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] Caspase is a type of enzyme that exists as a tetramer in the α2β2 form of cysteine ​​protease, and caspase inhibitors are compounds that can regulate inflammation and apoptosis induced by the action of caspases by inhibiting the activity of such caspases. Diseases that can be treated with such compounds 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. Also, 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 having a novel structure which exhibits excellent inhibitory activity against caspases.

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

[0007] A further 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] A further object of the present invention is to provide use of the caspase inhibitor compound having the novel structure for preventing or treating 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 will be clearly understood by those having ordinary skill 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 pharma- ceutically 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 or not replaced by, Q is an aryl, aminoaryl, heteroaryl, or non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5-7 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 0-3 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 the isoindolinone derivative compound represented by formula I, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

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

[0016] In still another aspect, the present invention provides use of the isoindolinone derivative compound represented by the above chemical formula I, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof for preventing or treating a caspase-associated disease.

[0017] In yet another aspect of the present invention, there is provided a pharmaceutical composition comprising the isoindolinone derivative compound represented by formula I, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically 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. Effect of the Invention

[0019] 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 it has been revealed that it can be used 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 pharmaceutical science 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 above effects, 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 PREFERRED EMBODIMENTS

[0022] The present invention provides an isoindolinone derivative compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, or a pharma- ceutically 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 or not replaced by, Q is an aryl, aminoaryl, heteroaryl, or non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5-7 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 0-3 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 replaced 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, where 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)butanamide)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)butanamide)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)butanamide)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)butanamide)pentanoic acid,

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

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

[35] 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamide)-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)butanamide)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)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)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)butanamide)-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)butanamide)-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)butanamide)-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 the compounds of formula I herein, the following definitions apply unless otherwise stated.

[0032] The term "alkyl" refers to a linear or branched saturated hydrocarbon having a C1-C 10Alkyl is preferred, for example, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, 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 replaced with one or more halogen atoms.

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

[0037] The term "aryl" means an aromatic hydrocarbon, preferably a 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 an aromatic hydrocarbon having 3 to 12 ring members, more preferably 5 to 10 ring members, which contains one or more heteroatoms selected from N, O and S as ring atoms and may be fused to benzo or C3-C8 cycloalkyl. For example, the heteroaryl includes, but is 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, benzooxolane, benzothiolane, and benzothiane.

[0040] The arylalkyl, alkylaryl and heteroarylalkyl refer to a group formed by combining the aryl and alkyl or heteroaryl and alkyl defined above, 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 ring 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. Compounds within the scope of the term "aryl" as used herein also include 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 pharma- ceutically acceptable salt in order to enhance in vivo absorption or increase solubility, and the prodrug, hydrate, solvate, or pharma-ceutically acceptable salt also falls within the scope of the present invention. In addition, since the compound represented by formula I has a chiral carbon, 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 transformed 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 buccal administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of the compounds according to the invention and pharma-ceutically acceptable salts thereof. Yet another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group that is converted by metabolism to reveal the active site of the peptide.

[0044] The term "hydrate" refers to 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 invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this context include solvents that are volatile, non-toxic, and / or suitable for administration to humans.

[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 stereochemically different. Such isomers include all 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 also included within the scope of the present invention.

[0047] The term "pharmaceutical acceptable salt" refers to a salt form of a compound that does not induce significant 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 pharmaceutical acceptable anions, such as 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, pharma- ceutically 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., 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 may 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 3 -B(OH)2, R 3 and one of the compounds of formula Ic below to prepare a compound of formula I-2 below: This step comprises the steps of: 1) reacting an aryl bromide compound of the following formula I-1 with R 3-B(OH)2 or a pinacolboron compound of the following formula Ic to obtain a compound of aryl-aryl type. The catalyst used in this step may be a catalyst commonly used in Suzuki coupling reaction, for example, but not limited to, a palladium catalyst. The reaction may be carried out at a reaction temperature commonly used in Suzuki coupling reaction using a solvent commonly used in Suzuki coupling reaction. For example, but not limited to, the reaction may be carried out at a high temperature (80 to 110°C) in toluene or 1,4-dioxane solvent condition for a suitable reaction time (for example, about 10 hours). This step may be 2) a Buchwald reaction in which the compound of formula I-1 is reacted with an amine compound to obtain a compound of aryl-amine type. The catalyst used in this step may be a catalyst commonly used in Buchwald reaction, for example, but not limited to, a palladium catalyst. The reaction may be carried out at a reaction temperature commonly used in Buchwald reaction using a solvent commonly used in Buchwald reaction. For example, but not limited to, the reaction may be carried out at a high temperature (for example, 80°C) in toluene solvent condition for a suitable reaction time (for example, about 10 hours).

[0050] (2) preparing a compound of the following formula I-3 by hydrolyzing the compound of the following formula I-2: 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-aqueous 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 formula I-3 with a compound of formula I-4 to prepare a compound of formula I-5: In this step, a compound of the following formula I-3 having a carboxylic acid group is reacted with a compound of the following 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) preparing a compound of the following formula I-6 by hydrolyzing the compound of the following formula I-5: 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-aqueous 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 group reaction in which the compound of formula I-6 in the form of dimethylketone is treated with an acid to obtain a ketone compound. The solvent used in this step may be a solvent commonly used in deprotection group reactions, such as an aqueous hydrochloric acid solution, but is not limited thereto.

[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 the above methods. The preparation methods of Reaction Schemes 1 to 64 are merely illustrative, and it is obvious that they can be easily modified by those skilled in the art according to specific substituents.

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

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

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

[0070] In one embodiment, the caspase-associated 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 pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0073] The additives may contain pharma- ceutically acceptable carriers or diluents, and each of them can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, topical preparations, suppositories, and sterile injection solutions by a conventional method.

[0074] The pharma- ceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc. Also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, etc., and may include 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, freeze-dried 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, etc. As the base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, etc. may be used.

[0075] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the active ingredient, the administration route and period, and can be appropriately adjusted according to the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg, preferably 0.01 to 100 mg / kg per day, and the administration can be administered once or several times a day. In addition, the pharmaceutical composition of the present invention can contain the active ingredient at a weight percentage of 0.001 to 90% based on 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 a variety of routes, for example, orally, intraperitoneally, rectally, or intravenously, intramuscularly, subcutaneously, intrauterinely, intradurally, or intracerebroventricularly.

[0077] The present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are for illustrative purposes only 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 the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 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 1-1 (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), and then phenylboronic acid (70.3 mg, 0.58 mmol), 2M aqueous potassium carbonate solution (0.6 mL, 1.2 mmol), and tetrakis(triphenylphosphine)palladium (27.76 mg, 0.024 mmol) were added and stirred at 110 °C for 10 hours. After the reaction was completed, brine (50 mL) was added and extracted with ethyl acetate (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using column chromatography to obtain 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), lithium hydroxide (33.44 mg, 1.39 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the tetrahydrofuran solvent was concentrated and removed, and 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 using column chromatography to obtain 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), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.68 mg, 0.254 mmol), compound 1-4 (WO2006 / 090997) (59.53 mg, 0.267 mmol) synthesized by a known method, 1-hydroxybenzotriazole (34.32 mg, 0.254 mmol), and N,N-diisopropylethylamine (DIPEA, 39.48 mg, 0.305 mmol) were added and stirred at room temperature for 24 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate (30 mL) was added and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated using 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), lithium hydroxide (17.8 mg, 0.743 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the tetrahydrofuran solvent was concentrated and removed, and 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 using column chromatography to obtain 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), and then 6N aqueous hydrochloric acid (2 mL) was added and stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution 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, and then 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) were added and the tube was sealed and stirred at 80 ° C for 10 hours. After the reaction was completed, 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 obtain 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), and then HATU (144 mg, 0.379 mmol) and DIPEA (61.33 mg, 0.473 mmol) were added and stirred 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 the reaction was completed, a saturated aqueous solution of sodium bicarbonate (30 mL) was added and extracted using ethyl acetate (40 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 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 [Step 3-4 / 3-5]: Compound 3-3 was used as a starting material and the target compound 3 (31 mg) was obtained by sequentially following Method E / F.

[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 by 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 and the mixture was sealed and stirred at 80 ° C for 10 hours. After the reaction was completed, 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 1,4-dioxane solution, 2 mL) was added and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated to obtain compound 6-2 (95 mg, 93%) in the form of 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 and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was diluted with water (40 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using 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 in sequence according to 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) according to 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), hydrogen chloride solution (4.0 M 1,4-dioxane solution, 2 mL) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated to obtain 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 and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was diluted with water (40 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated using 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 in sequence according to 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 using Methods B / C / D' / E / F in sequence.

[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 by sequentially using Methods C / D' / E / F.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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)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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 using Methods B / C / D / E / F in sequence.

[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 to obtain the target compound 23 (4 mg) 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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / A / C / D' / E / F in sequence.

[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] The target compound 33 (20 mg) was obtained 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 in sequence 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 using Methods B / A / C / D' / E / F in sequence.

[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] Using isoquinolin-8-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, 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] Using isoquinolin-5-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, 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 using Methods B / A / C / D' / E / F in sequence.

[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 using Methods B / C' / D / E / F in sequence.

[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 benzothiophene-3-ylboronic acid as starting materials, the target compound 40 (30 mg) was obtained using Methods B / A / C' / D / E / F in sequence.

[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 using Methods B / A / C' / D / E / F in sequence.

[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), and N-bromosuccinimide (NBS, 333.55 mg, 1.87 mmol) and AIBN (25 mg, 0.16 mmol) were added and the mixture was refluxed and stirred for 24 hours. After completion of the reaction, the reaction solution was washed with brine (50 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to obtain the target 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, and brine (50 mL) was added and extracted using ethyl acetate (40 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated solution 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 and diluted with brine (30 mL), and then extracted using ethyl acetate (40 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 42-3 (199 mg, 57%).

[0298] Step 42-4 / 42-5: Compound 42-3 (150 mg, 0.408 mmol) was reacted in sequence according to Method 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 using Methods B / G / H / D' / E / F in sequence.

[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 using Methods B / G / H / D' / E / F in sequence.

[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 sequentially subjected to Methods H / D' / E / F to give the target compound 46 (24 mg).

[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 sequentially subjected to Methods H / D' / E / F to give the target compound 47 (31 mg).

[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 using Methods H / D' / E / F in sequence.

[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 sequentially subjected to Methods H / D' / E / F to give the target compound 49 (29 mg).

[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 solution 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.

[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 and stirred under reflux for 5 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (300 mL), saturated aqueous ammonium chloride solution (300 mL), and brine (300 mL) in sequence, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and separated 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 and benzofuran-2-ylboronic acid were reacted as starting materials 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), then added to hydrogen chloride solution (4N HCl in dioxane, 20 mL) and stirred at room temperature for 8 hours. After the reaction was completed, the solvent was concentrated, and diethyl ether (20 mL) and ethyl acetate (20 mL) were added. The resulting solid was filtered and dried to obtain the 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 / carbon (0.053 g, 0.05 mmol) were added, followed by stirring for 12 hours in the presence of hydrogen. After completion of the reaction, the palladium was filtered through a Celite filter, and the filtrate was concentrated and separated by HPLC to obtain 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 the 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 the 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 used as starting materials and reacted sequentially by Method B' / I / D' / J to obtain the 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 the 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 solution 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 concentrated solution 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-butoxycaboylpropyl] ammonium chloride (8.541 g, 43.65 mmol) and DIPEA (22.81 mL, 130.95 mmol) were added and refluxed for 5 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (300 mL), washed with water (100 mL), saturated aqueous ammonium chloride solution (300 mL), and brine (300 mL) in sequence, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and separated 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 and benzofuran-3-ylboronic acid were reacted as starting materials 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 obtain the 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 obtain the 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 obtain the 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 the 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 manner of Methods B' / I / D' / E / F to obtain the 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 manner of Methods B' / I / D' / E / F to give the 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 B' / I / D' / E / F to obtain 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. Caspase-1 inhibitory activity evaluation In order 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 showed fluorescence.

[0434] The compounds were dissolved in DMSO and kept at -20°C. The enzyme reaction was carried out 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 inactivity was measured in the presence of various concentrations of compounds using 50 μM of 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 science). The reaction rate over time was measured at 400 / 505 nm (Ex / Em) wavelength using a CLARIOstar Plus spectrometer (BMG Labtech). The inhibition rate constant k of the compound was calculated according to the following formula 1. observance (k obs ) and then calculate the concentration and the resulting k obs Linear regression analysis of k obs / [I]. k obs When / [I] is 20 or more, it is represented by A; when it is 10 or more and less than 20, it is represented by B; when it is 1 or more and 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 at 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 compound of the present invention is a direct caspase-1 inhibitor.

[0437] Experimental Example 2. Measurement of pro-inflammatory Interleukin-1β inhibitory activity in human monocytic cells THP-1 Caspase-1 is known as IL-1β converting enzyme (ICE). Activated caspase-1 is involved in the generation of mature IL-1β from pro-form IL-1β by cleavage, and mature IL-1β is secreted to induce inflammation. Therefore, we confirmed whether the caspase-1 inhibitory activity of the compound confirmed in Experimental Example 1 affects the generation 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 in growth medium at a concentration of 10 ... 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, the correlation with the caspase-1 suppression activity confirmed in Experimental Example 1 was confirmed.

[0440] Experimental Example 3. Measurement of apoptosis-inhibiting activity in human T lymphocyte Jurkat 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 through apoptosis receptors or the intrinsic pathway through 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 intracellular ATP reduction.

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

[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 4The cells were dispensed into growth medium at a concentration of 10000 cells / well, pretreated with 50 nM of compound for 1 hour, and then treated with 1 μg / ml of anti-FAS antibody and incubated in an incubator for 24 hours. After 24 hours, ATP was measured using an ATP lite Luminescence assay kit (PerkinElmer), and luminescence was measured at 580 nm using a CLARIOstar Plus spectrometer. Inhibitory activity of 30% or more is represented as a', 20% or more and less than 30% as b', 10% or more and 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. From this, it was confirmed that the compounds of the present invention are effective in suppressing apoptosis.

[0444] [Table 1] JPEG2024546192000077.jpg255161 JPEG2024546192000078.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 idea or essential features of the present invention. Therefore, it should be understood that the above-described embodiments are illustrative in all respects and are not limiting. For example, each component described as a single type can be implemented in a distributed manner, 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 set forth below, and all modifications and variations 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 pharma- ceutically acceptable salt thereof: 【Chemistry 1】 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 halogen or Q, and Q is one to three independent R ａ or not replaced by, Q is an aryl, aminoaryl, heteroaryl, or a non-aromatic heterocycle, where Q is optionally fused to a saturated or unsaturated 5-7 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 , C.O.N.R. 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 5-7 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 １ The isoindolinone derivative compound according to claim 1, characterized in that: is F, or phenoxy substituted with 1 to 5 F, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof.

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

4. The R ３ The isoindolinone derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein: 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.

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

6. The isoindolinone derivative compound, its hydrate, its solvate or its pharma- ceutically 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)butanamide)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)butanamide)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)butanamide)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)butanamide)pentanoic acid, [15] 3-(2-(6-(3,6-dihydro-2H-pyran-4-yl)-1-oxoisoindolin-2-yl)butanamide)-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)butanamide-5-fluoro-4-oxopentanoic acid, [19] 3-(2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)butanamide)-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)butanamide)-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)butanamide)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)butanamide)pentanoic acid, [31] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-4-yl)isoindolin-2-yl)butanamide)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)butanamide)pentanoic acid, [35] 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamide)-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)butanamide)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)acetamide)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)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)butanamide)-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)butanamide)-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)butanamide)-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)butanamide)-5-fluoro-4-oxopentanoic acid, [58] 3-((S)-2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamide)-5-fluoro-4-oxopentanoic acid, [59] 3-((S)-2-(5-(benzo[b]thiophen-3-yl)-1-oxoisoindolin-2-yl)butanamide)-5-fluoro-4-oxopentanoic acid, [60] 3-((S)-2-(5-(benzofuran-5-yl)-1-oxoindolin-2-yl)butanamide)-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)butanamide)-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.

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

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

9. The pharmaceutical composition according to claim 7, wherein the prevention or treatment of the caspase-related disease is by reducing IL-1β or reducing apoptosis.

10. A pharmaceutical composition comprising the isoindolinone derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to any one of claims 1 to 6, and a pharma- ceutically acceptable excipient.

11. The compound of the following formula I-1 is ３ -B(OH) ２ , R ３ -H and one of the compounds of formula I-c below to prepare a compound of formula I-2 below: preparing a compound of formula I-3 by hydrolyzing a compound of formula I-2 below: reacting a compound of formula I-3 with a compound of formula I-4 to prepare a compound of formula I-5: preparing a compound of formula I-6 by hydrolyzing a compound of formula I-5: and treating a compound of the following formula I-6 with an acid. 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 In the above formula, R １ , R ２ , R3 are defined as in formula I of claim 1.

12. The method according to claim 11, wherein the compound of formula I-1 is obtained by reacting a compound of formula I-a with a compound of formula I-b: 【Chemistry 9】 【Chemistry 10】 In the above formula, R ２ The definitions of are the same as those of formula I in claim 1.

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