / kg of CCh was intraperitoneally administered twice a week to induce liver fibrosis for a total of 4 weeks. After administration, liver tissues were collected from the mice and the fibrosis index was evaluated by Masson's trichrome staining, and a portion of the liver tissues was confirmed to have aSMA, an indicator of stellate cell activation, by western blot. The experimental results are shown in Fig. 4. As confirmed in Fig. 4, in the compound 4 administration group, the expression of aSMA was reduced, and the fibrosis score was significantly reduced. From these experimental results, it was confirmed that compound 4, a relatively good ADAMTS-4 inhibitor, has an effect of inhibiting liver fibrosis. Experimental Example 5. Inhibition of TGFP-induced stellate cell activation index by ADAMTS-4 inhibitor treatment LX2 cells, a human-derived stellate cell line, were seeded in 96-well plates at 5xl0 4 , and after 18 hours, the medium was changed to serum-free medium, and AGG523 and compounds 4 and 53 according to the present invention were treated at concentrations of 2, 5, 10, 20, 30, 50, and 100 yM for 24 hours, respectively. After removing the supernatant, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was reacted at 37 °C for 2 hours at 1 mg / ml. After removing the supernatant, DMSO was added and reacted for 15 minutes, and the absorbance was measured at 540 °C to evaluate drug toxicity. AGG523 and compound 4 according to the present invention did not show drug toxicity except when treated at a concentration of 100 uM, and it was confirmed that compound 53 according to the present invention did not show drug toxicity at all tested concentrations, including the case of a concentration of 100 uM. Also, 3xl0 in 6-well plates 5LX2 cells were laid down, and after 18 hours, each drug was pretreated for 1 hour at a concentration that did not show toxicity, and TGFP was reacted for 24 hours. After completion of the reaction, stellate cell activation indices were confirmed through western blot, and the results are shown in Fig. 5. According to Fig. 5, AGG523 and compounds 4 and 53 according to the present invention decreased stellate cell activation indices (Col lai, aSMA, PAI-1) by ADAMTS-4 inhibition even in . The above description of the present invention is for the purpose of illustration, and those skilled in the art to which the present invention pertains will understand that the present invention can be easily modified into other specific forms without changing the technical spirit or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all aspects and not limiting.

Claims

Scope of the claim

1. A compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, R1 is hydrogen, halogen or allyl; One of R2 and O4 is hydrogen, and the other is and; 3 3 6 R is hydrogen or C r C6 alkyl, or R and R are C r It can be linked to C3 alkylene to form a ring; 5 Q 5 R is hydrogen or C r C6 alkyl, or R and R are C r It can be linked to C3 alkylene to form a ring; 6 R is hydrogen; L is -CO-, -S02-, or -CONH-; 7 R is C r C6 alkyl, C 6-10 Aryl, - CH2- C 6-10 Aryl, C3-i4 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C r C6 alkyl, C 6-10 Aryl, C3-14 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r c6alkoxy, or c substituted with 1 to 3 halogens or hydroxyl r c6 alkyl or c r Can be substituted with C6 alkoxy; R 8 is hydrogen, C 6-10 aryl, C3-8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein said C 6-10 aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, -O-(CH2) p -C 6-10 aryl (wherein, 日 is an integer from 1 to 5), or c substituted with 1 to 3 halogens or hydroxy r c6 alkyl, C r C6 alkoxy or -O-(CH2) D -c 6-10 aryl and may be substituted; Q R is 4-10 membered heterocyclyl- C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy may be substituted; n is 0 or 1; m is an integer from 0 to 5, and when m is 0, it is a simple bond; said heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and , and said heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and .

2. In claim 1, the compound of formula 1 is a compound of formula 2 below, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 2] In the above formula, Ri is hydrogen, halogen or allyl; One of R2 and R4 is hydrogen, and the other is and; 3 3 6 R is hydrogen or C r C6 alkyl, or R and R are C r It can be linked to C3 alkylene to form a ring; 5 6 R and R are hydrogen; L is -CO-, -S02- or -CONH-; 7 R is C r C6 alkyl, C 6-10 Aryl, - CH2- C 6-10 Aryl, C3-i4 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C r C6 alkyl, C 6-10 Aryl, C3-14 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r c6alkoxy, or c substituted with 1 to 3 halogens or hydroxyl r c6 alkyl or c r may be substituted with C6 alkoxy; R 8 Silver hydrogen, C 6-10 Aryl, C3-8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein said C 6-10 Aryl, 3-8 membered cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxide, or (wherein, the day is an integer from 1 to 5), or C substituted with 1 to 3 halogens or hydroxy r 丄 C6O alkyl, C r 丄 C6kJ alkoxy or - 0- (CH2) p - C 6-1 丄0V aryl may be substituted; Q R is 4-10 membered heterocyclyl- C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy may be substituted; m is an integer from 0 to 5, and when m is 0, it is a simple bond; said heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and , and said heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and . [

3. In claim 2, R 7 is Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl or piperazinyl, wherein said Ci-C6 alkyl, phenyl, benzyl, azetidinyl, adamantanyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, benzofuranyl, indolyl, isoquinolinyl, piperidinyl and piperazinyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or c substituted with 1 to 3 halogens or hydroxyl r c6 alkyl or C r may be substituted with C6 alkoxy; R 8 is hydrogen, phenyl, C3-8 cycloalkyl, furan, thiophene, pyrazole, furanyl, thiophenyl, pyrazolyl, pyridinyl, indanyl, benzofuranyl, benzothiophenyl, or morpholinyl, wherein the phenyl, C3-8 cycloalkyl, furanyl, thiophenyl, pyrazolyl, pyridinyl, indanyl, benzofuranyl, benzothiophenyl, and morpholinyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, -O-(CH2) p -C 6-10 aryl (wherein, 日 is an integer of 1 to 5), or c r c6 alkyl, C r C6 alkoxy or -O-(CH2) D -c 6-10 aryl may be substituted; Q R is piperazinylphenyl, wherein said phenyl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r A compound which may be substituted with C6 alkoxy, an isomer thereof or a pharmaceutically acceptable salt thereof.

4. In claim 2, the compound is any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran-2-sulfonamide; / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; 4-Cyclohexyl- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)benzenesulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; >((3-Allyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; 4'-Chloro- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; 4'-Bromo- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4'-methyl- [1, 1' -biphenyl]- 4 -sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4'- (Trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 3'- (Trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; 2'-(benzyloxy)- / V-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)- 4'-fluoro—[1,1'_biphenyl]—4-sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'- (Trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2'- (Trifluoromethyl)-[1,1'-biphenyl]-4-sulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-4-yl)benzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(pyridin-3-yl)benzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(6-methoxypyridin-3-yl)benzenesulfonamide; 110 4-(2,6-dimethoxypyridin-3-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(1-methyl- 1-pyrazol- 5 -yl)benzenesulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4-(1-methyl- 1-pyrazol- 4 -yl)benzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(furan-2-yl)benzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(thiophene-2-yl)benzenesulfonamide; 4-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; 4-(Benzo[b]thiophene-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-morpholinobenzenesulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-3-sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4,5-trifluorobenzenesulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3,4-trifluorobenzenesulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,4'-difluoro-[1,1'-biphenyl]-4-sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,4'-difluoro- [1,1'-Biphenyl]-4-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 2, 4' , 5 - trifluoro- [1 , 1 ' -biphenyl ] - 4 -sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-2-methyl-[1,1'-biphenyl]-4-sulfonamide; #-((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)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methoxybenzenesulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-(4-fluorophenyl)pyridine-2-sulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-(4-fluorophenyl)pyridine-3-sulfonamide; 5-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-2-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)pyridine-3-sulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3,5-difluoro-4-morpholinobenzenesulfonamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2,3-difluoro-4-morpholinobenzenesulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-fluoropyridine-3-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-fluoropyridine-3-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2-methylpyridine-3-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5-methylpyridine-3-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)- 4-(trifluoromethyl)pyridine-3-sulfonamide; 6-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)- 5-(Trifluoromethyl)pyridine-sulfonamide; 1-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)isoquinoline-4-sulfonamide; 5-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)furan-2-sulfonamide; 5-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiophene-2-sulfonamide; 2-(Benzofuran-2-yl)- / V-((2,4-dioxo-1,3-diazaspiro[4.4]nonan-6-yl)methyl)thiazole-5-sulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(4-fluorophenyl)piperazine-1-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 5 -methoxy- 1-indol- 2 -Carboxamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 6 -methoxy- 1-indol- 2 -Carboxamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4 -methoxy- 1-indol- 2 -Carboxamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4,6-difluoro-1-indole-2-carboxamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5- (Trifluoromethyl)-1-indole-2-carboxamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methylbenzofuran-2-carboxamide; JV-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-[1,1'-biphenyl]-4-carboxamide; 4-(Cyclopent-1-en-1-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1-indole-2-carboxamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4- (Hydroxymethyl)-1-indole-2-carboxamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-hydroxy-1-indol-2-carboxamide; 5 -Chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzofuran- 2 -Carboxamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-5- (Trifluoromethyl)benzofuran-2-carboxamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4 -ethoxy- 1-indol- 2 -Carboxamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 6 -yl)methyl)- 4- (Trifluoromethoxy)-1-oindole-2-carboxamide; 4-(difluoromethoxy)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-1-indole-2-carboxamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-7-fluoro-4-methoxy-1-indole-2-carboxamide; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-6-fluoro-4-methoxy-1-indole-2-carboxamide; 5 -Chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1-indole-2-carboxamide; 6-Chloro->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-methoxy-1-indole-2-carboxamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4, 7-dimethoxy-1-indole-2-carboxamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4, 6-dimethoxy-1-indole-2-carboxamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4, 5-dimethoxy-1-indole-2-carboxamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3-methyl-2-(4-(trifluoromethyl)benzyl)butanamide; 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; Diazaspiro [4.4]nonane-6-yl)methyl)urea; 2-(Benzofuran-2-sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane- 7, 9 -dione ; 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-((4-(benzofuran-2-yl)phenyl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-((5-(4-fluorophenyl)pyridin-2-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-((5-(benzofuran-2-yl)pyridin-2-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-((6-(4-fluorophenyl)pyridin-3-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-((6-(benzofuran-2-yl)pyridin-3-yl)sulfonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; 2-(5-(trifluoromethyl)benzofuran-2-carbonyl)-2,6,8-triazadispiro [3.0.4 5 .3 4 ]dodecane-7,9-dione; #-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; 4-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)benzenesulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 5-(4-fluorophenyl)pyridine- 2 -sulfonamide; 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-2-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(4-fluorophenyl)pyridine- 3 -sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyridine-3-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(4-fluorobenzofuran-2-yl)pyridine-3-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(5-fluorobenzofuran- 2 -yl)pyridine- 3 -sulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(5-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; #-((2, 4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(6-methoxybenzofuran-2-yl)pyridine-3-sulfonamide; #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(3 -methylbenzofuran- 2-(3-pyridine-sulfonamide); #-((2, 4 -dioxo- 1, 3 -diazaspiro [4.4]nonane- 7 -yl)methyl)- 6-(5 -methylbenzofuran- 2 -yl)pyridine- 3 -sulfonamide; 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)pyrimidine-5-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-fluoropyridine-3-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-fluoropyridine-3-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-2-methylpyridine-3-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5-methylpyridine-3-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)- 4-(trifluoromethyl)pyridine-3-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)- 5-(trifluoromethyl)pyridine-3-sulfonamide; 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)furan-2-sulfonamide; 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiophene-2-sulfonamide; 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)thiazole-5-sulfonamide; 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-imidazole-5-sulfonamide; 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-1-methyl-1-imidazole-5-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-5- (Trifluoromethyl)benzofuran-2-carboxamide; 6-((5)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; 6-((5)-4-(3,4-difluorophenyl)-3-methylpiperazine-1-carbonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione; 4-(4,4-difluorocyclohexyl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2'-fluoro-[1,1'-biphenyl]-4-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3'-fluoro-[1,1'-biphenyl]-4-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',4'-difluoro- [ 1 , 1' -Biphenyl] -4 -sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-3',4',5'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-2',3',4'-trifluoro-[1,1'-biphenyl]-4-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4-(5-fluoropyridin-2-yl)benzenesulfonamide; 4-(2,6-difluoropyridin-3-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)benzenesulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide; >((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)->(4'-fluoro-[1,1'-biphenyl]-4-yl)acetamide; 4-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-yl)methyl)piperidine-1-sulfonamide; 4-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)piperidine-1-sulfonamide; 3-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)azetidine-1-sulfonamide; 6-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)- 4-Methylpyridine-3-sulfonamide; 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)- 4-Methylpyridine-2-sulfonamide; >((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-6-(1-inden-2-yl)pyridine-3-sulfonamide; 2-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)- 4-Methylthiazole-5-sulfonamide; and 5-(Benzofuran-2-yl)->((2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-yl)methyl)-4-methylthiophene-2-sulfonamide.

5. In claim 1, the compound of formula 1 is a compound of formula 3 below, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] In the above formula, Ri is hydrogen, halogen or allyl. One of R2 and R4 is hydrogen, and the other is and ; 3 R is hydrogen; R is hydrogen or C r C6 alkyl, or R and R are C r Can be linked to C3 alkylene to form a ring; 6 R is hydrogen; L is -CO-, -S02-, or -CONH-; R is C 6-10 Aryl or 5-10 membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxyl r C6 alkyl or C r may be substituted with C6 alkoxy; R 8 is hydrogen or C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxyl r C6 alkyl or C r may be substituted with C6 alkoxy; R is 4-10 membered heterocyclyl- C 6-10 Aryl, and at this time the above C 6-10 Aryl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r C6 alkoxy may be substituted; m is an integer from 0 to 5, and when m is 0, it is a simple bond; said heteroaryl is an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and , and said heterocyclyl is an aliphatic heterocycle containing 1 to 4 heteroatoms selected from N, 0 and .

6. In claim 5, R 7 is phenyl, benzofuranyl or indolyl, wherein said phenyl, benzofuranyl and indolyl are each independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, c r c6alkoxy, or c substituted with 1 to 3 halogens or hydroxyl r c6 alkyl or c r may be substituted with c6 alkoxy; R 8 is hydrogen or phenyl, wherein each of said phenyl is independently unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl, C r C6 alkoxy, or C substituted with 1 to 3 halogens or hydroxyl r C6 alkyl or C r may be substituted with C6 alkoxy; R is piperazinylphenyl, wherein said phenyl is unsubstituted or substituted with 1 to 3 halogens, hydroxy, C r C6 alkyl or C r A compound which may be substituted with C6 alkoxy, an isomer thereof or a pharmaceutically acceptable salt thereof.

7. In claim 5, the compound is any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: >(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4'-fluoro-[1,1'-biphenyl]-4-sulfonamide; >(2,4-dioxo-1,3-diazaspiro[4.5]decane-8-yl)-4-methoxy-1-indole-2-carboxamide; 5 -Chloro->(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; l-((S)-4-(3,5-difluorophenyl)-3-methylpiperazine-1-carbonyl)spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione; and l-((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 a compound according to any one of claims 1 to 7, an isomer thereof, or a salt thereof.

9. A pharmaceutical composition for preventing or treating liver fibrosis, comprising a compound according to any one of claims 1 to 7, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A 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 hepatic fibrosis, comprising administering to a subject a compound according to any one of claims 1 to 7, an isomer thereof, or a pharmaceutically acceptable salt thereof.

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