Novel isoindolinone derivative compounds as caspase inhibitors

Abstract

The present invention provides a novel isoindolinone derivative compound as a caspase inhibitor, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof. The novel isoindolinone derivative compound of the present invention has been confirmed to exhibit excellent activity as a caspase inhibitor by exhibiting excellent interleukin-1β (IL-1β) reducing effect and excellent apoptosis reducing effect, and therefore it has been revealed that it can be used for preventing or treating caspase-related diseases. Therefore, the novel isoindolinone derivative compounds of the present invention can be usefully used in the fields of medicine and pharmaceutical science for the prevention or treatment of caspase-related diseases.

Description

[Technical Field]

[0001] The present invention relates to a caspase inhibitor, and more particularly to a novel isoindolinone derivative compound as a caspase inhibitor. [Background technology]

[0002] Caspases are cysteine ​​proteases that exist as α2β2 tetramers, and caspase inhibitors are compounds that can inhibit the activity of caspases and thereby regulate inflammation and apoptosis induced by caspase activity. Diseases for which these compounds can be administered to eliminate or alleviate symptoms include osteoarthritis, rheumatoid arthritis, degenerative arthritis, destructive bone disease, hepatitis virus-induced liver disease, acute hepatitis, liver cirrhosis, hepatitis virus-induced brain damage, human fulminant hepatic failure, sepsis, organ transplant rejection, ischemic heart disease, dementia, stroke, AIDS-induced brain damage, diabetes, and gastric ulcers.

[0003] Among compounds with various structures known as caspase inhibitors, isoxazoline derivatives have been applied for in Korean Patent Application Nos. 10-2004-0066726, 10-2006-0013107, and 10-2008-0025123. In addition, prodrugs of caspase inhibitors based on isoxazoline derivatives have been disclosed in International Publication WO2007 / 015931 (applicant: Vertex Pharmaceuticals Incorporated, USA). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Korean Patent Application No. 10-2004-0066726 [Patent Document 2] Korean Patent Application No. 10-2006-0013107 [Patent Document 3] Korean Patent Application No. 10-2008-0025123 [Patent Document 4] International Publication No. WO2007 / 015931 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a caspase inhibitor compound with a novel structure that exhibits excellent inhibitory activity against caspases.

[0006] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating caspase-related diseases, which comprises the caspase inhibitor compound having the novel structure.

[0007] Another object of the present invention is to provide a method for preventing or treating diseases associated with caspase inhibition using the caspase inhibitor compound having the novel structure.

[0008] Another object of the present invention is to provide a use of the caspase inhibitor compound having the novel structure for the prevention or treatment of caspase-related diseases.

[0009] A further object of the present invention is to provide a method for producing the caspase inhibitor compound having the novel structure.

[0010] The problems to be solved by the present invention are not limited to the problems described above, and other technical problems not mentioned above will be clearly understood by those skilled in the art to which the present invention pertains from the following description. [Means for solving the problem]

[0011] In order to solve the above problems, according to one aspect of the present invention, there is provided an isoindolinone derivative compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0012] [ka]

[0013] In the above formula, R 1 is halogen or aryloxy substituted with 1 to 5 halogens, R 2 is hydrogen, or C 1-6 is a straight or branched chain alkyl; R 3 is a halogen or Q, and Q is one to three independent R a may or may not be replaced by Q is an aryl, aminoaryl, heteroaryl, or non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5- to 7-membered ring containing 0-3 heteroatoms; R a is C 1-6 Straight or branched chain alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, CO2R b , C.O.R. b ,CONHR b , CON(R b )2, NHR b , N(R b )2, NHCOR b , S(O)2R b or heteroaryl fused to a saturated or unsaturated 5- to 7-membered ring containing 0 to 3 heteroatoms; R b is hydrogen or C 1-6 It is a straight or branched chain alkyl.

[0014] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a caspase-related disease, comprising, as an active ingredient, an isoindolinone derivative compound represented by chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0015] In yet another aspect, the present invention provides a method for preventing or treating a caspase-related disease using the isoindolinone derivative compound represented by the chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0016] In yet another aspect, the present invention provides use of the isoindolinone derivative compound represented by the chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a caspase-related disease.

[0017] In yet another aspect, the present invention provides a pharmaceutical composition comprising an isoindolinone derivative compound represented by formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In accordance with yet another aspect of the present invention, there is provided a method for preparing the isoindolinone derivative compound represented by Formula I. [Effects of the Invention]

[0019] The novel isoindolinone derivative compounds of the present invention have been confirmed to exhibit excellent activity as caspase inhibitors by exhibiting excellent interleukin-1β (IL-1β) reducing effects and excellent apoptosis reducing effects, and have been found to be usable for the prevention or treatment of caspase-related diseases.

[0020] Therefore, the novel isoindolinone derivative compounds of the present invention can be usefully used in the fields of medicine and pharmaceuticals for the prevention or treatment of caspase-related diseases.

[0021] It should be understood that the effects of the present invention are not limited to the effects described above, but include all effects that can be inferred from the configuration of the invention described in the detailed description of the present invention or the claims. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention provides an isoindolinone derivative compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0023] [ka]

[0024] In the above formula, R 1 is halogen or aryloxy substituted with 1 to 5 halogens, R 2 is hydrogen, or C 1-6 is a straight or branched chain alkyl; R 3 is a halogen or Q, and Q is one to three independent R a may or may not be replaced by Q is an aryl, aminoaryl, heteroaryl, or non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5- to 7-membered ring containing 0-3 heteroatoms; R a is C 1-6 Straight or branched chain alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, CO2R b , C.O.R. b ,CONHR b , CON(R b )2, NHR b , N(R b )2, NHCOR b , S(O)2R b or heteroaryl fused to a saturated or unsaturated 5- to 7-membered ring containing 0 to 3 heteroatoms; R b is hydrogen or C 1-6 It is a straight or branched chain alkyl.

[0025] In one embodiment, the R 1 can be F or phenoxy substituted with 1 to 5 F.

[0026] In one embodiment, the R 2 can be hydrogen, methyl, ethyl, or straight or branched chain propyl.

[0027] In one embodiment, the R 3 is Br or Q, wherein said Q can be phenyl, pyridinyl, tetrahydropyridinyl, pyrazolyl, pyrimidinyl, dihydropyranyl, thiophenyl, pyrrolidinyl, piperazinyl, aminonaphthalenyl, naphthalenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl, or dihydroimidazopyrazinyl.

[0028] In one embodiment, the R a can be methyl, methoxy, F, trifluoromethyl, carboxy, acetyl, amino, methylsulfonyl or benzisothiazolyl.

[0029] Specific examples of the isoindolinone derivative compounds according to the present invention are as follows:

[0030] [1] 5-fluoro-4-oxo-3-(2-(1-oxo-6-phenylisoindolin-2-yl)butanamido)pentanoic acid, [2] 5-fluoro-3-(2-(6-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [3] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)pentanoic acid, [4] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [5] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(1H-pyrazol-4-yl)isoindolin-2-yl)butanamido)pentanoic acid, [6] 5-fluoro-3-(2-(6-(4-(methylsulfonyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [7] 5-fluoro-3-(2-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)butanamide-4-oxopentanoic acid, [8] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)pentanoic acid, [9] 3-(2-(6-bromo-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[10] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[11] 5-fluoro-3-(2-(6-(naphthalen-1-ylamino)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[12] 5-fluoro-3-(2-(6-(2-fluoro-4-(methylsulfonyl)phenyl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[13] 5-fluoro-3-(2-(6-(6-methoxypyridin-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[14] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)butanamide)pentanoic acid,

[15] 3-(2-(6-(3,6-dihydro-2H-pyran-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-pentanoic acid,

[16] 3-(2-(6-benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[17] 4-(2-(1-((1-carboxy-4-fluoro-3-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-3-oxoisoindolin-5-yl)pentanoic acid,

[18] 3-(2-(6-(4-acetylphenyl)-1-oxoisoindolin-2-yl)butanamido-5-fluoro-4-oxopentanoic acid,

[19] 3-(2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[20] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[21] (3-(2-(6-(2-aminopyrimidin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[22] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[23] 3-(2-(6-(2-aminopyridin-4-yl)1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[24] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[25] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[26] 3-(2-(6-benzofuran-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[27] 3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[28] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(thiophen-3-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[29] 5-fluoro-3-(2-(6-(isoquinolin-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[30] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-6-yl)isoindolin-2-yl)butanamido)pentanoic acid,

[31] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-4-yl)isoindolin-2-yl)butanamido)pentanoic acid,

[32] 3-(2-(6-(benzo[d]thiazol-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[33] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrazolo[1,5-a]pyridin-3-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[34] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-5-yl)isoindolin-2-yl)butanamido)pentanoic acid,

[35] 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[36] 5-fluoro-3-(2-(6-(isoquinolin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[37] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid,

[38] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)acetamido)pentanoic acid,

[39] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid,

[40] 3-(2-(6-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid,

[41] 3-(2-(6-(benzofuran-5-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid,

[42] 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid,

[43] 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamide) 4-oxopentanoic acid,

[44] 3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid,

[45] 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[46] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)propanamido)pentanoic acid,

[47] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)propanamide)pentanoic acid,

[48] ​​3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)propanamido-5-fluoro-4-oxopentanoic acid,

[49] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)propanamido)-5-fluoro-4-oxopentanoic acid,

[50] (S)-3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid,

[51] (S)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid,

[52] (S)-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid,

[53] (S)-4-oxo-3-((S)-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid,

[54] (R)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid,

[55] 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[56] 5-fluoro-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[57] 3-((S)-2-(5-(benzofuran-3-yl)-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[58] 3-((S)-2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[59] 3-((S)-2-(5-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[60] 3-((S)-2-(5-(benzofuran-5-yl)-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[61] 5-fluoro-3-((S)-2-(5-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid,

[62] 5-fluoro-4-oxo-3-((S)-2-(1-oxo-5-(2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamide)pentanoic acid,

[63] 3-((S)-2-(5-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid,

[64] 5-Fluoro-4-oxo-3-((S)-2-(1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)butanamide)pentanoic acid.

[0031] In defining compounds of Formula I herein, the following definitions apply unless otherwise stated.

[0032] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon having C1-C 10Alkyl is preferred, for example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0033] The term "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0034] The term "alkoxy" means an alkyloxy having 1 to 10 carbon atoms, unless otherwise specified.

[0035] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy substituted with one or more halogen atoms.

[0036] The term "heteroatom" means N, O or S.

[0037] The term "aryl" means an aromatic hydrocarbon, preferably C5-C 12 Aryl, more preferably C6-C 10 Aryl. For example, the aryl includes, but is not limited to, phenyl, naphthyl (naphthalenyl), and the like.

[0038] The term "heteroaryl" refers to a 3- to 12-membered, more preferably 5- to 10-membered, aromatic hydrocarbon ring containing one or more heteroatoms selected from N, O, and S as ring atoms, and forming a single or fused ring, which may be fused to benzo or C3-C8 cycloalkyl. Examples of heteroaryl include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, quinolinyl, indolinyl, tetrahydropyridinyl, pyrazolyl, dihydropyranyl, etc.

[0039] A non-aromatic heterocycle is a non-aromatic carbocyclic ring that contains one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring. The ring may be 5-, 6-, 7-, or 8-membered and / or fused to other rings, such as cycloalkyl or aromatic rings. Examples of such compounds include 3-1H-benzimidazol-2-one, 3-1-alkyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoic acid, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolane, and benzothiane.

[0040] Arylalkyl, alkylaryl, and heteroarylalkyl refer to groups formed by combining the above-defined aryl and alkyl, or heteroaryl and alkyl, and examples thereof include, but are not limited to, benzyl, thiophenemethyl, pyrimidinemethyl, etc.

[0041] Aryl groups include polyaromatic ring systems in which a carbocyclic aromatic or heteroaryl ring is fused to one or more other rings. Examples of such compounds include naphthyl (naphthalenyl), tetrahydronaphthyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl, or dihydroimidazopyrazinyl. Also included within the scope of the term "aryl" as used herein are groups in which one or more carbocyclic aromatic and / or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocycle, such as indanyl or tetrahydrobenzopyranyl.

[0042] The compound represented by formula I according to the present invention can be used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, and the prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. In addition, since the compound represented by formula I has chiral carbon atoms, stereoisomers exist, and such stereoisomers are also included in the scope of the present invention.

[0043] The term "prodrug" refers to a substance that is converted into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug may not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound according to the invention and its pharmaceutically acceptable salt. Yet another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group that is metabolically converted to reveal the active site.

[0044] The term "hydrate" means a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0045] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Desirable solvents in this context include solvents that are volatile, non-toxic, and / or suitable for human administration.

[0046] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers and geometric isomers (trans, cis). All of these isomers and mixtures thereof are included within the scope of the present invention.

[0047] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not induce serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt includes acid addition salts formed with acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylate salts include metal or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compounds of formula I according to the present invention can be converted into their salts by conventional methods.

[0048] The present invention also provides a method for preparing the compound of Formula I, comprising the steps of:

[0049] (1) The compound of the following chemical formula I-1 is reacted with R 3 -B(OH)2, R 3 and one of the compounds of formula Ic to prepare a compound of formula I-2: This step comprises: 1) reacting an aryl bromide compound of the following formula I-1 with R 3This step may be a Suzuki coupling reaction in which the compound of Formula I-1 is reacted with a pinacolboron compound represented by Formula Ic (Ic) to obtain an aryl-aryl compound. The catalyst used in this step may be a catalyst commonly used in Suzuki coupling reactions, such as, but not limited to, a palladium catalyst. The reaction may be carried out using a solvent commonly used in Suzuki coupling reactions at a temperature commonly used in Suzuki coupling reactions. For example, but not limited to, the reaction may be carried out in toluene or 1,4-dioxane solvent at a high temperature (80-110°C) for a suitable reaction time (e.g., about 10 hours). This step may also be a Buchwald reaction in which the compound of Formula I-1 is reacted with an amine compound to obtain an aryl-amine compound. The catalyst used in this step may be a catalyst commonly used in Buchwald reactions, such as, but not limited to, a palladium catalyst. The reaction may be carried out using a solvent commonly used in Buchwald reactions at a temperature commonly used in Buchwald reactions. For example, but not limited to, the reaction may be carried out in toluene solvent at a high temperature (e.g., 80°C) for a suitable reaction time (e.g., about 10 hours).

[0050] (2) Hydrolyzing the compound of the following formula I-2 to prepare a compound of the following formula I-3: This step is a hydrolysis reaction in which the compound of formula I-2 is reacted with lithium hydroxide. The solvent used in this step may be a solvent commonly used in hydrolysis reactions, such as a tetrahydrofuran-water solution mixed solvent, and the reaction is carried out at an appropriate temperature (e.g., room temperature) for an appropriate reaction time (e.g., about 24 hours) to obtain the compound of formula I-3.

[0051] (3) reacting a compound of the following formula I-3 with a compound of the following formula I-4 to prepare a compound of the following formula I-5: In this step, a compound of Formula I-3 having a carboxylic acid group is reacted with a compound of Formula I-4 having an amine group to form an amide bond. The solvent used in this step may be a solvent commonly used in amide bond reactions, such as DMF, and the reaction may be carried out at an appropriate temperature (e.g., room temperature).

[0052] (4) Hydrolyzing the compound of the following formula I-5 to prepare a compound of the following formula I-6: This step is a hydrolysis reaction in which the compound of formula I-5 is reacted with lithium hydroxide. The solvent used in this step may be a solvent commonly used in hydrolysis reactions, such as a tetrahydrofuran-water solution mixed solvent, and the reaction is carried out at an appropriate temperature (e.g., room temperature) for an appropriate reaction time (e.g., about 24 hours) to obtain the compound of formula I-6.

[0053] (5) treating the compound of the following formula I-6 with an acid: This step is a deprotection / grouping reaction in which a dimethylketone compound of Formula I-6 is treated with an acid to obtain a ketone compound. The solvent used in this step may be a solvent commonly used in deprotection / grouping reactions, such as, but not limited to, aqueous hydrochloric acid.

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] In the above formula, R 1 , R 2 , R 3 is the same as that of Formula I above.

[0062] In one embodiment, the compound of formula I-1 can be obtained by reacting a compound of formula Ia with a compound of formula Ib:

[0063] [ka]

[0064] [ka]

[0065] In the above formula, R 2 is the same as that of Formula I above.

[0066] Reaction Schemes 1 to 64 are shown as examples of methods for preparing the compound of Formula I of the present invention, but the methods for preparing the compound of Formula I of the present invention are not limited to these methods. The preparation methods of Reaction Schemes 1 to 64 are merely illustrative and can be easily modified by those skilled in the art depending on the specific substituents.

[0067] The present invention also provides a pharmaceutical composition for preventing or treating a caspase-related disease, comprising, as an active ingredient, an isoindolinone derivative compound represented by chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0068] The present invention also provides a method for treating or preventing a caspase-related disease by administering to a patient in need thereof an isoindolinone derivative compound represented by chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0069] The present invention also provides use of the isoindolinone derivative compound represented by the chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of a caspase-related disease.

[0070] In one embodiment, the caspase-related disease may be osteoarthritis or pain.

[0071] The caspase inhibitory activity of the isoindolinone derivative compounds of the present invention was measured, and it was confirmed that the caspase inhibitory activity was exhibited by a decrease in interleukin-1β (IL-1β) or a decrease in apoptosis.

[0072] The present invention also provides a pharmaceutical composition comprising the isoindolinone derivative compound represented by formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0073] The additives may contain pharmaceutically acceptable carriers or diluents, and can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, and sterile injection solutions by conventional methods.

[0074] The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. Also included are diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. Oral solid preparations include tablets, pills, powders, granules, capsules, etc. These solid preparations contain at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., and may also contain lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, etc., and may contain diluents such as water and liquid paraffin, wetting agents, sweeteners, flavorings, preservatives, etc. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases that can be used include witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerogelatin, etc.

[0075] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration of administration, and can be adjusted appropriately for each patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 100 mg / kg per day, and can be administered once or in several divided doses per day. Furthermore, the pharmaceutical composition of the present invention can contain the active ingredient in a weight percentage of 0.001 to 90% of the total weight of the composition.

[0076] The pharmaceutical compositions of the present invention can be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, intraperitoneally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebroventricular injection.

[0077] The present invention will be described in more detail below with reference to examples and experimental examples. However, the following examples and experimental examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0078] Example 1. 5-fluoro-4-oxo-3-(2-(1-oxo-6-phenylisoindolin-2-yl)butanamido)pentanoic acid

[0079] [ka]

[0080] Step 1-1 (Method A): 6-Bromoindolin-1-one (500 mg, 2.36 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (99.4 mg, 2.59 mmol) and methyl (R)-2-bromobutanoate (426.86 mg, 2.36 mmol) were added and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target compound 1-1 (324 mg, 44%).

[0081] Step 1-2 (Method B): Compound 1-1 (150 mg, 0.48 mmol) was dissolved in 1,4-dioxane (10 mL). Phenylboronic acid (70.3 mg, 0.58 mmol), 2 M aqueous potassium carbonate (0.6 mL, 1.2 mmol), and tetrakis(triphenylphosphine)palladium (27.76 mg, 0.024 mmol) were added and the mixture was stirred at 110 °C for 10 h. After completion of the reaction, brine (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to give the target compound 1-2 (108 mg, 72%).

[0082] Step 1-3 (Method C): Compound 1-2 (108 mg, 0.349 mmol) was dissolved in tetrahydrofuran / water (3 / 1, 150 mL), followed by addition of lithium hydroxide (33.44 mg, 1.39 mmol) and stirring at room temperature for 24 hours. After completion of the reaction, the tetrahydrofuran solvent was removed by concentration. The mixture was acidified (pH 1) with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to yield the target compound 1-3 (99 mg, 96%).

[0083] Step 1-4 (Method D): Compound 1-3 (75 mg, 0.254 mmol) was dissolved in dichloromethane (10 mL). To the solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.68 mg, 0.254 mmol), compound 1-4 (synthesized by a known method [WO2006 / 090997]) (59.53 mg, 0.267 mmol), 1-hydroxybenzotriazole (34.32 mg, 0.254 mmol), and N,N-diisopropylethylamine (DIPEA, 39.48 mg, 0.305 mmol). The mixture was stirred at room temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to obtain the target compound 1-5 (93 mg, 73%).

[0084] Step 1-5 (Method E): Compound 1-5 (93 mg, 0.186 mmol) was dissolved in tetrahydrofuran / water (3 / 1, 50 mL), followed by addition of lithium hydroxide (17.8 mg, 0.743 mmol) and stirring at room temperature for 24 hours. After completion of the reaction, the tetrahydrofuran solvent was removed by concentration. The mixture was acidified (pH 1) with 1N aqueous hydrochloric acid and extracted with ethyl acetate (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to yield the target compound 1-6 (69 mg, 78%).

[0085] Step 1-6 (Method F): Compound 1-6 (69 mg, 0.146 mmol) was dissolved in acetic acid (2 mL), followed by the addition of 6N aqueous hydrochloric acid (2 mL) and stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using column chromatography to obtain the target compound 1 (17 mg, 27%).

[0086] 1 H NMR(400MHz,DMSO-d6) d 12.96(s,1H), 8.01-7.82(m,2H), 7.80-7.61(m,3H), 7.61-7.20(m,4H), 4.86-4.31(m,6H), 2.79-2.22(m, 2H), 2.23-1.64(m,2H), 0.94-0.67m,3H).

[0087] MS(ESI,LR) Calculated for C 23 H 24 FN2O5(MH + ):427.2, found:427.2.

[0088] Example 2. 5-fluoro-3-(2-(6-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0089] [ka]

[0090] Compound 1-1 and naphthalene-1-boronic acid were used as starting materials and the target compound 2 (21 mg) was obtained using Methods B / C / D / E / F in sequence.

[0091] 1 H NMR(400MHz,DMSO-d6)d 8.88-8.76(m,1H), 8.01(dd,J=13.73, 8.24Hz, 2H), 7.81-7.65(m,4H), 7.64-7.43( m,4H), 5.28-4.39(m,6H), 2.74-2.42(m,2H), 2.21-1.70(m,2H), 0.95-0.70(m,3H).

[0092] MS(ESI,LR) Calculated for C 27 H 26FN2O5(MH + ):477.2, found:477.2.

[0093] Example 3. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0094] [ka]

[0095] Step 3-1 (Method B'): Compound 1-1 (150 mg, 0.481 mmol) was dissolved in toluene (10 mL) in a sealed tube, followed by the addition of cesium carbonate (172.22 mg, 0.529 mmol), palladium acetate (1.08 mg, 0.005 mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (59.84 mg, 0.096 mmol), and pyrrolidine (47.84 mg, 0.673 mmol). The tube was then sealed and stirred at 80°C for 10 hours. After completion of the reaction, the mixture was diluted with brine (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to obtain the target compound 3-1 (109 mg, 75%).

[0096] Step 3-2: Compound 3-1 (109 mg, 0.36 mmol) was purified by Method C to give the target compound 3-2 (91 mg, 86%).

[0097] Step 3-3 (Method D'): Compound 3-2 (91 mg, 0.316 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of HATU (144 mg, 0.379 mmol) and DIPEA (61.33 mg, 0.473 mmol) and stirring at room temperature for 10 minutes. Compound 1-4 (73.97 mg, 0.331 mmol) was added to the reaction solution and stirred at room temperature for 24 hours. After completion of the reaction, saturated aqueous sodium bicarbonate (30 mL) was added and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target compound 3-3 (111 mg, 71%). [HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate,Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium),DIPEA(N,N-Diisopropylethylamine)] Step 3-4 / 3-5: Compound 3-3 was used as a starting material and the target compound 3 (31 mg) was obtained by methods E and F in sequence.

[0098] 1 H NMR(400MHz,MeOD)d 12.46(s,1H), 8.81-8.44(m,1H), 7.40-7.20(m,1H), 6.84-6.60(m,2H), 5.35-3.87( m,6H), 3.40-3.09(m,4H), 2.78-2.34(m,2H), 2.05-1.57(m,6H), 0.90-0.65(m,3H).

[0099] MS(ESI, LR) Calculated for C 21 H 27 FN3O5(MH + ):420.2, found:420.2.

[0100] Example 4. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0101] [ka]

[0102] Compound 1-1 and pyridine-3-boronic acid were used as starting materials and the target compound 4 (31 mg) was obtained sequentially using Methods B / C / D' / E / F.

[0103] 1 H NMR(400MHz,DMSO-d6)d 8.84(s,1H), 8.59-8.47(m,1H), 8.19-7.81(m,4H), 7.72(t,J=7.02Hz,1H), 7.55(t,J=7 .63Hz,1H), 5.26-4.03(m,6H), 2.96-2.54(m,2H), 2.20-1.81(m,2H), 1.07-0.79(m,3H).

[0104] MS(ESI,LR) Calculated for C 22 H 23 FN3O5(MH + ):428.2, found:428.1.

[0105] Example 5. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(1H-pyrazol-4-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0106] [ka]

[0107] Compound 1-1 and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials and the target compound 5 (21 mg) was obtained using Methods B / C / D' / E / F in sequence.

[0108] 1 H NMR(400MHz,DMSO-d6) d 12.86(s,2H), 8.89-8.61(m,1H), 8.18(s,2H), 7.98-7.73(m, 2H), 7.58(d,J=7.63Hz,1H), 5.32-4.28(m,6H), 2.84-2.37(m,2H), 2.10-1.68(m,2H), 0.93-0.70(m,3H).

[0109] MS(ESI,LR) Calculated for C 20 H 22 FN4O5(MH + )417.1, found:417.1.

[0110] Example 6. 5-fluoro-3-(2-(6-(4-(methylsulfonyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0111] [ka]

[0112] Step 6-1 (Method B): Compound 1-1 (150 mg, 0.481 mmol) was dissolved in toluene (15 mL) and then cesium carbonate (172.22 mg, 0.529 mmol), tetrakis(triphenylphosphine)palladium (27.76 mg, 0.024 mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (59.84 mg, 0.096 mmol), and tert-butyl 1-piperazinecarboxylate (47.84 mg, 0.673 mmol) were added. The mixture was sealed and stirred at 80 °C for 10 hours. After completion of the reaction, the mixture was diluted with brine (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using column chromatography to obtain the target compound 6-1 (120 mg, 60%).

[0113] Step 6-2: Compound 6-1 (120 mg, 0.287 mmol) was dissolved in ethyl acetate (5 mL), and then hydrogen chloride solution (4.0 M in 1,4-dioxane, 2 mL) was added and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated to give compound 6-2 (95 mg, 93%) as a white solid.

[0114] Step 6-3: Compound 6-2 (95 mg, 0.268 mmol) was dissolved in dichloromethane (30 mL), and methanesulfonyl chloride (33.83 mg, 0.295 mmol) and triethylamine (54.33 mg, 0.537 mmol) were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with water (40 mL) and extracted with dichloromethane (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target compound 6-3 (88 mg, 82%).

[0115] Step 6-4 / 6-5 / 6-6 / 6-7: Compound 6-3 (88 mg, 0.223 mmol) was reacted sequentially using Method C / D / E / F to obtain the target compound 6 (21 mg).

[0116] 1 H NMR(400MHz, DMSO-d6) d 8.72-8.58(m, 1H), 7.46(dd,J=8.39,4.20Hz,1H), 7.29(d,J=8.39Hz,1H), 7.20(dd,J=5.72,2.29Hz,1 H), 5.36-4.29(m,6H), 3.55-3.11(m,8H), 2.93(s,3H), 2.59-2.34(m,2H), 2.03-1.62(m, 2H), 0.90-0.64(m,3H).

[0117] MS(ESI,LR) Calculated for C 22 H 30 FN4O7S(MH + ):513.2, found:513.2.

[0118] Example 7. 5-fluoro-3-(2-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)butanamido-4-oxopentanoic acid

[0119] [ka]

[0120] Step 7-1 [Step 7-1]: Compound 1-1 (150 mg, 0.48 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (178.3 mg, 0.58 mmol) using Method B to obtain the target compound 7-1 (124 mg, 62%).

[0121] Step 7-2: Compound 7-1 (124 mg, 0.297 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride solution (4.0 M in 1,4-dioxane, 2 mL) was added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated to give the target compound 7-2 (99 mg, 95%).

[0122] Step 7-3: Compound 7-2 (99 mg, 0.282 mmol) was dissolved in dichloromethane (30 mL), and methanesulfonyl chloride (35.56 mg, 0.31 mmol) and triethylamine (57.11 mg, 0.564 mmol) were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with water (40 mL) and extracted with dichloromethane (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target compound 7-3 (89 mg, 80%).

[0123] Step 7-4 / 7-5 / 7-6 / 7-7: Compound 7-3 (89 mg, 0.227 mmol) was reacted sequentially using Methods C / D / E / F to obtain the target compound 7 (19 mg).

[0124] 1 H NMR (400MHz, DMSO-d6) d 12.49(s,1H), 8.87-8.69(m,1H), 7.79-7.50(m,3H), 6.31(s, 1H), 5.34-4.23(m,6H), 3.88(s,2H), 3.40(t, J=5.72Hz,2H), 2.95(s,3H), 2.87-2.35(m,4H), 2.10-1.64(m,2H), 0.93-0.66(m,3H).

[0125] MS(ESI,LR) Calculated for C 23 H 29 FN3O7S(MH + ):510.2, found:510.1.

[0126] Example 8. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0127] [ka]

[0128] Compound 1-1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one were used as starting materials and the target compound 8 (19 mg) was obtained sequentially using Methods B / C / D' / E / F.

[0129] 1 H NMR(400MHz,DMSO-d6)d 10.80-10.64(m,2H), 8.80-8.64(m,1H), 7.90-7.74(m,2H), 7.70-7.58(m,1H), 7.28(d,J=7.93H) z,1H), 7.20(s,1H), 7.01(d,J=7.93Hz,1H), 5.25-4.32(m,6H), 2.70-2.39(m,2H), 2.14-1.64(m, 2H), 0.95-0.68(m,3H).

[0130] MS(ESI,LR) Calculated for C 24 H 23 FN4O6(MH + ):483.2, found:483.0.

[0131] Example 9. 3-(2-(6-bromo-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0132] [ka]

[0133] Compound 1-1 was used as the starting material and the target compound 9 (23 mg) was obtained using Methods C / D' / E / F in sequence.

[0134] 1 H NMR(400MHz,DMSO-d6) d 12.51(s,1H), 8.89-8.67(m,1H), 7.94-7.73(m,2H), 7.65-7.50(m,1H), 5.36-4.23(m,6H), 2.90-2.34(m, 2H), 2.10-1.67(m,2H), 0.94-0.71(m,3H).

[0135] MS(ESI,LR) Calculated for C 17 H 19 BrFN2O5(MH + ):429.0, found:429.0.

[0136] Example 10. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0137] [ka]

[0138] Compound 1-1 and 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine were used as starting materials and the target compound 10 (31 mg) was obtained using Methods B' / C / D / E / F in sequence.

[0139] 1 H NMR(400MHz,DMSO-d6)d 12.58(s,1H), 8.92-8.66(m,1H), 7.79(s,1H), 7.64-7.14(m, 3H), 5.39-3.67(m,12H), 2.97-2.24(m,2H), 2.14-1.62(m,2H), 1.05-0.60(m,3H).

[0140] MS(ESI,LR) Calculated for C 24 H 26 F4N5O5(MH + ):540.2, found:540.1.

[0141] Example 11. 5-fluoro-3-(2-(6-(naphthalen-1-ylamino)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0142] [ka]

[0143] Compound 1-1 and 1-naphthylamine were used as starting materials and the target compound 11 (18 mg) was obtained using Methods B' / C / D / E / F in sequence.

[0144] 1H NMR(400MHz,DMSO-d6) d 12.18(s,1H), 8.55-8.41(m,1H), 8.19(d,J=8.77Hz,1H), 8.12(d,J=8.39Hz,1H), 7.92(d,J =8.01Hz,1H), 7.61(d,J=8.01Hz,1H), 7.56-7.39(m,4H), 7.35(d,J=7.25Hz,1H), 7.28(d,J=7.63Hz) ,1H), 7.14(s,1H), 4.77-4.17(m,6H), 2.70-2.25(m,2H), 1.95-1.58(m,2H), 0.79(t,J=7.25Hz,3H).

[0145] MS(ESI,LR) Calculated for C 27 H 27 FN3O5(MH + ):492.2, found:492.1.

[0146] Example 12. 5-fluoro-3-(2-(6-(2-fluoro-4-(methylsulfonyl)phenyl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0147] [ka]

[0148] Compound 1-1 and (2-fluoro-4-(methylsulfonyl)phenyl)boronic acid were used as starting materials and the target compound 12 (32 mg) was obtained sequentially using Methods B / C / D / E / F.

[0149] 1H NMR(400MHz,DMSO-d6) d 7.99-7.72(m,4H), 7.67-7.48(m,3H), 5.34-4.23(m,6H), 3.34(s,3H), 2.91-2.40(m,2H), 2.15-1.68(m, 2H), 0.96-0.75(m,3H).

[0150] MS(ESI,LR) Calculated for C 24 H 25 F2N2O7S(MH + ):523.1, found:523.1.

[0151] Example 13. 5-fluoro-3-(2-(6-(6-methoxypyridin-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0152] [ka]

[0153] Compound 1-1 and (6-methoxypyridin-3-yl)boronic acid were used as starting materials and the target compound 13 (31 mg) was obtained sequentially using Methods B / C / D / E / F.

[0154] 1 H NMR(400MHz,DMSO-d6)d 12.53(s,1H), 8.54(s,1H), 8.10(d,J=8.85Hz,1H), 7.95-7.80(m,2H), 7.74-7.50(m,2H), 6.93(d,J=8 .54Hz,1H), 5.35-4.22(m,6H), 3.90(s,3H), 2.91-2.37(m,2H), 2.14-1.67(m,2H), 0.94-0.73(m,3H).

[0155] MS(ESI,LR) Calculated for C 23 H 25 FN3O6(MH + ):458.2, found:458.1.

[0156] Example 14. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)butanamido)pentanoic acid

[0157] [ka]

[0158] Compound 1-1 and (4-(trifluoromethyl)phenyl)boronic acid were used as starting materials and the target compound 14 (28 mg) was obtained sequentially using Methods B / C / D / E / F.

[0159] 1 H NMR(400MHz,DMSO-d6) d 12.93(s,1H), 8.18-7.37(m,8H), 5.33-4.30(m,6H), 2.78-2.23(m,2H), 2.25-1.62(m,2H), 1.00-0.66(m, 3H).

[0160] MS(ESI,LR) Calculated for C 24 H 23 F4N2O5(MH + ):495.1, found:495.1.

[0161] Example 15. 3-(2-(6-(3,6-dihydro-2H-pyran-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-pentanoic acid

[0162] [ka]

[0163] Compound 1-1 and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were used as starting materials and the target compound 15 (18 mg) was obtained using Methods B / C / D / E / F in sequence.

[0164] 1 H NMR(400MHz,DMSO-d6)d 7.79-7.69(m,1H), 7.67-7.50(m,3H), 6.86(s,1H), 4.87-3.78(m,6H), 3.75-3.54(m,2H), 3. 49-3.27(m,2H), 1.85-1.61(m,2H), 1.62-1.44(m,2H), 1.41-1.28(m,2H), 0.97-0.73(m,3H).

[0165] MS(ESI,LR) Calculated for C 22 H 26 FN2O6(MH + ):433.2, found:433.1.

[0166] Example 16. 3-(2-(6-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0167] [ka]

[0168] Compound 1-1 and benzo[b]thiophen-3-ylboronic acid were used as starting materials and the target compound 16 (23 mg) was obtained sequentially using Methods B / C / D / E / F.

[0169] 1 H NMR(400MHz,DMSO-d6) d 12.55(s,1H), 8.17-8.07(m,1H), 8.01-7.73(m,6H), 7.53-7.41(m,2H), 5.37-4.41(m,6H), 2.94-2.36(m, 2H), 2.16-1.61(m,2H), 1.00-0.75(m,3H).

[0170] MS(ESI,LR) Calculated for C 25 H 24 FN2O5S(MH + ):483.1, found:483.1.

[0171] Example 17. 4-(2-(1-((1-carboxy-4-fluoro-3-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-3-oxoisoindolin-5-yl)pentanoic acid [4-(2-(1-((1-carboxy-4-fluoro-3-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-3-oxoisoindolin-5-yl)benzoic acid]

[0172] [ka]

[0173] Compound 1-1 and (4-(tert-butoxycarbonyl)phenyl)boronic acid were used as starting materials and the target compound 17 (18 mg) was obtained sequentially using Methods B / C / D / E / F.

[0174] 1 H NMR(400MHz,DMSO-d6) d 12.97(s,2H), 8.24-7.58(m,8H), 5.03-4.26(m,6H), 2.91-2.34(m,2H), 2.19-1.63(m,2H), 1.08-0.69(m, 3H).

[0175] MS(ESI,LR) Calculated for C 24 H 24 FN2O7(MH + ):471.1, found:471.1.

[0176] Example 18. 3-(2-(6-(4-acetylphenyl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0177] [ka]

[0178] Compound 1-1 and (4-acetylphenyl)boronic acid were used as starting materials and the target compound 18 (29 mg) was obtained sequentially using Methods B / C / D / E / F.

[0179] 1 H NMR(400MHz,DMSO-d6) d 8.19-7.31(m,8H), 5.33-4.13(m,6H), 2.62(s,3H), 2.84-2.18(m,2H), 2.12-1.33(m,2H), 0.95-0.68(m,3H).

[0180] MS(ESI, LR) Calculated for C 25 H 26 FN2O6(MH +):469.2, found:469.1.

[0181] Example 19. 3-(2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0182] [ka]

[0183] Compound 1-1 and 3-(piperazin-1-yl)benzo[d]isothiazole were used as starting materials and the target compound 19 (22 mg) was obtained using Methods B″ / C / D / E / F in sequence.

[0184] 1 H NMR(400MHz,DMSO-d6)d 8.20-8.03(m, 2H), 7.66-7.42(m,4H), 7.41-7.30(m,1H), 7.28-7.20(m,1H), 5.31-4.10(m,6H), 3 .62(s,4H), 3.44(s,4H), 2.87-2.34(m,2H), 2.14-1.67(m,2H), 0.96-0.73(m,3H).

[0185] MS(ESI,LR) Calculated for C 28 H 31 FN5O5S(MH + ):568.2, found:568.2.

[0186] Example 20. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0187] [ka]

[0188] Compound 1-1 and (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used as starting materials and the target compound 20 (31 mg) was obtained sequentially using Methods B / C / D / E / F.

[0189] 1 H NMR(400MHz,DMSO-d6)d 12.89(s,1H), 9.18(s,1H), 8.83(s,1H), 8.47(d,J=6.10Hz,1H), 8.18-8.06(m,2H), 8.01(d,J=8.01Hz,1 H), 7.80(d,J=7.63Hz,1H), 5.40-4.40(m,6H), 2.85-2.39(m,2H), 2.16-1.72(m,2H), 0.98-0.77(m,3H).

[0190] MS(ESI, LR) Calculated for C 23 H 22 F4N3O5(MH + ):496.1, found:496.1.

[0191] Example 21 (3-(2-(6-(2-aminopyrimidin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0192] [ka]

[0193] Compound 1-1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine were used as starting materials and the target compound 21 (17 mg) was obtained sequentially using Methods B / C / D / E / F.

[0194] 1 H NMR(400MHz,DMSO-d6)d 12.57(s,1H), 8.87-8.69(m,1H), 8.64(s,2H), 7.98-7.76(m,2H), 7.67(d,J=7.93Hz,1H), 6.82(s,2H), 5.35-4.20(m,6H), 2.95-2.37(m,2H), 2.14-1.68(m,2H), 0.98-0.71(m,3H).

[0195] MS(ESI,LR) Calculated for C 21 H 23 FN5O5(MH + ):444.2, found:444.1.

[0196] Example 22. 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0197] [ka]

[0198] Compound 1-1 and benzofuran-3-ylboronic acid were used as starting materials and the target compound 22 (24 mg) was obtained sequentially using Methods B / C / D / E / F.

[0199] 1 H NMR(400MHz,DMSO-d6) d 12.50(s,1H), 8.87-8.73(m,1H), 8.50(s,1H), 8.06-7.79(m, 2H), 7.93(d,J=6.71Hz,1H), 7.80-7.73(m,1H), 7.69(d,J=7.32Hz,1H), 7.46-7.35( m,2H), 5.33-4.25(m,6H), 2.92-2.36(m,2H), 2.11-1.70(m,2H), 0.96-0.74(m,3H).

[0200] MS(ESI,LR) Calculated for C 25 H 24 FN2O6(MH + ):467.2, found:467.1.

[0201] Example 23. 3-(2-(6-(2-aminopyridin-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0202] [ka]

[0203] Compound 1-1 and (2-aminopyridin-4-yl)boronic acid were used as starting materials, and the target compound 23 (4 mg) was obtained using Methods B / C / D / E / F in sequence.

[0204] MS(ESI,LR) Calculated for C 22 H 24 FN4O5(MH + ):443.2, found:443.0. Example 24. 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0205] [ka]

[0206] Using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 6-bromoisoindolin-1-one as starting materials, the target compound 24 (28 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0207] 1 H NMR(400MHz,DMSO-d6)d 12.76(s,1H), 8.27(d,J=4.58Hz,1H), 7.96(d,J=4.58Hz,1H), 7.91-7.72 (m,2H), 7.68-7.47(m,2H), 5.39-4.22(m,6H), 3.87(s,3H), 2.91-2.39(m, 2H), 2.15-1.69(m,2H), 1.02-0.74(m,3H).

[0208] MS(ESI,LR) Calculated for C 21 H 24 FN4O5(MH + ):431.2, found:431.2.

[0209] Example 25. 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0210] [ka]

[0211] Using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 6-bromoisoindolin-1-one as starting materials, the target compound 25 (21 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0212] 1 H NMR(400MHz,DMSO-d6)d 8.87-8.68(m, 1H), 8.03(t,J=8.01Hz,2H), 7.75(d,J=2.29Hz,1H), 7.65-7.47(m,1H), 6.87-6.68(m,1H) , 5.28-4.27(m,6H), 3.89(s,3H), 2.77-2.25(m,2H), 2.17-1.62(m,2H), 1.00-0.58(m,3H).

[0213] MS(ESI,LR) Calculated for C 21 H 24 FN4O5(MH + ):431.2, found:431.2.

[0214] Example 26. 3-(2-(6-benzofuran-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0215] [ka]

[0216] Using benzofuran-5-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 26 (19 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0217] 1 H NMR(400MHz,DMSO-d6) d 8.82-8.63(m, 1H), 8.11-7.85(m,4H), 7.77-7.54(m,3H), 7.01(s,1H), 5.28-4.23(m,6H), 2.76-2.25(m, 2H), 2.13-1.63(m,2H), 0.95-0.62(m,3H).

[0218] MS(ESI,LR) Calculated for C 25 H 22 FN2O6(MH + ):467.2, found:467.1.

[0219] Example 27. 3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0220] [ka]

[0221] Using (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 27 (21 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0222] 1 H NMR(400MHz,DMSO-d6)d 8.79-8.63(m, 1H), 7.82(t,J=9.16Hz,2H), 7.68-7.55(m,1H), 7.22-7.12(m,2H), 6.95(d,J=8.01Hz,1H), 5.27-4.32(m,6H), 4.28(s,4H), 2.77-2.29(m, 2H), 2.16-1.62(m,2H), 0.93-0.62(m,3H).

[0223] MS(ESI,LR) Calculated for C 25 H 26 FN2O7(MH + ):485.2, found:485.2.

[0224] Example 28. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(thiophen-3-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0225] [ka]

[0226] Using thiophen-3-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 28 (27 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0227] 1 H NMR(400MHz,MeOD) d 8.20-7.34(m,7H), 5.26-4.22(m,6H), 2.95-2.35(m,2H), 2.31-1.75(m,2H), 1.11-0.73(m,3H).

[0228] MS(ESI,LR) Calculated for C 21 H 22 FN2O5S(MH + ):433.1, found:433.1.

[0229] Example 29. 5-fluoro-3-(2-(6-(isoquinolin-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0230] [ka]

[0231] Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline and 6-bromoisoindolin-1-one as starting materials, the target compound 29 (31 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0232] 1 H NMR(400MHz,DMSO-d6)d 12.90(s,1H), 9.35(s,1H), 8.45(s,1H), 8.21(d,J=7.63Hz,1H), 7.86-7.68(m,5H), 7.63- 7.47(m,2H), 5.32-4.21(m,6H), 2.90-2.36(m,2H), 2.14-1.71(m,2H), 0.99-0.73(m,3H).

[0233] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.2.

[0234] Example 30. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-6-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0235] [ka]

[0236] Using quinolin-6-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 30 (29 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0237] 1 H NMR(400MHz,DMSO-d6)d 12.92(s,1H), 8.99-8.89(m,1H), 8.55-8.39(m,2H), 8.26-8.08(m,4H), 7.89-7.74(m,1H), 7. 72-7.51(m,2H), 5.39-4.36(m,6H), 2.95-2.39(m,2H), 2.20-1.68(m,2H), 1.00-0.76(m,3H).

[0238] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.1.

[0239] Example 31. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-4-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0240] [ka]

[0241] Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline and 6-bromoisoindolin-1-one as starting materials, the target compound 31 (27 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0242] 1 H NMR(400MHz,DMSO-d6) d 12.99(s,1H), 8.98(s,1H), 8.13(d,J=7.32Hz,1H), 7.93-7.75(m,4H), 7.68-7.48(m,4H), 5.36-4.51(m, 6H), 2.89-2.38(m,2H), 2.18-1.78(m,2H), 1.03-0.76(m,3H).

[0243] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:477.5.

[0244] Example 32. 3-(2-(6-(benzo[d]thiazol-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0245] [ka]

[0246] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole and 6-bromoisoindolin-1-one as starting materials, the target compound 32 (24 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0247] 1 H NMR(400MHz,DMSO-d6)d 9.46(s,1H), 8.61-8.38(m,2H), 8.28(d,J=8.24Hz,1H), 8.09-8.00(m,2H), 7.87(d,J=8.2 4Hz,1H), 7.75(d,J=7.93Hz,1H), 5.54-4.24(m,6H), 2.18-1.66(m,2H), 0.97-0.76(m,3H).

[0248] MS(ESI,LR) Calculated for C 24 H 23 FN3O5S(MH + ):484.1, found:483.4 Example 33. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrazolo[1,5-a]pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0249] [ka]

[0250] Using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine and 6-bromoisoindolin-1-one as starting materials, the target compound 33 (20 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0251] 1 H NMR(400MHz,DMSO-d6)d 12.94(s,1H), 8.76(d,J=7.02Hz,1H), 8.47(s,1H), 8.05-7.89(m,3H), 7.70(d,J=7.63Hz,1H), 7.37(t,J=7.0 2Hz,1H), 6.98(t,J=6.41Hz,1H), 5.35-4.28(m,6H), 2.93-2.41(m,2H), 2.16-1.66(m,2H), 1.00-0.75(m,3H).

[0252] MS(ESI,LR) Calculated for C 24 H 24 FN4O5(MH + ):467.2, found:467.1.

[0253] Example 34. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-5-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0254] [ka]

[0255] Using quinolin-5-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 34 (31 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0256] 1H NMR(400MHz,DMSO-d6)d 12.98(s,1H), 8.95(d,J=3.66Hz,1H), 8.18(d,J=8.24Hz,1H), 8.10(d,J=8.54Hz,1H), 7.91-7.71(m,4H), 7.62(d,J=7. 02Hz,1H), 7.53(dd,J=8.39,3.66Hz,1H), 5.32-4.52(m,6H), 2.91-2.41(m,2H), 2.18-1.72(m,2H), 1.00-0.78(m,3H).

[0257] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.2.

[0258] Example 35. 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0259] [ka]

[0260] Starting from isoquinolin-8-ylboronic acid and 6-bromoisoindolin-1-one, the target compound 35 (19 mg) was obtained using Methods B / A / C / D' / E / F in sequence.

[0261] 1 H NMR(400MHz,DMSO-d6)d 9.14(s,1H), 8.59-8.46(m,1H), 8.05(d,J=7.63Hz,1H), 7.96-7.72(m,6H), 7.66(d,J=7 .63Hz,1H), 5.35-4.47(m,6H), 2.85-2.38(m,2H), 2.16-1.75(m,2H), 0.98-0.75(m,3H).

[0262] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.2.

[0263] Example 36. 5-fluoro-3-(2-(6-(isoquinolin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0264] [ka]

[0265] Starting from isoquinolin-5-ylboronic acid and 6-bromoisoindolin-1-one, the target compound 36 (23 mg) was obtained using Methods B / A / C / D' / E / F in sequence.

[0266] 1 H NMR(400MHz,DMSO-d6)d 9.42(s,1H), 8.50(d,J=5.80Hz,1H), 8.24-8.18(m,1H), 7.84-7.73(m,6H), 7.65(d,J=4 .88Hz,1H), 5.34-4.50(m,6H), 2.84-2.30(m,2H), 2.17-1.78(m,2H), 0.96-0.80(m,3H).

[0267] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.1.

[0268] Example 37. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0269] [ka]

[0270] Using quinolin-3-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 37 (25 mg) was obtained sequentially using Methods B / A / C / D' / E / F.

[0271] 1 H NMR(400MHz,DMSO-d6)d 12.60(s,1H), 9.32(s,1H), 8.78(s,1H), 8.35-7.97(m,4H), 7.95-7.49(m,4 H), 5.40-4.28(m,6H), 2.94-2.31(m,2H), 2.19-1.69(m,2H), 1.00-0.61(m, 3H).

[0272] MS(ESI,LR) Calculated for C 26 H 25 FN3O5(MH + ):478.2, found:478.2.

[0273] Example 38. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)acetamido)pentanoic acid

[0274] [ka]

[0275] Using methyl 2-bromoacetate and 6-bromoisoindolin-1-one as starting materials, the target compound 38 (23 mg) was obtained using Methods A / B / C / D / E / F in sequence.

[0276] 1 H NMR(400MHz,DMSO-d6)d 12.23(s,1H), 10.72(s,2H), 8.41(s,1H), 7.98-7.77(m,2H), 7.66(s,1H), 7 .37-7.14(m,2H), 7.11-6.94(m,1H), 5.48-3.94(m,7H), 3.59-2.69(m,2H).

[0277] MS(ESI,LR) Calculated for C 22 H 20 FN4O6(MH + ):455.1, found:455.1.

[0278] Example 39. 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid

[0279] [ka]

[0280] Compound 38-1 and benzofuran-3-ylboronic acid were used as starting materials and the target compound 39 (33 mg) was obtained sequentially using Methods B / C' / D / E / F.

[0281] 1H NMR(400MHz,DMSO-d6) d 12.93(s,1H), 8.52(s,1H), 8.12-7.85(m,3H), 7.83-7.50(m, 4H), 7.49-7.31(m,2H), 5.45-3.93(m,3H), 4.59(s,2H), 4.32(s,2H), 2.95-2.25(m,2H).

[0282] MS(ESI,LR) Calculated for C 23 H 20 FN2O6(MH + ):439.1, found:439.1.

[0283] Example 40. 3-(2-(6-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid

[0284] [ka]

[0285] Using 6-bromoisoindolin-1-one and benzothiophen-3-ylboronic acid as starting materials, the target compound 40 (30 mg) was obtained sequentially using Methods B / A / C' / D / E / F.

[0286] 1 H NMR(400MHz,DMSO-d6) d 12.52(s,1H), 8.15-8.02(m,1H), 8.00-7.70(m,3H), 7.68-7.38(m,5H), 5.41-5.06(m,1H), 4.80-4.16(m, 6H), 2.97-2.38(m,2H).

[0287] MS(ESI,LR) Calculated for C 23 H 20FN2O5S(MH + ):455.1, found:455.1.

[0288] Example 41. 3-(2-(6-(benzofuran-5-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid

[0289] [ka]

[0290] Using 6-bromoisoindolin-1-one and benzofuran-5-ylboronic acid as starting materials, the target compound 41 (29 mg) was obtained sequentially using Methods B / A / C' / D / E / F.

[0291] 1 H NMR(400MHz,DMSO-d6)d 12.91(s,1H), 8.05(d,J=2.14Hz,1H), 8.01(s,1H), 7.98-7.93(m,2H), 7. 77-7.51(m,4H), 7.06-7.00(m,1H), 5.41-3.96(m,7H), 2.98-2.41(m,2H).

[0292] MS(ESI,LR) Calculated for C 23 H 20 FN2O6(MH + ):439.1, found:439.1.

[0293] Example 42. 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid

[0294] [ka]

[0295] Step 42-1: Methyl 5-bromo-2-methylbenzoate (400 mg, 1.75 mmol) and (2,3-dihydrobenzo[b][1,4]dioxy-6-yl)boronic acid (330 mg, 1.83 mmol) were used as starting materials and reacted according to Method B to obtain the target compound 42-1 (444 mg, 89%).

[0296] Step 42-2 (Method G): Compound 42-1 (450 mg, 1.58 mmol) was dissolved in chloroform (60 mL). N-bromosuccinimide (NBS, 333.55 mg, 1.87 mmol) and AIBN (25 mg, 0.16 mmol) were added and the mixture was refluxed for 24 hours. After completion of the reaction, the reaction mixture was washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to give the desired compound 42-2 (345 mg, 60%).

[0297] Step 42-3 (Method H): Compound 42-2 (345 mg, 0.95 mmol) was dissolved in acetonitrile (40 mL), tert-butyl L-valinate (172.8 mg, 0.997 mmol), and DIPEA (147.3 mg, 1.14 mmol) were added, and the mixture was refluxed and stirred for 12 hours. After completion of the reaction, the solvent was concentrated by distillation under reduced pressure, brine (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, diluted with brine (30 mL), and extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using column chromatography to obtain the target compound 42-3 (199 mg, 57%).

[0298] Step 42-4 / 42-5: Compound 42-3 (150 mg, 0.408 mmol) was reacted sequentially according to Methods D' / E / F to give the target compound 42 (44 mg).

[0299] 1 H NMR(400MHz,DMSO-d6) d 12.45(s,1H), 9.05-8.91(m,1H), 7.90-7.76(m,2H), 7.70-7.59(m,1H), 7.25-7.12(m,2H), 6.95(dd,J=8.09,2.14 Hz,1H), 5.34-4.34(m,6H), 4.28(s,4H), 2.90-2.46(m,2H), 2.35-2.17(m,1H), 1.00-0.69(m,6H).

[0300] MS(ESI,LR) Calculated for C 26 H 28 FN2O7(MH + ):499.2, found:499.1.

[0301] Example 43. 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0302] [ka]

[0303] Using methyl 5-bromo-2-methylbenzoate and pyrrolidine as starting materials, the target compound 43 (66 mg) was obtained using Methods B' / G / H / D' / E / F in sequence.

[0304] 1 H NMR(400MHz,DMSO-d6) d 8.96(s,1H), 7.92-7.29(m,1H), 7.23-6.69(m,2H), 5.57-4.24(m,6H), 4.10-3.11(m,4H), 3.05-2.45(m, 3H), 2.42-1.85(m,4H), 1.54-0.64(m,6H).

[0305] MS(ESI,LR) Calculated for C 22 H 29 FN3O5(MH + ):434.2, found:434.1.

[0306] Example 44. 3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid

[0307] [ka]

[0308] Using methyl 5-bromo-2-methylbenzoate and benzofuran-3-ylboronic acid as starting materials, the target compound 44 (71 mg) was obtained sequentially using Methods B / G / H / D' / E / F.

[0309] 1 H NMR(400MHz,DMSO-d6) d 9.06-8.84(m, 1H), 8.50(s,1H), 8.12-7.89(m,3H), 7.84-7.65(m,2H), 7.52-7.34(m,2H), 5.37-4.44(m, 6H), 2.86-2.46(m,2H), 2.39-2.16(m,1H), 1.13-0.67(m,6H).

[0310] MS(ESI,LR) Calculated for C 26 H 26 FN2O6(MH + ):481.2, found:481.1.

[0311] Example 45. 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0312] [ka]

[0313] Using methyl 5-bromo-2-methylbenzoate and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one as starting materials, the target compound 45 (54 mg) was obtained sequentially using Methods B / G / H / D' / E / F.

[0314] 1 H NMR(400MHz,DMSO-d6)d 12.43(s,1H), 10.72(d,J=9.46Hz,2H), 9.05-8.91(m,1H), 7.79-7.76(m,2H), 7.70-7.61(m,1H), 7.28(d,J=7.93Hz,1 H), 7.20(s,1H), 7.01(d,J=7.93Hz,1H), 5.32-4.21(m,6H), 2.92-2.44(m,2H), 2.35-2.16(m,1H), 1.06-0.70(m,6H).

[0315] MS(ESI,LR) Calculated for C 25 H 26 FN4O6(MH + ):497.2, found:497.1.

[0316] Example 46. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)propanamido)pentanoic acid

[0317] [ka]

[0318] Compound 43-2 and tert-butyl L-alanine monohydrochloride were used as starting materials and the target compound 46 (24 mg) was obtained sequentially using Methods H / D' / E / F.

[0319] 1 H NMR(400MHz,DMSO-d6) d 12.81(s,1H), 7.36(d,J=8.01Hz,1H), 6.80(dd,J=8.39,2.29Hz,1H), 6.75-6.67(m,1H), 5.41-4.12(m, 6H), 3.57-2.94(m,4H), 2.81-2.27(m,2H), 1.98(s,4H), 1.47(d,J=7.63Hz,3H).

[0320] MS(ESI,LR) Calculated for C 20 H 25 FN3O5(MH + ):406.2, found:406.1.

[0321] Example 47. 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)propanamido)pentanoic acid

[0322] [ka]

[0323] Compound 45-2 and tert-butyl L-alanine monohydrochloride were used as starting materials and the target compound 47 (31 mg) was obtained sequentially using Methods H / D' / E / F.

[0324] 1H NMR(400MHz,DMSO-d6)d 12.91(s,1H), 10.72(s,2H), 7.90-7.76(m,3H), 7.66(dd,J=7.63,3.81Hz,1H), 7.29(d,J=8.39Hz,1H) , 7.20(s,1H), 7.01(dd,J=8.01,4.20Hz,1H), 5.39-4.18(m,6H), 2.85-2.27(m,2H), 1.57-1.47(m,3H).

[0325] MS(ESI,LR) Calculated for C 23 H 22 FN4O6(MH + ):469.1, found:469.1.

[0326] Example 48. 3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)propanamido-5-fluoro-4-oxopentanoic acid

[0327] [ka]

[0328] Compound 42-2 and tert-butyl L-alanine monohydrochloride were used as starting materials and the target compound 48 (19 mg) was obtained sequentially using Methods H / D' / E / F.

[0329] 1 H NMR(400MHz,DMSO-d6)d 7.91-7.74(m,2H), 7.64(d,J=7.63Hz,1H), 7.25-7.12(m,2H), 6.95(d,J=8.01Hz ,1H), 4.99-3.94(m,6H), 4.28(s,4H), 2.63-2.22(m,2H), 1.51(d,J=7.63Hz,3H).

[0330] MS(ESI,LR) Calculated for C 24 H 24 FN2O7(MH + ):471.1, found:471.1.

[0331] Example 49. 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)propanamido)-5-fluoro-4-oxopentanoic acid

[0332] [ka]

[0333] Compound 44-2 and tert-butyl L-alanine monohydrochloride were used as starting materials and the target compound 49 (29 mg) was obtained sequentially using Methods H / D' / E / F.

[0334] 1 H NMR(400MHz,DMSO-d6) d 8.52(s,1H), 8.07-7.50(m,6H), 7.47-7.29(m,2H), 5.41-4.23(m,6H), 2.96-2.17(m,2H), 1.54(d,J=7.25Hz,3H).

[0335] MS(ESI,LR) Calculated for C 24 H 22 FN2O6(MH + ):453.1, found:453.1.

[0336] Example 50 (S)-3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

[0337] [ka]

[0338] Step 50-1: 5-Bromo-2-methylbenzoate (25 g, 109.14 mmol) was dissolved in chloroform (100 mL), NBS (19.424 g, 109.14 mmol) and dibenzoyl peroxide (1.322 g, 5.46 mmol) were added, and the mixture was stirred at 75 °C for 1 hour. The reaction mixture was washed with water (100 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give the target compound 50-1. This concentrate was used in the next reaction without further purification.

[0339] Step 50-2: Compound 50-1 was dissolved in acetonitrile (300 mL), and [(1S)-1-tert-butoxycarbonylpropyl]ammonium chloride (21.287 g, 108.78 mmol) and DIPEA (56.84 mL, 326.33 mmol) were added. The mixture was refluxed and stirred for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (500 mL) and washed sequentially with water (300 mL), saturated aqueous ammonium chloride (300 mL), and brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 50-2 (25.1 g, 65% over 2 steps).

[0340] MS(ESI,LR) Calculated for C 16 H20 BrNO3Na(MNa + ):376.1, found:376.1.

[0341] Step 50-3: Compound 50-2 was reacted with benzofuran-2-ylboronic acid as a starting material according to Method B to obtain the target compound 50-3.

[0342] MS(ESI,LR) Calculated for C 24 H 25 NO4Na(MNa + ):414.2, found:414.2.

[0343] Step 50-4 (Method I): Compound 50-3 (0.456 g, 1.17 mmol) was dissolved in 1,4-dioxane (20 mL) and then added to a hydrogen chloride solution (4N HCl in dioxane, 20 mL) and stirred at room temperature for 8 hours. After completion of the reaction, the solvent was concentrated, and diethyl ether (20 mL) and ethyl acetate (20 mL) were added. The resulting solid was filtered and dried to give target compound 50-4 (0.365 g, 84%).

[0344] MS(ESI,LR) Calculated for C 20 H 17 NO4Na(MNa + ):358.1, found:358.1.

[0345] Step 50-5: Compound 50-5 was synthesized by a known method (WO2008 / 068615A1).

[0346] MS(ESI,LR) Calculated for C 18 H 16 F4NO4(MH + ):386.1, found:386.1.

[0347] Step 50-6 (Method D'): Compound 50-4 and compound 50-5 were reacted according to Method D' to obtain the target compound 50-6.

[0348] MS(ESI,LR) Calculated for C 38 H 31 F4N2O7(MH + ):703.2, found:703.2.

[0349] Step 50-7 (Method J): Compound 50-6 (0.499 g, 0.71 mmol) was dissolved in tetrahydrofuran (7 mL), and acetic acid (0.7 mL) and 10% palladium on carbon (0.053 g, 0.05 mmol) were added. The mixture was stirred under hydrogen for 12 hours. After completion of the reaction, the palladium was removed by filtration through a Celite filter. The filtrate was concentrated and separated by HPLC to give the target compound 50 (0.328 mg, 75.5%).

[0350] 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H), 8.88(dd,J=11.7,7.5Hz,1H), 8.54(d,J=1.9Hz, 1H), 8.08-8.01(m,2H), 8.00-7.93(m,1H), 7.79(dd,J=8.5,1.8Hz,1H), 7.77-7.71(m, 1H), 7.65-7.51(m,1H), 7.45(dtd,J=15.9,7.3,1.4Hz,2H), 5.36-5.16(m,2H), 4.88-4.81(m,1H), 4.81-4.65(m,2H), 4.59(dd,J=17.9, 3.0Hz,1H), 4.07(q,J=7.1Hz,1H), 2.82(ddd,J=16.9,5.9,1.7Hz,1H), 2.69-2.59(m,1H), 2.03(s,2H), 1.93-1.80(m,1H), 1.22(t,J=7.1 Hz,1H), 0.91(t,J=7.3Hz,3H).

[0351] MS(ESI,LR) Calculated for C 31 H25 F4N2O7(MH + ):613.2,found:613.2.

[0352] Example 51 (S)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

[0353] [ka]

[0354] Compound 50-2 was used as the starting material and reacted sequentially according to Method B / I / D' / J to obtain target compound 51.

[0355] 1 H NMR(400MHz,DMSO-d6)δ12.51(s,1H), 8.85(dd,J=11.2,7.5Hz,1H), 7.91-7.82(m,2H), 7.68(d,J=7.8Hz,1H), 7. 66-7.52(m,1H), 7.23(d,J=8.0Hz,2H), 7.00(d,J=8.2Hz,1H), 5.27(d,J=4.1Hz,2H), 4.81(dd,J=9.7,5.7Hz,1H), 4.74-4.62(m,2H), 4.53(d,J=17.7Hz,1H), 4.33(s,4H), 4.07(q,J=7.1Hz,1H), 2.80(dd,J=16.9,6.0Hz,1H), 2.6 2(dd,J=16.9,7.0Hz,1H), 2.03(s,2H), 1.84(dq,J=9.5,7.2Hz,1H), 1.21(t,J=7.1Hz,1H), 0.88(t,J=7.3Hz,3H).

[0356] MS(ESI,LR) Calculated for C 31 H 27 H4N2O8(MH + ):631.17,found:631.2.

[0357] Example 52 (S)-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

[0358] [ka]

[0359] Compound 50-2 (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) and boronic acid were reacted sequentially using Method B / I / D' / J to obtain target compound 52.

[0360] 1H NMR(400MHz,DMSO-d6)δ12.48(s,1H), 10.73(d,J=7.7Hz,2H), 8.84(d,J=7.4Hz,1H), 7.89-7.80(m,2H), 7.66(d,J=7.9Hz,1H), 7.55(ddd,J=11.0,7.3,3.6Hz,1H), 7.29(d d,J=8.1,1.8Hz,1H), 7.21(d,J=1.8Hz,1H), 7.03(d,J=8.0Hz,1H), 5.25(d,J=4.2Hz, 2H), 4.79(dd,J=9.6,5.7Hz,1H), 4.73-4.60(m,2H), 4.51(d,J=17.6Hz,1H), 4.03(q,J =7.1Hz,1H), 2.78(dd,J =16.9,5.9Hz,1H), 2.60(dd,J =16.9,7.0Hz,1H), 2.00-1.92(m,2H), 1.87-1.77(m,1H), 1.18(t,J=7.1Hz,1H), 0.86(t,J =7.3Hz,3H).

[0361] MS(ESI,LR) Calculated for C 30 H 25 F4N4O7(MH + ):629.2, found:629.2.

[0362] Example 53 (S)-4-oxo-3-((S)-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

[0363] [ka]

[0364] Compound 50-2 and pyrrolidine were reacted sequentially using Method B' / I / D' / J to obtain target compound 53.

[0365] 1 H NMR(400MHz,CDCl3)δ8.11(s,1H), 7.47(s,1H), 7.33(dd,J=15.5,8.3 Hz,1H), 7.15-7.04(m,1H), 7.04-6.91(m,1H), 6.72(s,1H), 4.95(s,1H), 4.68(d,J=17.7Hz,2H), 4.41(dd,J=17.3,11.7Hz,1H), 4.12(q,J=7 .2Hz,1H), 3.39(q,J=5.5Hz,4H), 2.84-2.69(m,1H), 2.09(h,J=4.5Hz,6H), 1.96-1.83(m,1H), 1.26(t,J=7.1Hz,1H), 0.96(td,J=7.4,3.7Hz, 3H).

[0366] MS(ESI,LR) Calculated for C 27 H 28 F4N3O6(MH + ):566.2, found:566.2.

[0367] Example 54 (R)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

[0368] [ka]

[0369] Step 54-1: Compound 54-1 was synthesized by a known method (WO2008 / 068615A1).

[0370] MS(ESI,LR) Calculated for C 18 H 16 F4NO4(MH + ):386.1,found:386.1.

[0371] Step 54-2: Compound 51-2 and compound 54-1 were used as starting materials and reacted sequentially by Method D' / J to obtain the target compound 54.

[0372] 1 H NMR(400MHz,DMSO-d6)δ12.51(s,1H), 8.85(dd,J=11.2,7.5Hz,1H), 7.92-7.82(m,2H), 7.68(dd,J=7.8,1.8H z,1H), 7.58(dddd,J=18.1,10.8,8.9,5.3Hz,1H), 7.23(dd,J=8.1,1.4Hz,2H), 7.00(d,J=8.1Hz,1H), 5.35-5. 14(m,2H), 4.80(ddd,J=12.4,9.6,5.9Hz,1H), 4.76-4.63(m,2H), 4.54(dd,J=17.8,3.1Hz,1H), 4.33(s,4H), 4.07(q,J=7.1Hz,1H), 2.81(ddd,J=16.9,5.9,2.2Hz,1H), 2.63(dt,J=16.8,7.1Hz,1H), 2.03(s,2H), 1.84(s, 1H), 1.22(t,J=7.1Hz,1H), 0.89(t,J=7.3Hz, 3H).

[0373] MS(ESI,LR) Calculated for C 31 H 27 H4N2O8(MH + ):631.2,found 631.2.

[0374] Example 55. 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0375] [ka]

[0376] Compound 51-2 and 1-4 were reacted sequentially by Method D' / E / F to obtain the target compound 55.

[0377] 1 H NMR (400MHz, DMSO-d6) δ(ppm)=12.51(s, 1H), 8.78(dd,J=10.8,7.3Hz,1H), 7.92-7.76(m,2H), 7.69-7.60(m,1H), 7.20(dd,J=8.1, 2.0Hz,2H), 7.02-6.90(m,1H), 5.32-5.05(m, 1H), 4.88-4.56(m,3H), 4.55-4.49(m,1H), 4.49-4.34(m,1H), 4.29(s,4H), 2.91-2.67(m, 1H), 2.58(ddd,J=16.9,7.3,5.9Hz,1H), 1.96(d,J=17.8Hz,1H), 1.81(dp,J=15.0,7.1Hz,1H), 0.94-0.75(m,3H).

[0378] MS(ESI,LR) Calculated for C 30 H 25 F4N4O7(MH + ):485.2,found 485.2.

[0379] Example 56. 5-fluoro-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0380] [ka]

[0381] Compound 52-2 and compound 1-4 were reacted sequentially by Method D' / E / F to obtain target compound 56.

[0382] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=12.51(s,1H), 10.72(d,J=7.3Hz,2H), 8.96-8.31(m,1H), 7.85(d,J=11.4Hz,2H), 7.67(dd,J=8.3,3.9Hz,1H), 7.30(d,J=8.2Hz,1H), 7.21(s,1H), 7 .03(d,J=8.1Hz,1H), 5.36-5.06(m,1H), 4.91-4.57(m,3H), 4.51(d,J=17.8Hz,2H), 2.78( d,J=17.1Hz,1H), 2.65-2.55(m,1H), 1.89(d,J=62.7Hz,2H), 0.87(qt,J=9.1,6.4Hz,3H).

[0383] MS(ESI,LR) Calculated for C 30 H 25 F4N4O7(MH + ):483.2, found 483.2.

[0384] Example 57. 3-((S)-2-(5-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0385] [ka]

[0386] Step 57-1: 4-Bromo-2-methylbenzoate (10 g, 43.65 mmol) was dissolved in chloroform (50 mL), NBS (7.77 g, 43.65 mmol) and dibenzoyl peroxide (0.528 g, 2.18 mmol) were added, and the mixture was stirred at 75 °C for 1 hour. The reaction mixture was washed with water (100 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the target compound 50-1. This concentrate was used in the next reaction without further purification.

[0387] Step 57-2: Compound 57-1 was dissolved in acetonitrile (150 mL), and [(1S)-1-tert-butoxycarbonylpropyl]ammonium chloride (8.541 g, 43.65 mmol) and DIPEA (22.81 mL, 130.95 mmol) were added. The mixture was refluxed and stirred for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (300 mL) and washed sequentially with water (100 mL), saturated aqueous ammonium chloride (300 mL), and brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target compound 50-2 (10.4 g, 67% over 2 steps).

[0388] 1H NMR(400MHz,CDCl3)δ(ppm)=7.74-7.73(m,1H), 7.64-7.61(m,2H), 4.99(m,1H), 4.61-4.36(m,2H), 2.16-1.84(m,2H), 1.49(s, 9H), 0.97-0.94(m,3H).

[0389] Step 57-3: Compound 57-2 was reacted with benzofuran-3-ylboronic acid as a starting material according to Method B to obtain the target compound 57-3.

[0390] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.99-9.94(m,1H), 7.89-7.84(m,2H), 7.77-7.75(m,2H), 7.60-7.58(m,1H), 7 .49-7.35(m,2H), 5.05-5.00(m,1H), 4.74-4.43(m,2H), 2.23-1.87(m,2H), 1.48(s,9H), 1.01-0.97(m,3H) Step 57-4 (Method I): Compound 57-3 was reacted according to Method I to obtain the target compound 57-4.

[0391] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.08-8.07(m,1H), 8.01-7.99(m,1H), 7.92-7.90(m, 1H), 7.81-7.66(m,5H), 4.78-4.68(m,1H), 4.62-4.48(m,2H), 2.13-1.82(m,2H), 0.92-0.85(m,3H).

[0392] Step 57-5 (Method D'): Compound 57-4 and compound 1-4 were used to obtain the target compound 57-5 according to Method D'.

[0393] 1H NMR(400MHz,CDCl3)δ(ppm)=7.95-7.51(m,7H), 6.8(s,1H), 6.66-6.60(m,1H), 4.87-4.05(m,9H) , 3.36-3.08(m,6H), 2.75-2.65(m,1H), 2.52-2.45(m,1H), 2.23-2.08(m,1H), 1.27-0.93(m,6H).

[0394] Step 57-6 (Method E): Compound 57-5 was reacted according to Method E to obtain the target compound 57-6.

[0395] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.41-7.51(m,7H), 7.05(s,1H), 4.86-4.25(m,6) H), 3.34-3.23(m,6H), 2.63-2.45(m,2H), 2.03-1.71(m,2H), 0.84-0.82(m,3H).

[0396] Step 57-7 (Method F): Compound 57-6 was reacted according to Method F to obtain the target compound 57.

[0397] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.87-8.73(m,1H), 8.50(s,1H), 8.06-7.93(m,2H), 7.8 3-7.75(m,1H), 7.80-7.73(m,1H), 7.46-7.35(m,2H), 5.33-4.25(m,6H), 2.92-2.36(m, 2H), 2.11-1.70(m,2H), 0.96-0.74(m,3H).

[0398] MS(ESI,LR) Calculated for C 25 H 24 FN2O6(MH + ):467.2,found:467.1.

[0399] Example 58. 3-((S)-2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0400] [ka]

[0401] Compound 57-2 (2,3-dihydrobenzo[b][1,4]dioxin-6-yl) was reacted with boronic acid in the order of Methods B / I / D' / E / F to give target compound 58.

[0402] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.85-8.66(m,1H), 7.83-7.82(m,1H), 7.71(s,2H), 7.23-7.20(m,2H), 6.9 9-6.97(m,1H), 5.27-4.32(m,6H), 4.28(s,4H), 2.77-2.29(m,2H), 2.16-1.62(m,2H), 0.93-0.62(m,3H).

[0403] MS(ESI,LR) Calculated for C 25 H 26 FN2O7(MH + ):485.4,found:485.

[0404] Example 59. 3-((S)-2-(5-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0405] [ka]

[0406] Compound 57-2 was reacted with benzothiopen-3-ylboronic acid in the order of Methods B / I / D' / E / F to give target compound 59.

[0407] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.79-8.72(m,1H), 8.13-8.10(m,1H), 7.97-7.96(m, 2H), 7.86-7.75(m,2H), 7.71-7.68(m,1H), 7.48-7.46(m,2H), 5.37-4.41(m,6H), 2.54-2.46(m,2H), 2.16-1.61(m,2H), 1.00-0.75(m, 3H).

[0408] MS(ESI, LR) Calculated for C 25 H 24 FN2O5S(MH + ):483.1,found:483.1 Example 60. 3-((S)-2-(5-(benzofuran-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0409] [ka]

[0410] Compound 57-2 was reacted with benzofuran-3-ylboronic acid in the order of Methods B / I / D' / E / F to give target compound 60.

[0411] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.80-8.72(m,1H), 8.11-7.85(m,3H), 7.77-7.54(m, 4H), 7.04(s,1H), 5.28-4.23(m,6H), 2.66-2.59(m,2H), 2.03-1.71(m,2H), 0.87-0.82(m, 3H).

[0412] MS(ESI,LR) Calculated for C 25 H 23 FN2O6(MH + ):467.2,found:467.1.

[0413] Example 61. 5-fluoro-3-((S)-2-(5-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

[0414] [ka]

[0415] Compound 57-2 was reacted with naphthalene-1-boronic acid in the order of Methods B / I / D' / E / F to obtain target compound 61.

[0416] 1H NMR(400MHz,DMSO-d6)δ(ppm)=8.75-8.69(m,1H), 8.09(m,2H), 7.91-7.77(m,2H), 7.6 4-7.43(m,6H), 5.28-4.39(m,6H), 2.74-2.42(m,2H), 2.21-1.70(m,2H), 0.85-0.70(m, 3H).

[0417] MS(ESI,LR) Calculated for C 27 H 26 FN2O5(MH + ):477.2,found:477.2.

[0418] Example 62. 5-fluoro-4-oxo-3-((S)-2-(1-oxo-5-(2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0419] [ka]

[0420] Compound 57-2 was reacted with 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazole[1,2-a]pyrazine in the order of Methods B' / I / D' / E / F to obtain target compound 62.

[0421] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.67-8.59(m,1H), 7.80(s,1H), 7.57-7.45(m,1H ), 7.23-7.18(m,2H), 5.39-3.67(m,12H), 2.14-1.62(m,2H), 1.05-0.60(m,3H).

[0422] MS(ESI,LR) Calculated for C 24 H 26 F4N5O5(MH + ):540.2,found:540.1.

[0423] Example 63. 3-((S)-2-(5-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

[0424] [ka]

[0425] Compound 57-2 was reacted with 3-(piperazin-1-yl)benzo[d]isothiazole in the following manner according to Methods B' / I / D' / E / F to give target compound 63.

[0426] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=8.72-8.64(m,1H), 8.20-8.03(m,2H), 7.66-7.42(m, 3H), 7.20-7.15(m,2H), 5.31-4.10(m,6H), 3.62(s,4H), 3.44(s,4H), 2.57-2.44(m,2H), 1.94-1.67(m,2H), 0.83-0.73(m,3H).

[0427] MS(ESI,LR) Calculated for C 28 H 31 FN5O5S(MH + ):568.2,found:568.2.

[0428] Example 64. 5-fluoro-4-oxo-3-((S)-2-(1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)pentanoic acid

[0429] [ka]

[0430] Compound 57-2 was reacted with pyrrolidine in the order of Methods B' / I / D' / E / F to give target compound 64.

[0431] 1 H NMR(400MHz,DMSO-d6)δ(ppm)=7.47-7.41(m,1H), 6.64-6.59(m,2H), 5.13-4.18(m, 6H), 3.29(s,4H), 2.56-2.50(m,2H), 2.05-1.65(m,6H), 0.821-0.74(m,3H).

[0432] MS(ESI,LR) Calculated for C 21 H 27 FN3O5(MH + ):420.2,found:420.2.

[0433] Experimental Example 1: Evaluation of Caspase-1 Inhibitory Activity To measure the caspase-1 inhibitory activity of the compounds of the present invention prepared in the Examples, caspase-1 activity was measured using a substrate to which a fluorescent dye was attached. The fluorescent dye attached to the substrate was released from the substrate by caspase and emitted fluorescence.

[0434] Compounds were dissolved in DMSO and kept at -20°C. Enzyme reactions were performed in a buffer solution containing 50 mM HEPES (pH 8.0), 50 mM KCl, 200 mM NaCl, 10 mM DTT, and 0.1% CHAPS (w / v). Enzyme inactivation was measured in the presence of various concentrations of compounds using 50 μM fluorescent substrate N-Acetyl-Tyr-Val-Ala-Asp-7-amido-4-trifluoromethylcoumarin (Ac-YVAD-AFC) (Sigma) and 1 unit of recombinant human caspase-1 (Enzo Life Sciences). The reaction rate versus time was measured at 400 / 505 nm (Ex / Em) wavelength using a CLARIOstar Plus spectrometer (BMG Labtech). The inhibitory rate constant k of the compound was calculated using the following equation: observance (k obs ) and then calculate the concentration and the resulting k obs Perform linear regression analysis on k obs / [I]. k obs When / [I] is 20 or more, it is represented by A; when it is 10 or more but less than 20, it is represented by B; when it is 1 or more but less than 10, it is represented by C; and when it is less than that, it is represented by D.

[0435] <Formula 1> k obs =-ln(1-A t / A max ) / t In the above formula, A t means the enzyme reaction rate in time t (min), and A max means the maximum response rate.

[0436] As a result, as shown in Table 1, it was confirmed that each compound inhibited caspase-1 activity. Therefore, it was confirmed that the compounds of the present invention are direct caspase-1 inhibitors.

[0437] Experimental Example 2: Measurement of pro-inflammatory interleukin-1β inhibitory activity in human monocytic cells THP-1 Caspase-1 is known as an IL-1β converting enzyme (ICE). Activated caspase-1 cleaves pro-IL-1β to produce mature IL-1β, which is secreted and induces inflammation. Therefore, we investigated whether the caspase-1 inhibitory activity of the compounds confirmed in Experimental Example 1 affects the production of IL-1β.

[0438] THP-1 (ATCC) cells were cultured in RPMI 1640 (Hyclone) growth medium containing 10% fetal bovine serum (FBS, Gibco) and antibiotics (100 U / ml penicillin, 0.1 mg / ml streptomycin, Cytiva) at 37°C and 5% CO2. Cultured THP-1 cells were plated in 24-well plates (Celvest) at 3 × 10 5 After dispensing the cells in growth medium at a concentration of 1000 cells / well, differentiation was induced by treatment with 1 μM phorbol 12-myristate 13-acetate (PMA) (Sigma) for 24 hours. Differentiated THP-1 cells were pretreated with 10 μg / ml lipopolysaccharide (LPS) from E. coli 0111:B4 (InvivoGen) in serum-free RPMI 1640 medium for 24 hours to induce an inflammatory response. After LPS removal, the cells were pretreated with compounds at a concentration of 100 nM in the same medium for 1 hour, followed by the addition of 5 mM ATP (InvivoGen) and incubation in an incubator for 24 hours. The treated medium was collected and centrifuged, and IL-1β was quantified using an enzyme-linked immunoassay kit (ELISA kit, R&D System). The absorbance was measured at 450 nm using a CLARIOstar Plus spectrometer. Inhibitory activity of 50% or more is represented by a, 30% or more and less than 50% by b, 10% or more and less than 30% by c, and less than 10% by d.

[0439] As shown in Table 1, it was confirmed that IL-1β was reduced when the compound of the present invention was treated. This confirmed the possibility that the compound of the present invention can suppress inflammation by reducing IL-1β. In particular, since intracellular caspase-1 is involved in the maturation of IL-1β, a correlation with the caspase-1 inhibitory activity confirmed in Experimental Example 1 was confirmed.

[0440] Experimental Example 3: Measurement of apoptosis-inhibitory activity in Jurkat human T lymphocyte cells Apoptosis is a type of programmed cell death and a genetically regulated pathway that plays an important role in maintaining cellular homeostasis. It is usually induced by the extrinsic pathway via apoptosis receptors or the intrinsic pathway via mitochondria. Caspase-8 and caspase-9, known as initiators, are activated by extrinsic and intrinsic factors, respectively, and mediate cell death by activating the subordinate executioner, caspase-3. Morphologically, apoptosis is characterized by cell shrinkage, DNA fragmentation, and a decrease in intracellular ATP.

[0441] To evaluate the effect of the compounds of the present invention on apoptosis, Jurkat (ATCC) cells were treated with the anti-FAS antibody CH-11 (Merck) to induce apoptosis via the Fas (CD95) receptor, and the amount of intracellular ATP was evaluated.

[0442] Jurkat cells were cultured in RPMI 1640 growth medium containing 10% FBS and antibiotics (100 U / ml penicillin, 0.1 mg / ml streptomycin) at 37°C and 5% CO2. 8 × 10 cells were plated in a 96-well plate (SPL). 4Cells were dispensed into growth medium at a concentration of 1000 cells / well and pretreated with 50 nM compounds for 1 hour. After treatment with 1 μg / ml anti-FAS antibody, the cells were incubated in an incubator for 24 hours. After 24 hours, ATP was measured using an ATP lite Luminescence Assay Kit (PerkinElmer). Luminescence was measured at 580 nm using a CLARIOstar Plus spectrometer. Inhibitory activity of 30% or greater is represented as a', 20% or greater but less than 30% as b', 10% or greater but less than 20% as c', and less than 10% as d'.

[0443] As shown in Table 1, it was confirmed that apoptosis was reduced when the compounds were treated, which confirmed that the compounds of the present invention are effective in inhibiting apoptosis.

[0444] [Table 1] JPEG0007747372000077.jpg255161 JPEG0007747372000078.jpg34169

[0445] The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. Therefore, it should be understood that the above-described embodiments are illustrative in all respects and not limiting. For example, each component described as a single type can be implemented in a distributed form, and similarly, each component described as a distributed type can be implemented in a combined form.

[0446] The scope of the present invention is defined by the claims that follow, and all changes and modifications that fall within the meaning and scope of the claims and their equivalent concepts are intended to be included within the scope of the claims.

Claims

1. An isoindolinone derivative compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above formula, R １ is F or 2,3,5,6-tetrafluorophenoxy, R ２ is hydrogen or C １－６ is a straight or branched chain alkyl; R ３ is a halogen or Q, Q is 1 to 3 independent R ａ an aryl, aminoaryl, heteroaryl or non-aromatic heterocycle substituted or unsubstituted by Q is optionally fused to a saturated or unsaturated 5- to 7-membered ring containing 0-3 heteroatoms; R ａ is C １－６ Straight or branched chain alkyl, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, CO ２ R ｂ , C.O.R. ｂ , CONHR ｂ , CON(R ｂ ) ２ , N.H.R. ｂ , N(R ｂ ) ２ , NHCOR ｂ , S(O) ２ R ｂ or heteroaryl fused to a saturated or unsaturated 5- to 7-membered ring containing 0-3 heteroatoms; R ｂ is hydrogen or C １－６ It is a straight or branched chain alkyl.

2. The R ２ The isoindolinone derivative compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that: is hydrogen, methyl, ethyl, or straight-chain or branched-chain propyl.

3. The R ３ is Br or Q, and Q is phenyl, pyridinyl, tetrahydropyridinyl, pyrazolyl, pyrimidinyl, dihydropyranyl, thiophenyl, pyrrolidinyl, piperazinyl, aminonaphthalenyl, naphthalenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl, or dihydroimidazopyrazinyl. The isoindolinone derivative compound, its hydrate, its solvate, or its pharmaceutically acceptable salt according to claim 1,

4. The R ａ The isoindolinone derivative compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that: is methyl, methoxy, F, trifluoromethyl, carboxy, acetyl, amino, methylsulfonyl or benzisothiazolyl.

5. The isoindolinone derivative compound, its hydrate, its solvate, or its pharmaceutically acceptable salt according to claim 1, wherein the isoindolinone derivative compound represented by chemical formula I is any one selected from the group consisting of the following compounds: [1] 5-fluoro-4-oxo-3-(2-(1-oxo-6-phenylisoindolin-2-yl)butanamido)pentanoic acid, [2] 5-fluoro-3-(2-(6-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [3] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)pentanoic acid, [4] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyridin-3-yl)isoindolin-2-yl)butanamide)pentanoic acid, [5] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(1H-pyrazol-4-yl)isoindolin-2-yl)butanamido)pentanoic acid, [6] 5-fluoro-3-(2-(6-(4-(methylsulfonyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [7] 5-fluoro-3-(2-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)butanamide-4-oxopentanoic acid, [8] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)pentanoic acid, [9] 3-(2-(6-bromo-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [10] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamide)pentanoic acid, [11] 5-fluoro-3-(2-(6-(naphthalen-1-ylamino)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [12] 5-fluoro-3-(2-(6-(2-fluoro-4-(methylsulfonyl)phenyl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [13] 5-fluoro-3-(2-(6-(6-methoxypyridin-3-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [14] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)butanamido)pentanoic acid, [15] 3-(2-(6-(3,6-dihydro-2H-pyran-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-pentanoic acid, [16] 3-(2-(6-benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [17] 4-(2-(1-((1-carboxy-4-fluoro-3-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-3-oxoisoindolin-5-yl)pentanoic acid, [18] 3-(2-(6-(4-acetylphenyl)-1-oxoisoindolin-2-yl)butanamido-5-fluoro-4-oxopentanoic acid, [19] 3-(2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [20] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-2-yl)butanamide)pentanoic acid, [21] (3-(2-(6-(2-aminopyrimidin-5-yl)-1-oxoisoindolin-2-yl)butanamide)-5-fluoro-4-oxopentanoic acid, [22] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [23] 3-(2-(6-(2-aminopyridin-4-yl)1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [24] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [25] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [26] 3-(2-(6-benzofuran-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [27] 3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [28] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(thiophen-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [29] 5-fluoro-3-(2-(6-(isoquinolin-4-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [30] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-6-yl)isoindolin-2-yl)butanamido)pentanoic acid, [31] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-4-yl)isoindolin-2-yl)butanamido)pentanoic acid, [32] 3-(2-(6-(benzo[d]thiazol-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [33] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrazolo[1,5-a]pyridin-3-yl)isoindolin-2-yl)butanamide)pentanoic acid, [34] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-5-yl)isoindolin-2-yl)butanamido)pentanoic acid, [35] 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [36] 5-fluoro-3-(2-(6-(isoquinolin-5-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [37] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [38] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)acetamido)pentanoic acid, [39] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid, [40] 3-(2-(6-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid, [41] 3-(2-(6-(benzofuran-5-yl)-1-oxoisoindolin-2-yl)acetamido)-5-fluoro-4-oxopentanoic acid, [42] 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid, [43] 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamide)4-oxopentanoic acid, [44] 3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamide)-5-fluoro-4-oxopentanoic acid, [45] 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)-4-oxopentanoic acid, [46] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)propanamide)pentanoic acid, [47] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)propanamide)pentanoic acid, [48] ​​3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)propanamido-5-fluoro-4-oxopentanoic acid, [49] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)propanamido)-5-fluoro-4-oxopentanoic acid, [50] (S)-3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, [51] (S)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, [52] (S)-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, [53] (S)-4-oxo-3-((S)-2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamide)-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, [54] (R)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, [55] 3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [56] 5-fluoro-4-oxo-3-((S)-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamide)pentanoic acid, [57] 3-((S)-2-(5-(benzofuran-3-yl)-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [58] 3-((S)-2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [59] 3-((S)-2-(5-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [60] 3-((S)-2-(5-(benzofuran-5-yl)-1-oxoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [61] 5-fluoro-3-((S)-2-(5-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamide)-4-oxopentanoic acid, [62] 5-fluoro-4-oxo-3-((S)-2-(1-oxo-5-(2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)isoindolin-2-yl)butanamide)pentanoic acid, [63] 3-((S)-2-(5-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [64] 5-Fluoro-4-oxo-3-((S)-2-(1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)butanamide)pentanoic acid.

6. A pharmaceutical composition for preventing or treating a caspase-related disease, comprising the derivative compound, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient.

7. The pharmaceutical composition according to claim 6, wherein the caspase-related disease is osteoarthritis or pain.

8. The pharmaceutical composition according to claim 6, wherein the prevention or treatment of the caspase-related disease is due to a reduction in IL-1β or apoptosis.

9. A pharmaceutical composition comprising the isoindolinone derivative compound according to any one of claims 1 to 5, its hydrate, its solvate, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

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