RU2846274C2 - Novel compounds, derivatives of isoindolinone, as caspase inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to organic chemistry and involves a compound of formula I, pharmaceutically acceptable salts thereof, use thereof, a based pharmaceutical composition and a method of producing. In formula I, R¹ is halogen or C_6-12 aryloxy substituted with 1-5 halogens, R² is hydrogen or C_1-6 alkyl with a straight or branched chain, R³ is halogen or Q, Q is substituted or unsubstituted with 1-3 independent R^a, Q is phenyl, pyridinyl, tetrahydropyridinyl, pyrazolyl, pyrimidinyl, thiophenyl, pyrrolidinyl, naphthalenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl or dihydroimidazopyrazinyl, R^a is C_1-6 straight or branched chain alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, CO₂R^b, COR^b, NHR^b, S(O)₂R^b or 5-member heteroaryl, condensed with C6 aryl, R^b is hydrogen or C_1-6 alkyl with a straight or branched chain.

EFFECT: compound of formula I possessing caspase inhibiting activity.

12 cl, 1 tbl, 67 ex

Description

Field of technology

The present invention relates to caspase inhibitors, and more particularly to novel isoindolinone derivative compounds as caspase inhibitors.

State of the art

Caspase is a type of enzyme, a cysteine protease that exists as a tetramer in the α2β2 form, and a caspase inhibitor is a compound that can modulate inflammation or apoptosis caused by caspases by interfering with their activity. Diseases that can be treated with these compounds to eliminate or reduce symptoms include osteoarthritis, rheumatoid arthritis, degenerative arthritis, destructive bone diseases, liver diseases caused by hepatitis viruses, acute hepatitis, liver cirrhosis, brain injury caused by hepatitis viruses, fulminant liver failure in humans, sepsis, organ transplant rejection, coronary artery disease, dementia, stroke, AIDS-related traumatic brain injury, diabetes, and gastric ulcer.

Among various structural compounds known as caspase inhibitors, isoxazoline derivatives have been described in Korean Patent Applications No. 10-2004-0066726, No. 10-2006-0013107, and No. 10-2008-0025123. In addition, a prodrug of a caspase inhibitor based on an isoxazoline derivative is disclosed in WO 2007/015931 (applicant: Vertex Pharmaceuticals Incorporated, USA).

Purpose of the invention

The problem solved by the present invention is to provide new structured caspase inhibitory compounds that exhibit excellent caspase inhibitory activity.

Furthermore, the problem solved by the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases associated with caspase, comprising new structured compounds that inhibit caspase.

Furthermore, the problem solved by the present invention is to provide a method for preventing or treating diseases associated with caspase inhibition using a caspase inhibiting compound having a new structure.

Furthermore, the problem solved by the present invention is to provide the use of a caspase-inhibiting compound having a new structure for the prevention or treatment of caspase-related diseases.

Furthermore, the problem solved by the present invention is to provide a method for producing a caspase-inhibiting compound having a new structure.

The problem solved by the present invention is not limited to the problems mentioned above, and other technical problems not mentioned above can be clearly understood by those skilled in the art from the description given below.

The essence of the invention

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

<Formula I>

R ¹ is halogen or aryloxy substituted with 1-5 halogens,

R ² is hydrogen or C _1-6 straight or branched chain alkyl,

R ³ is halogen or Q, Q is substituted or unsubstituted by 1-3 independent R ^a ,

Q is aryl, aminoaryl, heteroaryl or non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5-7 membered ring having from 0 to 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 , COR ^b , CONHR ^b , CON(R ^b ) ₂ , NHR ^b , N(R ^b ) ₂ , NHCOR ^b , S(O) ₂ R ^b or heteroaryl fused to a saturated or unsaturated 5-7 membered ring having from 0 to 3 heteroatoms,

R ^b is hydrogen or C _1-6 straight or branched chain alkyl.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of caspase-related diseases, comprising an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, there is provided a method for preventing or treating a caspase-related disease, comprising: administering an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

According to another aspect of the present invention, there is provided the use of an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a caspase-related disease.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

According to another aspect of the present invention, there is provided a method for producing an isoindolinone derivative compound represented by the above formula I.

It was confirmed that the novel isoindolinone derivative compound of the present invention exhibits an excellent interleukin-1β (IL-1β)-reducing effect and an excellent apoptosis-reducing effect, thereby exhibiting excellent activity as a caspase inhibitor, and thus it was found that the novel isoindolinone derivative compound can be used for the prevention or treatment of caspase-related diseases.

Thus, the novel isoindolinone derivative compound of the present invention can be effectively used for the prevention or treatment of caspase-related diseases in the medical and pharmaceutical fields.

The effects of the present invention are not limited to the above effects, but should be understood to include all effects that can be deduced from the description of the invention or the composition of the invention set forth in the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound, an isoindolinone derivative, represented by the following formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein:

<Formula I>

R ¹ is halogen or aryloxy substituted with 1-5 halogens,

R ² is hydrogen or C _1-6 straight or branched chain alkyl,

R ³ is halogen or Q, Q is substituted or unsubstituted by 1-3 independent R ^a ,

Q is aryl, aminoaryl, heteroaryl or a non-aromatic heterocycle, and Q is optionally fused to a saturated or unsaturated 5-7 membered ring having from 0 to 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 , COR ^b , CONHR ^b , CON(R ^b ) ₂ , NHR ^b , N(R ^b ) ₂ , NHCOR ^b , S(O) ₂ R ^b , or heteroaryl fused to a saturated or unsaturated 5-7 membered ring having from 0 to 3 heteroatoms,

R ^b is hydrogen or C _1-6 straight or branched chain alkyl.

In one embodiment, R ¹ can be F or phenoxy substituted with 1-5 F.

In one embodiment, R ² may be hydrogen, methyl, ethyl, or propyl, straight or branched chain.

In one embodiment, ^R3 can be Br or Q, wherein 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.

In one embodiment, R ^a may be methyl, methoxy, F, trifluoromethyl, carboxy, acetyl, amino, methylsulfonyl or benzoisothiazolyl.

Representative examples of isoindolinone derivative compounds according to the present invention are as follows:

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

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

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

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

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

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

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

[9] 3-(2-(6-bromo-1-oxoisoindolin-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)butanamido)pentanoic acid,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In this description, the following definitions are used when defining a compound of formula I unless otherwise stated.

The term "alkyl" refers to a straight or branched chain hydrocarbonyl group, preferably _C1 - _C12 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl, and the like.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkoxy" means alkyloxy of 1 to 10 carbon atoms unless otherwise specified.

The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy substituted by one or more halogen atoms.

The term "heteroatom" means N, O, or S.

The term "aryl" means an aromatic hydrocarbon, preferably _C5 - _C12 aryl, more preferably _C5 - _C10 aryl. For example, aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term "heteroaryl" or "aromatic heterocycle" means a 3-12 membered, more preferably 5-10 membered aromatic hydrocarbon forming a single or fused cyclic ring which has one or more heteroatoms selected from N, O and S as ring atoms which may be fused to a benzo- or _C3 - _C8 cycloalkyl. For example, 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, and the like.

A non-aromatic heterocyclic ring is a non-aromatic carbocyclic ring having one or more heteroatoms, such as N, O, or S, within the ring. The ring may be 5, 6, 7, or 8-membered and/or fused to another ring, such as a cycloalkyl or aromatic ring. Examples of such compounds include 3-1H-benzimidazol-2-one, 3-1-alkylbenzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoic acid, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolan and benzothian, and the like.

Arylalkyl, alkylaryl and heteroarylalkyl refer to a group formed by combining aryl and alkyl or heteroaryl and alkyl as defined above and include, for example, benzyl, thiophene methyl, pyrimidine methyl and the like, but are not limited thereto.

Aryl groups include polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a 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, benzoisoxazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzoimidazolyl, benzothiophenyl, pyrazolopyridinyl, or dihydroimidazopyrazinyl. Also included within the scope of the term "aryl" as used herein are compounds having one or more carbocyclic aromatic and/or heteroaryl rings fused to a cycloalkyl or non-aromatic heterocyclic ring, such as indanyl or tetrahydrobenzopyranyl.

The compound represented by formula I according to the present invention can be prepared and used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts to enhance in vivo absorption or increase solubility, so that prodrugs, hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention. In addition, the compounds represented by formula I have chiral carbon atoms, so that their stereoisomers exist, and these stereoisomers are also within the scope of the present invention.

The term "prodrug" refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because in some cases they are easier to administer than the parent drug. For example, they may be orally bioavailable, whereas the parent drug may not be bioavailable. Prodrugs may also have better solubility in pharmaceutical compositions than the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound of the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid), in which the peptide is linked to an acidic group that is metabolically converted to expose the active site.

The term "hydrate" refers to a compound of the present invention or a salt thereof having a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "solvate" refers to a compound of the present invention or a salt thereof having a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefore include solvents that are volatile, non-toxic and/or suitable for human administration.

The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or sterically. Such isomers include both structural isomers, such as a tautomer, and stereoisomers, such as R- or S-isomers with an asymmetric carbon center, and geometric isomers (trans-, cis-). All isomers and mixtures thereof are also included within the scope of the present invention.

The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause significant irritation to the host or to the recipient thereof and does not impair the biological activity or physical properties of the compound. Pharmaceutical salts include an acid addition salt formed by an acid having a pharmaceutically acceptable anion and forming a non-toxic acid addition salt, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like, organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid and the like, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. For example, pharmaceutically acceptable salts of carboxylic acids include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine, guanidine and the like, organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine and the like. The compound of formula I of the present invention can also be converted into a salt thereof by conventional methods.

The present invention also provides a process for preparing a compound of formula I comprising the following steps.

(1) Obtaining a compound of formula I-2 by reacting a compound of formula I-1 below with one of R ³ -B(OH) ₂ , R ³ -H and formula Ic below.

This step may be a Suzuki coupling reaction in which 1) an aryl bromide compound of the formula I-1 below is reacted with R ³ -B(OH) ₂ or a pinacolboron compound of the formula Ic below to obtain an aryl-aryl compound. The catalyst used herein may be a catalyst commonly used in Suzuki coupling reactions, for example, but not limited to, a palladium catalyst may be used. Further, the reaction can be carried out at a reaction temperature commonly used in Suzuki coupling reactions using a solvent commonly used in Suzuki coupling reactions, for example, but not limited to, a toluene or 1,4-dioxane solvent at an elevated temperature (80-110°C) for an appropriate reaction time (for example, 10 hours or so). In addition, this step may be 2) a Birkwald reaction in which a compound of the formula I-1 is reacted with an amine compound to obtain an arylamine type compound. The catalyst used herein may be a catalyst commonly used in a Birkwald reaction, for example, but not limited to, a palladium catalyst may be used. In addition, the reaction may be carried out at a reaction temperature commonly used in a Burkhardt reaction using a solvent commonly used in a Burkhardt reaction, for example, but not limited to, a toluene solvent at an elevated temperature (e.g., 80°C) for an appropriate reaction time (e.g., 10 hours or so).

(2) Hydrolysis of the compound of formula I-2 below to obtain the compound of formula I-3 below.

This step is a hydrolysis reaction in which the compound of formula I-2 shown below is reacted with lithium hydroxide. The solvent used therein may be a solvent generally used in hydrolysis reactions, for example, a mixed solvent of tetrahydrofuran-water solution, etc., and the compound of formula I-3 can be obtained by reacting at an appropriate temperature (for example, room temperature) for an appropriate reaction time (for example, about 24 hours) to obtain the compound of formula I-3.

(3) Obtaining a compound of formula I-5 below by reacting a compound of formula I-3 below with a compound of formula I-4 below.

This step is a reaction in which a compound of formula I-3 having a carboxylic acid group reacts with a compound of formula I-4 having an amino group to form an amide bond. The solvent used in this step may be a solvent generally used in reactions of forming an amide bond, for example, DMF solvent, etc., and the reaction can be carried out at a suitable temperature (for example, room temperature).

(4) Hydrolysis of the compound of formula I-5 below to obtain the compound of formula I-6 below.

This step is a hydrolysis reaction in which a compound of formula I-5 below is reacted with lithium hydroxide. The solvent used in this step may be a solvent generally used in hydrolysis reactions such as a mixed solvent of tetrahydrofuran-water solution and the like, and the compound of formula I-6 can be obtained by reacting at an appropriate temperature (e.g., room temperature) for an appropriate reaction time (e.g., about 24 hours) to obtain a compound of formula I-6.

(5) Oxidation of the compound of formula I-6 below.

This step is a deprotection reaction in which the compound of formula I-6 below in the form of dimethyl chital is treated with an acid to obtain a ketone compound. The solvent used in this step may be any solvent commonly used in deprotection reactions, such as, but not limited to, aqueous hydrochloric acid.

<Formula I-1>

<Formula I-c>

<Formula I-2>

<Formula I-3>

<Formula I-4>

<Formula I-5>

<Formula I-6>

In the above formula, R ¹ , R ² and R ³ have the meanings as defined in formula I above.

In one embodiment, a compound of formula I-1 can be prepared by reacting a compound of formula I-a below with a compound of formula I-b below.

<Formula I-a>

<Formula I-b>

In the above formula, the definition of R ² is the same as in formula I above.

Schemes 1-64 of the examples are illustrated as a method for preparing a compound of formula I of the present invention, and the above-described preparation process does not limit the method for preparing a compound of formula I of the present invention. It is obvious that the preparation methods in Schemes 1-64 are only illustrative and can be easily modified by those skilled in the art depending on the particular substituent.

The present invention also provides a pharmaceutical composition for the prevention or treatment of a caspase-related disease, comprising an isoindolinone derivative compound represented by formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for preventing or treating a caspase-related disease, comprising: administering an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

The present invention also provides the use of an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a caspase-related disease.

In one embodiment, the caspase-associated disease may be osteoarthritis or pain.

Caspase inhibitory activity was measured for the isoindolinone derivative compounds of the present invention and they were found to exhibit caspase inhibitory activity either by reducing interleukin-1β (IL-1β) or by reducing apoptosis.

The present invention also provides a pharmaceutical composition comprising an isoindolinone derivative compound represented by the above formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

The additive may include a pharmaceutically acceptable carrier or diluent, each of which may be formulated according to conventional methods into the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols; for topical use; suppositories; and sterile injection solutions.

Pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. They also include diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents and surface-active agents. Solid dosage forms for oral use include tablets, pills, powders, granules, capsules and the like, which may include at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like, and may include lubricants such as magnesium stearate and talc. Liquid preparations for oral use may include suspensions, oral solutions, emulsions, syrups and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, flavoring agents, preservatives and the like. Parenteral preparations include sterilized aqueous solutions, non-aqueous vehicles, suspensions, emulsions, creams, lyophilized preparations and suppositories; non-aqueous vehicles and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl ester. Substrates for suppositories can be vitepsol, macrogol, tween 61, cocoa gum, lauric gum, glycerogelatin, etc.

The dosage of the active ingredient in the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the degree of the disease, the composition of the active ingredient, the route and duration of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dose of 0.0001-1000 mg/kg per day, preferably 0.01-100 mg/kg, and the dose can be administered once or in several divided doses per day. In addition, the pharmaceutical composition of the present invention can include 0.001-90% of the active ingredient by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock and humans by various routes, such as orally, dermally, intraperitoneally, rectally or by intravenous, intramuscular, subcutaneous, intrauterine dura mater injection or intracerebroventricular injection.

The present invention is now described in more detail using examples and experimental examples. However, the following examples and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

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

<Diagram 1>

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

Step 1-2 (Method B): Compound 1-1 (150 mg, 0.48 mmol) was dissolved in 1,4-dioxane (10 mL), then phenylboronic acid (70.3 mg, 0.58 mmol), 2 M 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 completion of the reaction, saturated brine (50 mL) was added, and extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give the target compound 1-2 (108 mg, 72%).

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

Step 1-4 (Method D): Compound 1-3 (75 mg, 0.254 mmol) was dissolved in dichloromethane (10 mL), then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.68 mg, 0.254 mmol), compounds 1-4 synthesized by known methods (WO2006/090997) (59.53 mg, 0.267 mmol), 1-hydroxybenzotriazole (34.32 mg, 0.254 mmol) and N,N-diisopropylethylamine (DIPEA, 39.48 mg, 0.305 mmol) were added and stirred at room temperature for 24 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution (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 by column chromatography to give the target compounds 1-5 (93 mg, 73%).

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

Step 1-6 (Method F): Compound 1-6 (69 mg, 0.146 mmol) was dissolved in acetic acid (2 ml), then 6 N aqueous hydrochloric acid solution (2 ml) was added and stirred at room temperature for 6 hours. After completion of the reaction, 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 and concentrated, and then separated by column chromatography to give the target compound 1 (17 mg, 27%).

^1H NMR (400 MHz, 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), 0.94-0.67 (m, 3H).

MS (ESI, LR) Calculated for _C23H24FN2O5 (MH ⁺ ₎ : _427.2 , found: _427.2 .

Example 2 5-fluoro-3-(2-(6-(naphthalene-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

<Diagram 2>

Using compound 1-1 and naphthalene-1-boronic acid as starting materials, the target compound 2 (21 mg) was obtained by method B/C/D/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 8.88-8.76 (m, 1H), 8.01 (dd, J=13.73, 8.24 Hz, 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).

MS (ESI, LR) Calculated for C ₂₇ H ₂₆ FN ₂ O ₅ (MH ⁺ ): 477.2, found: 477.2.

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

<Diagram 3>

Step 3-1 (Method B'): Compound 1-1 (150 mg, 0.481 mmol) was dissolved in toluene (10 mL) in a sealed tube, 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), pyrrolidine (47.84 mg, 0.673 mmol) were added, sealed and stirred at 80 °C for 10 hours. After completion of the reaction, diluted with saturated brine (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography to give the title compound 3-1 (109 mg, 75%).

Step 3-2: Using compound 3-1 (109 mg, 0.36 mmol), the target compound 3-2 (91 mg, 86%) was obtained using method C.

Step 3-3 (Method D'): After compound 3-2 (91 mg, 0.316 mmol) was dissolved in N,N-dimethylformamide (3 ml), HATU (144 mg, 0.379 mmol) and DIPEA (61.33 mg, 0.473 mmol) were added thereto, and stirred at room temperature for 10 min. Compound 1-4 (73.97 mg, 0.331 mmol) was added to the reaction solution, which was stirred at room temperature for 24 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution (30 ml) was added thereto, and it was extracted with ethyl acetate (40 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography to give the target compound 3-3 (111 mg, 71%). [HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide, Azabenzotriazole Tetramethyluronium hexafluorophosphate), DIPEA (N,N-diisopropylethylamine)]

Step 3-4/3-5: Using compound 3-3 as a starting material, the target compound 3 (31 mg) was obtained using method E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₇ FN ₃ O ₅ (MH ⁺ ): 420.2, found: 420.2.

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

<Diagram 4>

Using compound 1-1 and pyridine-3-boronic acid as starting materials, the target compound 4 (31 mg) was obtained by method B/C/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.84 (s, 1H), 8.59-8.47 (m, 1H), 8.19-7.81 (m, 4H), 7.72 (t, J= 7.02 Hz, 1H), 7.55 (t, J= 7.63 Hz, 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).

MS (ESI, LR) Calculated for _C22H23FN3O5 (MH ⁺ ₎ : _428.2 , found: _428.1 .

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

<Diagram 5>

Using compound 1-1 and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials, the target compound 5 (21 mg) was obtained using method B/C/D'/E/F sequentially.

¹H NMR (400 MHz, 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=7.63 Hz, 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).

MS (ESI, LR) Calculated _{for C20H22FN4O5} (MH ⁺ ) _417.1 , found: _417.1 .

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

<Diagram 6>

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

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

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

Step 6-4/6-5/6-6/6-7: Using compound 6-3 (88 mg, 0.223 mmol), the target compound 6 (21 mg) was obtained using method C/D/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.72-8.58 (m, 1H), 7.46 (dd, J= 8.39, 4.20 Hz, 1H), 7.29 (d, J =8.39 Hz, 1H), 7.20 (dd, J =5.72, 2.29 Hz, 1H), 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).

MS (ESI, LR) _Calculated for _C22H30FN4O7S (MH ⁺ ₎ : _513.2 , Found: 513.2.

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

<Diagram 7>

Step 7-1: Using compound 1-1 and (150 mg, 0.48 mmol), 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), the target compound 7-1 (124 mg, 62%) was obtained using method B.

Step 7-2: Compound 7-1 (124 mg, 0.297 mmol) was dissolved in ethyl acetate (5 mL), then 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 target compound 7-2 (99 mg, 95%) was obtained by concentration.

Step 7-3: Compound 7-2 (99 mg, 0.282 mmol) was dissolved in dichloromethane (30 mL), then 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 completion of the reaction, it 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 separated by column chromatography to give the target compound 7-3 (89 mg, 80%).

Step 7-4/7-5/7-6/7-7: Using compound 7-3 (89 mg, 0.227 mmol), the target compound 7 (19 mg) was obtained using method C/D/E/F sequentially.

¹H NMR (400 MHz, 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=5.72 Hz, 2H), 2.95 (s, 3H), 2.87-2.35 (m, 4H), 2.10-1.64 (m, 2H), 0.93-0.66 (m, 3H).

MS (ESI, LR) Calculated for C ₂₃ H ₂₉ FN ₃ O ₇ S (MH ⁺ ): 510.2, found: 510.1.

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

<Diagram 8>

Using 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 as starting materials, the target compound 8 (19 mg) was obtained using method B/C/D'/E/F sequentially.

¹H NMR (400 MHz, 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=7.93 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J= 7.93 Hz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₃ FN ₄ O ₆ (MH ⁺ ): 483.2, found: 483.0.

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

<Diagram 9>

Using compound 1-1 as the starting material, the target compound 9 (23 mg) was obtained by method C/D'/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₁₇ H ₁₉ BrFN ₂ O ₅ (MH ⁺ ): 429.0, found: 429.0.

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

<Diagram 10>

Using compound 1-1 and 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine as starting materials, the target compound 10 (31 mg) was obtained using method B'/C/D/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₆ F ₄ N ₅ O ₅ (MH ⁺ ): 540.2, found: 540.1.

Example 11 5-fluoro-3-(2-(6-(naphthalene-1-ylamino)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

<Diagram 11>

Using compound 1-1 and 1-naphthylamine as starting materials, the target compound 11 (18 mg) was obtained using method B'/C/D/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.18 (s, 1H), 8.55-8.41 (m, 1H), 8.19 (d, J =8.77 Hz, 1H), 8.12 (d, J = 8.39 Hz, 1H), 7.92 (d, J =8.01 Hz, 1H), 7.61 (d, J= 8.01 Hz, 1H), 7.56-7.39 (m, 4H), 7.35 (d, J =7.25 Hz, 1H), 7.28 (d, J =7.63 Hz, 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 =7.25 Hz, 3H).

MS (ESI, LR) Calculated for C ₂₇ H ₂₇ FN ₃ O ₅ (MH ⁺ ): 492.2, found: 492.1.

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

<Diagram 12>

Using compound 1-1 and (2-fluoro-4-(methylsulfonyl)phenyl)boronic acid as starting materials, the target compound 12 (32 mg) was obtained using method B/C/D/E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₅ F ₂ N ₂ O ₇ S (MH ⁺ ): 523.1, found: 523.1.

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

<Diagram 13>

Using compound 1-1 and (6-methoxypyridin-3-yl)boronic acid as starting materials, the target compound 13 (31 mg) was obtained using method B/C/D/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.53 (s, 1H), 8.54 (s, 1H), 8.10 (d, J = 8.85 Hz, 1H), 7.95-7.80 (m, 2H), 7.74-7.50 (m, 2H), 6.93 (d, J = 8.54 Hz, 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).

MS (ESI, LR) Calculated _{for C23H25FN3O6} (MH ⁺ ₎ : _458.2 , found: 458.1.

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

<Diagram 14>

Using compound 1-1 and (4-(trifluoromethyl)phenyl)boronic acid as starting materials, the target compound 14 (28 mg) was obtained using method B/C/D/E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₃ F ₄ N ₂ O ₅ (MH ⁺ ): 495.1, found: 495.1.

Example 15 3-(2-(6-(3,6-dihydro-2H-pyran-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid

<Diagram 15>

Using compound 1-1 and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as starting materials, the target compound 15 (18 mg) was obtained using method B/C/D/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated _{for C22H26FN2O6} (MH ⁺ ₎ : _433.2 , found: 433.1.

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

<Diagram 16>

Using compound 1-1 and benzo[b]thiophen-3-ylboronic acid as starting materials, the target compound 16 (23 mg) was obtained by method B/C/D/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₄ FN ₂ O ₅ S (MH ⁺ ): 483.1, found: 483.1.

Example 17 4-(2-(1-((1-carboxy-4-fluoro-3-oxobutan-2-yl)amino)-1-oxobutan-2-yl)-3-oxoisoindolin-5-yl)benzoic acid

<Diagram 17>

Using compound 1-1 and (4-(tert-butoxycarbonyl)phenyl)boronic acid as starting materials, the target compound 17 (18 mg) was obtained using method B/C/D/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₄ FN ₂ O ₇ (MH ⁺ ): 471.1, found: 471.1.

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

<Diagram 18>

Using compound 1-1 and (4-acetylphenyl)boronic acid as starting materials, the target compound 18 (29 mg) was obtained by method B/C/D/E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₆ FN ₂ O ₆ (MH ⁺ ): 469.2, found: 469.1.

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

<Diagram 19>

Using compound 1-1 and 3-(piperazin-1-yl)benzo[d]isothiazole as starting materials, the target compound 19 (22 mg) was obtained using method B''/C/D/E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₈ H ₃₁ FN ₅ O ₅ S (MH ⁺ ): 568.2, found: 568.2.

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

<Diagram 20>

Using compound 1-1 and (6-(trifluoromethyl)pyridin-3-yl)boronic acid as starting materials, the target compound 20 (31 mg) was obtained using method B/C/D/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 12.89 (s, 1H), 9.18 (s, 1H), 8.83 (s, 1H), 8.47 (d,J=6.10 Hz, 1H), 8.18-8.06 (m, 2H), 8.01 (d, J=8.01 Hz, 1H), 7.80 (d,J=7.63 Hz, 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).

MS (ESI, LR) Calculated for C ₂₃ H ₂₂ F ₄ N ₃ O ₅ (MH ⁺ ): 496.1, found: 496.1.

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

<Diagram 21>

Using compound 1-1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine as starting materials, the target compound 21 (17 mg) was obtained using method B/C/D/E/F sequentially.

¹H NMR (400 MHz, 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=7.93 Hz, 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₃ FN ₅ O ₅ (MH ⁺ ): 444.2, found: 444.1.

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

<Diagram 22>

Using compound 1-1 and benzofuran-3-ylboronic acid as starting materials, the target compound 22 (24 mg) was obtained using method B/C/D/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 6.71 Hz, 1H), 7.80-7.73 (m, 1H), 7.69 (d, J = 7.32 Hz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₄ FN ₂ O ₆ (MH ⁺ ): 467.2, found: 467.1.

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

<Diagram 23>

Using compound 1-1 and (2-aminopyridin-4-yl)boronic acid as starting materials, the target compound 23 (4 mg) was obtained using method B/C/D/E/F sequentially.

MS (ESI, LR) Calculated for C ₂₂ H ₂₄ FN ₄ O ₅ (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

<Diagram 24>

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 method B/A/C/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.76 (s, 1H), 8.27 (d, J = 4.58 Hz, 1H), 7.96 (d, J = 4.58 Hz, 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₄ FN ₄ O ₅ (MH ⁺ ): 431.2, found: 431.2.

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

<Diagram 25>

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 method B/A/C/D'/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 8.87-8.68 (m, 1H), 8.03 (t, J=8.01 Hz, 2H), 7.75 (d,J=2.29 Hz, 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₄ FN ₄ O ₅ (MH ⁺ ): 431.2, found: 431.2.

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

<Diagram 26>

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

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₂ FN ₂ O ₆ (MH ⁺ ): 467.2, found: 467.1.

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

<Diagram 27>

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 method B/A/C/D'/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 8.79-8.63 (m, 1H), 7.82 (t, J=9.16 Hz, 2H), 7.68-7.55 (m, 1H), 7.22-7.12 (m, 2H), 6.95 (d, J=8.01 Hz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₆ FN ₂ O ₇ (MH ⁺ ): 485.2, found: 485.2.

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

<Diagram 28>

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

¹ H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₂ FN ₂ O ₅ S (MH ⁺ ): 433.1, found: 433.1.

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

<Diagram 29>

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 method B/A/C/D'/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 12.90 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.21 (d,J=7.63 Hz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.2.

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

<Diagram 30>

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

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.1.

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

<Diagram 31>

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 method B/A/C/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.99 (s, 1H), 8.98 (s, 1H), 8.13 (d, J =7.32 Hz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 477.5.

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

<Diagram 32>

Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzo[d]thiazole and 6-bromoisoindolin-1-one as starting materials, the target compound 32 (24 mg) was obtained using method B/A/C/D'/E/F sequentially.

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

MS (ESI, LR) Calculated for C ₂₄ H ₂₃ FN ₃ O ₅ S (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

<Diagram 33>

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

¹H NMR (400 MHz, DMSO-d₆) d 12.94 (c, 1H), 8.76 (d,J=7.02 Hz, 1H), 8.47 (s, 1H), 8.05-7.89 (m, 3H), 7.70 (d, J=7.63 Hz, 1H), 7.37 (t,J=7.02 Hz, 1H), 6.98 (t,J=6.41 Hz, 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₄ FN ₄ O ₅ (MH ⁺ ): 467.2, found: 467.1.

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

<Diagram 34>

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

¹H NMR (400 MHz, DMSO-d₆) d 12.98 (c, 1H), 8.95 (d,J=3.66 Hz, 1H), 8.18 (d,J=8.24 Hz, 1H), 8.10 (d,J=8.54 Hz, 1H), 7.91-7.71 (m, 4H), 7.62 (d, J=7.02 Hz, 1H), 7.53 (dd,J=8.39, 3.66 Hz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.2.

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

<Diagram 35>

Using isoquinolin-8-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 35 (19 mg) was obtained using method B/A/C/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.14 (s, 1H), 8.59-8.46 (m, 1H), 8.05 (d, J =7.63 Hz, 1H), 7.96-7.72 (m, 6H), 7.66 (d, J =7.63 Hz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.2.

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

<Diagram 36>

Using isoquinolin-5-ylboronic acid and 6-bromoisoindolin-1-one as starting materials, the target compound 36 (23 mg) was obtained using method B/A/C/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.42 (s, 1H), 8.50 (d, J =5.80 Hz, 1H), 8.24-8.18 (m, 1H), 7.84-7.73 (m, 6H), 7.65 (d, J =4.88 Hz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.1.

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

<Diagram 37>

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

^1H NMR (400 MHz, 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, 4H), 5.40-4.28 (m, 6H), 2.94-2.31 (m, 2H), 2.19-1.69 (m, 2H), 1.00-0.61 (m, 3H).

MS (ESI, LR) Calculated for C ₂₆ H ₂₅ FN ₃ O ₅ (MH ⁺ ): 478.2, found: 478.2.

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

<Diagram 38>

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

¹H NMR (400 MHz, 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).

MS (ESI, LR) _Calculated for _C22H20FN4O6 (MH ⁺ ₎ : _455.1 , found: 455.1.

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

<Diagram 39>

Using compound 38-1 and benzofuran-3-ylboronic acid as starting materials, the target compound 39 (33 mg) was obtained using method B/C'/D/E/F sequentially.

¹H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for _C23H20FN2O6 (MH ⁺ ₎ : _439.1 , found: _439.1 .

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

<Diagram 40>

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

¹H NMR (400 MHz, 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).

MS (ESI, LR) _{Calculated for C23H20FN2O5S} (MH ⁺ ₎ : 455.1, found: 455.1.

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

<Diagram 41>

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

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.91 (s, 1H), 8.05 (d, J = 2.14 Hz, 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).

MS (ESI, LR) Calculated for _C23H20FN2O6 (MH ⁺ ₎ : _439.1 , found: _439.1 .

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

<Diagram 42>

Step 42-1: Using methyl 5-bromo-2-methylbenzoate (400 mg, 1.75 mmol) and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (330 mg, 1.83 mmol) as starting materials, the title compound 42-1 (444 mg, 89%) was prepared using Method B.

Step 42-2 (Method G): After compound 42-1 (450 mg, 1.58 mmol) was dissolved in chloroform (60 mL), N-bromosuccinimide and (NBS, 333.55 mg, 1.87 mmol) AIBN (25 mg, 0.16 mmol) were added and stirred under reflux for 24 hours. After completion of the reaction, the reaction solution was washed with saturated brine (50 mL), the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to give the target compound 42-2 (345 mg, 60%).

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

Step 42-4/42-5: Using compound 42-3 (150 mg, 0.408 mmol), the target compound 42 (44 mg) was obtained using method D'/E/F sequentially.

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₈ FN ₂ O ₇ (MH ⁺ ): 499.2, found: 499.1.

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

<Diagram 43>

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

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₂ H ₂₉ FN ₃ O ₅ (MH ⁺ ): 434.2, found: 434.1.

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

<Diagram 44>

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

^1H NMR (400 MHz, 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).

MS (ESI, LR) Calculated for C ₂₆ H ₂₆ FN ₂ O ₆ (MH ⁺ ): 481.2, found: 481.1.

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

<Diagram 45>

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 method B/G/H/D'/E/F sequentially.

¹H NMR (400 MHz, DMSO-d₆) d 12.43 (s, 1H), 10.72 (d, J=9.46 Hz, 2H), 9.05-8.91 (m, 1H), 7.79-7.76 (m, 2H), 7.70-7.61 (m, 1H), 7.28 (d, J=7.93 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J=7.93 Hz, 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₆ FN ₄ O ₆ (MH ⁺ ): 497.2, found: 497.1.

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

<Diagram 46>

Using compound 43-2 and tert-butyl L-alanine 1 hydrochloride as starting materials, the target compound 46 (24 mg) was obtained using the H/D'/E/F method sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 12.81 (s, 1H), 7.36 (d, J =8.01 Hz, 1H), 6.80 (dd, J =8.39, 2.29 Hz, 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 =7.63 Hz, 3H).

MS (ESI, LR) Calculated for _C20H25FN3O5 (MH ⁺ ₎ : _406.2 , found _: 406.1.

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

<Diagram 47>

Using compound 45-2 and tert-butyl L-alanine 1 hydrochloride as starting materials, the target compound 47 (31 mg) was obtained using the H/D'/E/F method sequentially.

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

MS (ESI, LR) Calculated for C ₂₃ H ₂₂ F N ₄ O ₆ (MH ⁺ ): 469.1, found: 469.1.

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

<Diagram 48>

Using compound 42-2 and tert-butyl L-alanine 1 hydrochloride as starting materials, the target compound 48 (19 mg) was obtained using the H/D'/E/F method sequentially.

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

MS (ESI, LR) Calculated for C ₂₄ H ₂₄ FN ₂ O ₇ (MH ⁺ ): 471.1, found: 471.1.

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

<Diagram 49>

Using compound 44-2 and tert-butyl L-alanine 1 hydrochloride as starting materials, the target compound 49 (29 mg) was obtained using the H/D'/E/F method sequentially.

¹H NMR (400 MHz, 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=7.25 Hz, 3H).

MS (ESI, LR) Calculated for C ₂₄ H ₂₂ FN ₂ O ₆ (MH ⁺ ): 453.1, found: 453.1.

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

<Diagram 50>

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

Step 50-2: Compound 50-1 was dissolved in acetonitrile (300 mL), then [(1S)-1-tert-butoxycarbonylpropyl]ammonium chloride (21.287 g, 108.78 mmol) and DIPEA (56.84 mL, 326.33 mmol) were added and the reaction mixture was stirred under reflux for 5 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (500 mL), then washed successively with water (300 mL), saturated aqueous ammonium chloride solution (300 mL) and saturated brine (300 mL), the organic layer was dried over magnesium anhydride, filtered, concentrated and separated by column chromatography to give the title compound 50-2 (25.1 g, 65% over 2 steps).

MS (ESI, LR) Calculated for C ₁₆ H ₂₀ BrNO ₃ Na (MNa ⁺ ): 376.1, found: 376.1.

Step 50-3: Using compound 50-2 and benzofuran-2-ylboronic acid as starting materials, the target compound 50-3 was prepared using Method B.

MS (ESI, LR) _{Calculated for C24H25NO4Na (} MNa ⁺ ): _414.2 , found: 414.2.

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

MS (ESI, LR) _Calculated for _C20H17NO4Na (MNa ⁺ ): _358.1 , found: 358.1.

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

MS (ESI, LR) Calculated for C ₁₈ H ₁₆ F ₄ NO ₄ (MH ⁺ ): 386.1, found: 386.1.

Step 50-6 (Method D'): Using compound 50-4 and compound 50-5 , the target compound 50-6 was prepared using Method D'.

MS (ESI, LR) Calculated for C ₃₈ H ₃₁ F ₄ N ₂ O ₇ (MH ⁺ ): 703.2, found: 703.2.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.50 (s, 1H), 8.88 (dd, J = 11.7, 7.5 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.08-8.01 (m, 2H), 8.00-7.93 (m, 1H), 7.79 (dd, J = 8.5, 1.8 Hz, 1H), 7.77-7.71 (m, 1H), 7.65-7.51 (m, 1H), 7.45 (dtd, J = 15.9, 7.3, 1.4 Hz, 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, 3.0 Hz, 1H), 4.07 (kv, J =7.1 Hz, 1H), 2.82 (ddd, J =16.9, 5.9, 1.7 Hz, 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 =7.3 Hz, 3H).

MS (ESI, LR) Calculated for C ₃₁ H ₂₅ F ₄ N ₂ O ₇ (MH ⁺ ): 613.2, found: 613.2.

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

<Diagram 51>

Using compound 50-2 as starting materials, the target compound 51 was obtained using the B/I/D'/J method sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 8.85 (dd, J = 11.2, 7.5 Hz, 1H), 7.91-7.82 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.66-7.52 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 5.27 (d, J = 4.1 Hz, 2H), 4.81 (dd, J = 9.7, 5.7 Hz, 1H), 4.74-4.62 (m, 2H), 4.53 (d, J = 17.7 Hz, 1H), 4.33 (s, 4H), 4.07 (q, J = 7.1 Hz, 1H), 2.80 (dd, J = 16.9, 6.0 Hz, 1H), 2.62 (dd, J = 16.9, 7.0 Hz, 1H), 2.03 (s, 2H), 1.84 (dq, J = 9.5, 7.2 Hz, 1H), 1.21 (t, J = 7.1 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H).

MS (ESI, LR) Calculated _{for C31H27H4N2O8} (MH ⁺ ₎ : _631.17 , found: _631.2 .

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

<Diagram 52>

Using compound 50-2 and (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)boronic acid as starting materials, the target compound 52 was prepared using method B/I/D'/J sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 10.73 (d, J = 7.7 Hz, 2H), 8.84 (d, J = 7.4 Hz, 1H), 7.89-7.80 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.55 (ddd, J = 11.0, 7.3, 3.6 Hz, 1H), 7.29 (dd, J = 8.1, 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 5.25 (d, J = 4.2 Hz, 2H), 4.79 (dd, J = 9.6, 5.7 Hz, 1H), 4.73-4.60 (m, 2H), 4.51 (d, J =17.6 Hz, 1H), 4.03 (kv, J =7.1 Hz, 1H), 2.78 (dd, J =16.9, 5.9 Hz, 1H), 2.60 (dd, J =16.9, 7.0 Hz, 1H), 2.00-1.92 (m, 2H), 1.87-1.77 (m, 1H), 1.18 (t, J =7.1 Hz, 1H), 0.86 (t, J =7.3 Hz, 3H).

MS (ESI, LR) Calculated for C ₃₀ H ₂₅ F ₄ N ₄ O ₇ (MH ⁺ ): 629.2, found: 629.2.

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

<Diagram 53>

Using compound 50-2 and pyrrolidine as starting materials, the target compound 53 was prepared using the B'/I/D'/J method sequentially.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (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 = 17.7 Hz, 2H), 4.41 (dd, J = 17.3, 11.7 Hz, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.39 (q, J = 5.5 Hz, 4H), 2.84-2.69 (m, 1H), 2.09 (h, J =4.5 Hz, 6H), 1.96-1.83 (m, 1H), 1.26 (t, J =7.1 Hz, 1H), 0.96 (td, J =7.4, 3.7 Hz, 3H).

MS (ESI, LR) Calculated for C ₂₇ H ₂₈ F ₄ N ₃ O ₆ (MH ⁺ ): 566.2, found: 566.2.

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

<Diagram 54>

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

MS (ESI, LR) Calculated for C ₁₈ H ₁₆ F ₄ NO ₄ (MH ⁺ ): 386.1, found: 386.1.

Step 54-2: Using compound 51-2 and compound 54-1 as starting materials, the target compound 54 was prepared using method D'/J sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 8.85 (dd, J = 11.2, 7.5 Hz, 1H), 7.92-7.82 (m, 2H), 7.68 (dd, J = 7.8, 1.8 Hz, 1H), 7.58 (dddd, J = 18.1, 10.8, 8.9, 5.3 Hz, 1H), 7.23 (dd, J = 8.1, 1.4 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 5.35-5.14 (m, 2H), 4.80 (ddd, J = 12.4, 9.6, 5.9 Hz, 1H), 4.76-4.63 (m, 2H), 4.54 (dd, J =17.8, 3.1 Hz, 1H), 4.33 (s, 4H), 4.07 (kv, J =7.1 Hz, 1H), 2.81 (ddd, J =16.9, 5.9, 2.2 Hz, 1H), 2.63 (dt, J =16.8, 7.1 Hz, 1H), 2.03 (s, 2H), 1.84 (s, 1H), 1.22 (t, J =7.1 Hz, 1H), 0.89 (t, J =7.3 Hz, 3H).

MS (ESI, LR ₎ Calculated _{for C31H27H4N2O8} (MH ⁺ ₎ : _631.2 , found 631.2.

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

<Diagram 55>

Using compound 51-2 and 1-4 , the target compound 55 was prepared using the D'/E/F method sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm)=12.51 (s, 1H), 8.78 (dd, J =10.8, 7.3 Hz, 1H), 7.92-7.76 (m, 2H), 7.69-7.60 (m, 1H), 7.20 (dd, J =8.1, 2.0 Hz, 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, 5.9 Hz, 1H), 1.96 (d, J =17.8 Hz, 1H), 1.81 (dp, J =15.0, 7.1 Hz, 1H), 0.94-0.75 (m, 3H).

MS (ESI, LR) Calculated for C ₃₀ H ₂₅ F ₄ N ₄ O ₇ (MH ⁺ ): 485.2, found 485.2.

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

<Diagram 56>

Using compound 52-2 and 1-4 , the target compound 56 was prepared using the D'/E/F method sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm)=12.51 (s, 1H), 10.72 (d, J =7.3 Hz, 2H), 8.96-8.31 (m, 1H), 7.85 (d, J =11.4 Hz, 2H), 7.67 (dd, J =8.3, 3.9 Hz, 1H), 7.30 (d, J =8.2 Hz, 1H), 7.21 (s, 1H), 7.03 (d, J =8.1 Hz, 1H), 5.36-5.06 (m, 1H), 4.91-4.57 (m, 3H), 4.51 (d, J =17.8 Hz, 2H), 2.78 (d, J =17.1 Hz, 1H), 2.65-2.55 (m, 1H), 1.89 (d, J = 62.7 Hz, 2H), 0.87 (kW, J = 9.1, 6.4 Hz, 3H).

MS (ESI, LR) Calculated for C ₃₀ H ₂₅ F ₄ N ₄ O ₇ (MH ⁺ ): 483.2, found 483.2.

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

<Diagram 57>

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

Step 57-2: Compound 57-1 was dissolved in acetonitrile (150 mL), and [(1S)-1-tert-butoxycarboylpropyl]ammonium chloride (8.541 g, 43.65 mmol) and DIPEA (22.81 mL, 130.95 mmol) were added, and the reaction mixture was stirred under reflux for 5 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (300 mL), then washed successively with water (100 mL), saturated aqueous ammonium chloride solution (300 mL), and saturated brine (300 mL), the organic layer was dried over magnesium anhydride, filtered, concentrated, and separated by column chromatography to give the title compound 50-2 (10.4 g, 67% over 2 steps).

¹ H NMR (400 MHz, CDCl ₃ ) 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).

Step 57-3: Using compound 57-2 and benzofuran-3-ylboronic acid as starting materials, the target compound 57-3 was prepared using Method B.

¹ H NMR (400 MHz, CDCl ₃ ) 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): By reacting compound 57-3 according to Method I, the target compound 57-4 was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Step 57-5 (Method D'): Using compound 57-4 and compound 1-4 , the target compound 57-5 was prepared using Method D'.

^1H NMR (400 MHz, CDCl ₃ ) 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).

Step 57-6 (Method E): By reacting compound 57-5 by Method E, the desired compound 57-6 was obtained.

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

Step 57-7 (Method F): By reacting compound 57-6 by Method F, the title compound 57 was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm)=8.87-8.73 (m, 1H), 8.50 (s, 1H), 8.06-7.93 (m, 2H), 7.83-7.75 (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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₄ FN ₂ O ₆ (MH ⁺ ): 467.2, found: 467.1.

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

<Diagram 58>

Using compound 57-2 and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid, the target compound 58 was prepared using method B/I/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm)=8.85-8.66 (m, 1H), 7.83-7.82 (m, 1H), 7.71 (s, 2H), 7.23-7.20 (m, 2H), 6.99-6.97 (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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₆ FN ₂ O ₇ (MH ⁺ ): 485.4 found: 485

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

<Diagram 59>

Using compound 57-2 and benzothiophen-3-ylboronic acid, the target compound 59 was prepared using method B/I/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₄ FN ₂ O ₅ S (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

<Diagram 60>

Using compound 57-2 and benzofuran-3-ylboronic acid, the target compound 60 was prepared using method B/I/D'/E/F sequentially.

^1H NMR (400 MHz, DMSO-d ₆ ) 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).

MS (ESI, LR) Calculated for C ₂₅ H ₂₃ FN ₂ O ₆ (MH ⁺ ): 467.2, found: 467.1.

Example 61. 5-fluoro-3-(( S )-2-(5-(naphthalene-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid

<Diagram 61>

Using compound 57-2 and naphthalene-1-boronic acid, the target compound 61 was prepared using method B/I/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm)=8.75-8.69 (m, 1H), 8.09 (m, 2H), 7.91-7.77 (m, 2H), 7.64-7.43 (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).

MS (ESI, LR) Calculated for C ₂₇ H ₂₆ FN ₂ O ₅ (MH ⁺ ): 477.2, found: 477.2.

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

<Diagram 62>

Using compound 57-2 and 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, the target compound 62 was prepared using method B'/I/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

MS (ESI, LR) Calculated for C ₂₄ H ₂₆ F ₄ N ₅ O ₅ (MH ⁺ ): 540.2, found: 540.1.

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

<Diagram 63>

Using compound 57-2 and 3-(piperazin-1-yl)benzo[d]isothiazole, the target compound 63 was prepared using method B'/I/D'/E/F sequentially.

^1H NMR (400 MHz, DMSO-d ₆ ) 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).

MS (ESI, LR) Calculated for C ₂₈ H ₃₁ FN ₅ O ₅ S (MH ⁺ ): 568.2, found: 568.2.

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

<Diagram 64>

Using compound 57-2 and pyrrolidine, the target compound 64 was prepared using method B'/I/D'/E/F sequentially.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

MS (ESI, LR) Calculated for C ₂₁ H ₂₇ FN ₃ O ₅ (MH ⁺ ): 420.2, found: 420.2.

Experimental Example 1. Evaluation of Caspase-1 Inhibition Activity

In order to determine the caspase-1 inhibiting activity of the compounds of the present invention obtained in Example, the caspase-1 activity was measured using a substrate with a fluorescent dye attached thereto. The fluorescent dye attached to the substrate is released from the substrate by the caspase and exhibits fluorescence.

The compound was dissolved in DMSO and stored at -20°C. Enzyme reactions were carried out in a buffer containing 50 mM HEPES (pH 8.0), 50 mM KCl, 200 mM NaCl, 10 mM DTT, 0.1% CHAPS (w/v). Enzyme inactivation was measured in the presence of different concentrations of the compound using the fluorescent substrate N-acetyl-Tyr-Val-Ala-Asp-7-amido-4-trifluoromethylcoumarin (Ac-YVAD-AFC) (Sigma) at a concentration of 50 μM and 1 unit of recombinant human caspase-1 (Enzo life science). A CLARIOstar Plus spectrometer (BMG Labtech) was used to measure the reaction rate as a function of time in the wavelength range of 400/505 nm (Ex/Em). The inhibition rate constant of the compound, k _observance (k _obs ), was obtained from Equation 1 below and was expressed as k _obs /[I] by linear regression analysis of concentration versus k _obs . If the value of k _obs /[I] is 20 or greater, it is designated as A, if it is 10 or greater but less than 20, it is designated as B, if it is 1 or greater but less than 10, it is designated as C, and if it is less than 1, it is designated as D.

<Equation 1>

k _obs = -ln(1 - A _t / A _max ) / t

In the above equation, A _t means the rate of the enzymatic reaction at time t (min), and A _max means the maximum rate of the reaction.

As a result, as shown in Table 1, each compound was confirmed to inhibit caspase-1 activity, thereby confirming that the compounds of the present invention are direct inhibitors of caspase-1.

Experimental Example 2. Measurement of proinflammatory activity of interleukin-1β inhibition in human THP-1 monocytic cells

Caspase-1 is known as IL-1β-converting enzyme (ICE). Activated caspase-1 is involved in the cleavage of the pro-form of IL-1β to produce the mature form, which is then secreted to cause inflammation. Therefore, the compounds identified in Experimental Example 1 were tested to determine whether their caspase-1 inhibition activities affected IL-1β production.

THP-1 cells (ATCC) were cultured in RPMI 1640 medium (Hyclone) containing 10% fetal bovine serum (FBS, Gibco) and antibiotics (100 U/ml penicillin, 0.1 mg/ml streptomycin, Cytiva) at 37°C under 5% _CO2 conditions. The cultured THP-1 cells were seeded in the medium at a concentration of 3× ¹⁰⁵ cells/well in 24-well plates (Celvest) and then treated with 1 μM phorbol 12-myristate 13-acetate (PMA) (Sigma) for 24 h to induce differentiation. Differentiated THP-1 cells were pretreated with 10 μg/ml lipopolysaccharide (LPS from E. coli 0111:B4 (InvivoGen)) in serum-free RPMI 1640 medium for 24 h to induce an inflammatory response. After removing LPS, the compounds were pretreated for 1 h at a concentration of 100 nM in the same medium, then 5 mM ATP (InvivoGen) was added and incubated for 24 h in an incubator. The treated medium was collected and centrifuged, IL-1β was quantified using an enzyme-linked immunosorbent assay kit (ELISA kit, R&D system), and the absorbance was measured at 450 nm using a CLARIOstar Plus spectrometer. The inhibition activity was designated as a if it was 50% or more, b if it was 30% or more but less than 50%, c if it was 10% or more but less than 30%, and d if it was less than 10%.

As shown in Table 1, treatment with the compounds of the present invention resulted in a decrease in the level of IL-1β. Thus, the inventors confirmed the ability of the compounds of the present invention to inhibit inflammation by reducing the level of IL-1β. In particular, since intracellular caspase-1 is involved in the maturation of IL-1β, the inventors confirmed the relationship with the caspase-1 inhibitory activity identified in Experimental Example 1 above.

Experimental Example 3. Measurement of Apoptosis Inhibition Activity in Human T-Lymphocyte Jurkat Cells

Apoptosis, a type of programmed cell death, is a genetically regulated pathway that plays an important role in maintaining cellular homeostasis. It is usually induced either exogenously through apoptotic receptors or endogenously through mitochondria. Caspase-8 and 9, known as initiators, are activated by exogenous and endogenous factors, respectively, and mediate cell death by activating the downstream effector caspase-3. Morphologically, apoptosis is characterized by cell shrinkage, DNA fragmentation, and decreased intracellular ATP.

To evaluate the effect of the compound of the present invention on apoptosis, Jurkat cells (ATCC) were treated with anti-FAS antibody CH-11 (Merck) to induce apoptosis through the Fas receptor (CD95), which was assessed by the amount of intracellular ATP.

Jurkat cells were cultured in RPMI 1640 medium containing 10% FBS and antibiotics (100 U/ml penicillin, 0.1 mg/ml streptomycin) under conditions of 37°C and 5% _CO2 . The cultured cells were seeded in the medium at a concentration of 8 × 10 ⁴ cells/well in 96-well plates (SPL), pretreated with the compound at a concentration of 50 nM for 1 h, and then treated with 1 μg/ml anti-FAS antibody for 24 h in an incubator. After 24 h, ATP lite luminescence assay kit (PerkinElmer) was used to measure ATP, and the luminescence was measured at 580 nm using a CLARIOstar Plus spectrometer. If the inhibition activity is 30% or more, it is designated as a', if it is 20% or more but less than 30%, it is designated as b', if it is 10% or more but less than 20%, it is designated as c', and if it is less than 10%, it is designated as d'.

As shown in Table 1, treatment with the compounds reduced apoptosis, thereby confirming that the compounds of the present invention are effective against apoptosis.

[Table 1]

k _obs /[I] (min ^-1 M ^-1 ) % inhibition Connection Caspase-1 Secreted IL-1β Apoptosis 1 C c b' 2 C b c' 3 C b b' 4 C b c' 5 C b c' 6 D c c' 7 C d NA 8 C a c' 9 C b a' 10 C b c' 11 D b NA 12 C c NA 13 C a b' 14 C d NA 15 D d NA 16 A a b' 17 C c NA 18 C a c' 19 D d NA 20 C c NA 21 C b NA 22 A b c' 23 C d NA 24 C c NA 25 C c NA 26 C b a' 27 C c a' 28 C c NA 29 C d d' 30 B d d' 31 C d NA 32 C d NA 33 C d NA 34 C d NA 35 C d NA 36 C d NA 37 C c d' 38 D d d' 39 C d d' 40 C d d' 41 C d d' 42 C b a' 43 D c NA 44 B a b' 45 C b c' 46 D NA NA 47 C NA NA 48 D NA NA 49 B NA NA 50 B a a' 51 B b b' 52 A c c' 53 C d NA 54 C b d' 55 C b a' 56 B a d' 57 C c b' 58 C c c' 59 D d NA 60 D d NA 61 D d NA 62 D NA NA 63 D NA NA 64 D NA NA

The above description of the invention is given by way of example only, and it will be obvious to those skilled in the art to which the present invention pertains that various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit of the invention or the essential features of the invention. It should therefore be understood that the embodiments described above are intended only to illustrate the invention and do not limit the scope of the present invention in any way. For example, each of the components described in a separate form can also be implemented in a distributed manner, and similarly, components described as distributed can also be implemented in a combined form.

The scope of the invention is indicated by the following claims. The meaning and scope of the claims, as well as all modifications or variations derived from their equivalents, are considered to be within the scope of the invention.

Claims (86)

1. A compound, an isoindolinone derivative, represented by the following formula I, or a pharmaceutically acceptable salt thereof , where R ¹ is halogen or C _6-12 aryloxy substituted with 1-5 halogens; R ² is hydrogen or C _1-6 straight or branched chain alkyl; R ³ is halogen or Q, Q is substituted or unsubstituted by 1-3 independent R ^a ; Q is phenyl, pyridinyl, tetrahydropyridinyl, pyrazolyl, pyrimidinyl, thiophenyl, pyrrolidinyl, naphthalenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl or dihydroimidazopyrazinyl; R ^a is C _1-6 straight or branched chain alkyl, C _1-6 alkoxy, halogen, C _1-6 haloalkyl, CO ₂ R ^b , COR ^b , NHR ^b , S(O) ₂ R ^b or 5-membered heteroaryl fused to C6 aryl; R ^b is hydrogen or C _1-6 straight or branched chain alkyl. 2. A compound, an isoindolinone derivative, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is F or phenoxy substituted with 1-5 F. 3. A compound derived from isoindolinone or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is hydrogen, methyl, ethyl or propyl with a straight or branched chain. 4. An isoindolinone derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is Br or Q, Q is phenyl, pyridinyl, tetrahydropyridinyl, pyrazolyl, pyrimidinyl, thiophenyl, pyrrolidinyl, naphthalenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxinyl, oxo-dihydrobenzimidazolyl, benzothiophenyl, pyrazolopyridinyl or dihydroimidazopyrazinyl. 5. An isoindolinone derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^a is methyl, methoxy, F, trifluoromethyl, carboxy, acetyl, amino or methylsulfonyl. 6. An isoindolinone derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the isoindolinone derivative compound represented by formula I is selected from the group consisting of: [1] 5-fluoro-4-oxo-3-(2-(1-oxo-6-phenylisoindolin-2-yl)butanamido)pentanoic acid, [2] 5-fluoro-3-(2-(6-(naphthalen-1-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [3] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrrolidin-1-yl)isoindolin-2-yl)butanamido)pentanoic acid, [4] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [5] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(1H-pyrazol-4-yl)isoindolin-2-yl)butanamido)pentanoic acid, [7] 5-fluoro-3-(2-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-oxoisoindolin-2-yl)butanamido-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)butanamido)pentanoic acid, [9] 3-(2-(6-bromo-1-oxoisoindolin-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)butanamido)pentanoic acid, [12] 5-fluoro-3-(2-(6-(2-fluoro-4-(methylsulfonyl)phenyl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [13] 5-fluoro-3-(2-(6-(6-methoxypyridin-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [14] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)butanamido)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, [20] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [21] (3-(2-(6-(2-aminopyrimidin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [22] 3-(2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [23] 3-(2-(6-(2-aminopyridin-4-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [24] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [25] 5-fluoro-3-(2-(6-(1-methyl-1H-pyrazol-3-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [26] 3-(2-(6-benzofuran-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [27] 3-(2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [28] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(thiophen-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [29] 5-fluoro-3-(2-(6-(isoquinolin-4-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [30] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-6-yl)isoindolin-2-yl)butanamido)pentanoic acid, [31] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-4-yl)isoindolin-2-yl)butanamido)pentanoic acid, [32] 3-(2-(6-(benzo[d]thiazol-5-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid, [33] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(pyrazolo[1,5-a]pyridin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [34] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-5-yl)isoindolin-2-yl)butanamido)pentanoic acid, [35] 5-fluoro-3-(2-(6-(isoquinolin-8-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [36] 5-fluoro-3-(2-(6-(isoquinolin-5-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxopentanoic acid, [37] 5-fluoro-4-oxo-3-(2-(1-oxo-6-(quinolin-3-yl)isoindolin-2-yl)butanamido)pentanoic acid, [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, [44] 3-((S)-2-(6-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)-3-methylbutanamido)-5-fluoro-4-oxopentanoic acid, [45] 5-fluoro-3-((S)-3-methyl-2-(1-oxo-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)isoindolin-2-yl)butanamido)-4-oxopentanoic acid, [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, [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)butanamido)pentanoic acid, [57] 3-((S)-2-(5-(benzofuran-3-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid and [58] 3-((S)-2-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-5-fluoro-4-oxopentanoic acid. 7. Use of a derivative compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of a medicinal product for the treatment of a disease associated with caspase. 8. Use of a derivative compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein the caspase-associated disease is osteoarthritis or pain. 9. Use of a derivative compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein the treatment of a caspase-associated disease is carried out by reducing the level of IL-1β or reducing apoptosis. 10. A pharmaceutical composition for treating a caspase-related disease, comprising a therapeutically effective amount of an isoindolinone derivative compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6 and a pharmaceutically acceptable additive. 11. A method for producing a compound, an isoindolinone derivative, represented by formula I, comprising: obtaining a compound of formula I-2 by reacting a compound of formula I-1 given below with one of the compounds R ³ -B(OH) ₂ , R ³ -H and formula Ic given below; hydrolyzing the compound of formula I-2 below to obtain the compound of formula I-3 below; obtaining a compound of formula I-5 below by reacting a compound of formula I-3 below with a compound of formula I-4 below; hydrolyzing the compound of formula I-5 below to obtain the compound of formula I-6 below; and oxidation of the compound of formula I-6 given below, , , , , , , , in the above formulas R ¹ , R ² and R ³ have the meanings as defined in formula I in paragraph 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 given below with a compound of formula I-b given below, , , , in the above formulas R ² has the meaning as defined in formula I in paragraph 1.