Arginase inhibitor and pharmaceutical composition containing the same

Abstract

The present invention relates to a compound represented by Chemical Formula 1 in this specification, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same can be usefully used for the prevention or treatment of cancer or tumors.

Description

Technical Field

[0001] The present invention relates to a compound having a novel structure that can be usefully used for the treatment or prevention of cancer or tumors.

Background Art

[0002] Currently, in relation to the development of immune anti-cancer agents emerging in the field of cancer therapeutic agent development, it is a well-known fact that depletion of arginine in the tumor microenvironment due to elevated levels of arginase has been observed in cancer patients. In fact, due to such a mechanism, it is known that tumor cells such as acute myeloid leukemia, breast cancer, prostate cancer, glioblastoma, esophageal cancer, and renal cell carcinoma can avoid destruction by the body's immune system. Therefore, there has been a need to develop an arginase inhibitor that suppresses arginase to restore arginine levels in the tumor microenvironment and promotes the tumor-killing activity of cytotoxic T-cells.

[0003] Regarding arginase inhibitors, pyrrolidine-based arginase inhibitors have been developed and are known to date, but the development of arginase inhibitors having a new chemical structure is required.

[0004] Therefore, as a result of studying a novel compound having a chemical structure different from the arginase inhibitors reported to date, the present inventors confirmed that a compound having an octahydropyrrolo[3,4-b]pyrrole of a bicyclic structure as a mother nucleus is excellent in arginase inhibitory activity, and completed the present invention.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention provides a compound having a novel structure that can be usefully used for the treatment or prevention of cancer or tumors.

Means for Solving the Problems

[0006] In order to solve the above problems, the present invention provides a compound represented by the following chemical formula 1, or a pharma- ceutically acceptable salt thereof: [Chemical formula 1] JPEG2025523364000001.jpg4854In the above Chemical Formula 1, R1 and R2 are each independently hydrogen; unsubstituted or amino, (C 1-4 alkyl)amino, or di(C 1-4 C substituted with alkyl)amino 1-4 alkyl; or -L1-R'1, L1 is -CO-, -CO-O-, -(CO)-O-(C 1-4 alkylene)-O-(CO)-, or -CH2-O-CO-; R'1 is -CH(NH2)-R A , -CH(N(CH3)2)-R A , R B , or R C and R3 is hydroxy or -L3-R'3; L3 is -NH-, -O-, or -O-(CH2) n3 -O-CO-, R'3 is -CH(COOH)-R A , -CH(NH2)-R A , R B , or R C and R A are each independently hydrogen; or unsubstituted or selected from hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, C 1-6 Alkylthio, phenyl, hydroxyphenyl, or C containing 1 or 2 N 4-10 Heteroaryl-substituted C 1-6 is alkyl, R B are each independently N-containing C 4-10 is heterocycloalkyl, R C are each independently unsubstituted or C 6-10 Aryl or N-containing C4-10 C substituted with heterocycloalkyl 1-6 alkyl; unsubstituted or C 1-6 alkyl substituted with alkoxy 6-10 aryl; or C 3-6 is cycloalkyl, n3 is an integer from 1 to 3.

[0007] Preferably, R1 and R2 are each independently hydrogen, methyl, methylaminoethyl, or a substituent represented by any one of the following: JPEG2025523364000002.jpg81118 In the above, R A , R B , and R C are as defined above, and n1 is an integer from 1 to 3.

[0008] Preferably, R3 is hydroxy or a substituent represented by any one of the following: JPEG2025523364000003.jpg74111 In the above, R A , R B , R C and n3 are as defined above.

[0009] Preferably, R A are each independently hydrogen; or C alkyl which is unsubstituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, methylthio, phenyl, hydroxyphenyl, indole, or imidazole. More preferably, R 1-6 are each independently hydrogen, methyl, ethyl, 1-hydroxy-1-ethyl, propyl, isopropyl, normal butyl, isobutyl, tert-butyl, or benzyl. A

[0010] Preferably, R A ​Each is independently a residue of a natural amino acid, and the residue of the natural amino acid means a structure excluding the terminal -CH(NH2)(COOH). For example, when A is a residue of alanine, it means methyl. Preferably, the natural amino acid is arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan.

[0011] Preferably, R B is pyrrolidinyl.

[0012] Preferably, R C is each independently unsubstituted or C substituted with phenyl or piperidinyl 1-6 alkyl; or unsubstituted or C substituted with methoxy 6-10 aryl. More preferably, R C is each independently methyl, pyrrolidinylmethyl, ethyl, propyl, isopropyl, normal butyl, isobutyl, tert - butyl, phenyl, methoxyphenyl, benzyl, or cyclohexyl.

[0013] Preferably, R1 is hydrogen, and R2 is hydrogen or R1 is hydrogen, and R3 is hydroxy, or R2 is hydrogen, and R3 is hydroxy.

[0014] Preferably, the chemical formula 1 is represented by any one of the following chemical formulas 2 to 5: [Chemical formula 2] JPEG2025523364000004.jpg4867[Chemical formula 3] JPEG2025523364000005.jpg5088[Chemical formula 4] JPEG2025523364000006.jpg4853[Chemical formula 5] JPEG2025523364000007.jpg4872In Chemical Formulas 2 to 5, R A is as defined above.

[0015] Typical examples of the compound represented by Chemical Formula 1 are as follows: 1) (3aS,4R,6aR)-4-(4-Boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, 2) (3aS,4R,6aR)-1-((S)-2-Aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 3) (3aS,4R,6aR)-1-((S)-2-Amino-3-phenylpropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 4) (3aS,4R,6aR)-4-(4-Boronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 5) (3aS,4R,6aR)-1-((2R,3S)-2-Amino-3-hydroxybutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 6) (3aS,4R,6aR)-1-((S)-2-Amino-3-methylbutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 7) (3aS,4R,6aR)-1-((S)-2-Amino-4-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 8) (3aS,4R,6aR)-1-((2S,3S)-2-Amino-3-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 9) (3aS,4R,6aR)-1-((R)-2-Aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 10) 4 - ((3aS,4R,6aR)-4-(Ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid, 11) 4 - ((3aS,4R,6aR)-4-(Isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid, 12) 4 - ((3aS,4R,6aR)-4 - ((((Isopropoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 13) 4 - ((3aS,4R,6aR)-4 - ((((tert-Butoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 14) 4 - ((3aS,4R,6aR)-4 - ((1-(Ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 15) 4 - ((3aS,4R,6aR)-4 - ((1-(Cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 16) 4 - ((3aS,4R,6aR)-4 - ((1-(Isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 17) 4 - ((3aS,4R,6aR)-4 - ((1-(Pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 18) 4 - ((3aS,4R,6aR)-4 - ((2-(Pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 19) (3aS,4R,6aR)-4-(4-Boronobutyl)-1 - ((1-(Cyclohexanecarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(pentyloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(cyclohexanecarbonyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-methyloctahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(butyryloxymethyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-1-(((acetoxymethoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (S)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)propanoic acid, (S)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-methylbutanoic acid, (S)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxamido)-4-methylpentanoic acid, (2S,3R)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-methylpentanoic acid, (S)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-phenylpropanoic acid, 4-(((3aS,4R,6aR)-4-((2-(((S)-2-aminopropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-yl)carboxylic acid, 4-(((3aS,4R,6aR)-4-((2-(((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 4-(((3aS,4R,6aR)-4-((2-(((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-yl)carboxylic acid, 4-(((3aS,4R,6aR)-4-((2-(((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-yl)carboxylic acid, 40) 4 - ((3aS,4R,6aR)-4 - ((2 - ((S)-2 - amino - 3 - phenylpropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3 - c]pyrrol - 4 - yl)carboxylic acid, 41) 4 - ((3aS,4R,6aR)-4 - ((2 - ((S)-pyrrolidine - 2 - carbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 42) 4 - ((3aS,4R,6aR)-4 - ((propionyloxymethoxy)carbonyl)octahydropyrrolo[2,3 - c]pyrrol - 4 - yl)carboxylic acid, 43) 4 - ((3aS,4R,6aR)-4 - ((isobutyryloxymethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 44) 4 - ((3aS,4R,6aR)-4 - (benzyloxycarbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 45) 4 - ((3aS,4R,6aR)-4 - ((piperidin - 4 - ylmethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 46) 4 - ((3aS,4R,6aR)-4 - (phenoxycarbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 47) 4 - ((3aS,4R,6aR)-4 - ((2 - methoxyphenoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid, 48) (3aS,4R,6aR)-1 - ((((S)-2 - amino - 3 - phenylpropanoyloxy)methoxy)carbonyl)-4 - (4 - boronobutyl)octahydropyrrolo[3,4 - b]pyrrole - 4 - carboxylic acid, 49) (3aS,4R,6aR)-1 - ((((S)-2 - aminopropanoyloxy)methoxy)carbonyl)-4 - (4 - boronobutyl)octahydropyrrolo[3,4 - b]pyrrole - 4 - carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-((((S)-Pyrrolidine-2-carbonyl-oxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-1-((((2S,3R)-2-Amino-3-hydroxybutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-1-((((S)-2-Amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-1-((((S)-2-Amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, or (3aS,4R,6aR)-1-((((2S,3S)-2-Amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

[0016] In addition, the compounds of the present invention can exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, salts commonly used in the art can be used without limitation, such as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means any and all organic or inorganic addition salts of the compound that are relatively non-toxic and harmless to patients at a concentration having an effective action, and the side effects caused by this salt do not reduce the advantageous efficacy of the compound represented by Chemical Formula 1.

[0017] In addition, salts or solvates of the compound represented by Chemical Formula 1 that are not pharmaceutically acceptable can be used as intermediates in the production of the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or solvate.

[0018] In addition, the compound represented by the chemical formula 1 according to the present invention includes not only its pharmaceutically acceptable salts, but also solvates such as possible hydrates that can be produced therefrom and all possible stereoisomers without limitation. The solvates and stereoisomers of the compound represented by the chemical formula 1 can be produced from the compound represented by the chemical formula 1 using methods known in the art.

[0019] Furthermore, the compound represented by the chemical formula 1 according to the present invention can be produced in crystalline or amorphous form, and when produced in crystalline form, it may optionally be hydrated or solvated. In the present invention, not only the stoichiometric hydrates of the compound represented by the chemical formula 1, but also compounds containing various amounts of water may be included. The solvates of the compound represented by the chemical formula 1 according to the present invention include all stoichiometric solvates and non-stoichiometric solvates.

[0020] Also, as an example, the compound represented by the chemical formula 1 according to the present invention can be produced as shown in the following Reaction Scheme 1: [Reaction Scheme 1] JPEG2025523364000008.jpg36140Reaction Scheme 1 illustrates the case where R1 is -L1-R'1, R2 is hydrogen, and R3 is hydroxy, and is applicable to the production of the remaining compounds represented by the chemical formula 1 other than those. The first reaction in Reaction Scheme 1 is an -L1-R'1 substitution reaction, and the second reaction is a protecting group removal reaction, and the production method can be further specified in the production examples described later.

[0021] In addition, the present invention provides any one compound selected from the group consisting of the following, and the following compounds can be used as intermediates in the production of the compound represented by the chemical formula 1 according to the present invention. JPEG2025523364000009.jpg115126In the above, PG1 and PG2 each independently represent the same or different protecting groups.

[0022] The protecting group is not particularly limited as long as it is widely used in the technical field to which the present invention pertains. Preferably, PG1 is an amine protecting group and PG2 is a carboxylic acid protecting group. Representative examples of PG1 include, but are not limited to, carbobenzyloxy, tert-butoxycarbonyl, p-methoxybenzylcarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl, and the like. Representative examples of PG2 include, but are not limited to, acetyl, benzoyl, benzyl, methoxyethoxymethyl ether, dimethoxytrityl, methoxymethyl ether, methoxytrityl ((4-methoxyphenyl)diphenylmethyl), p-methoxybenzyl ether, p-methoxyphenyl ether, methylthiomethyl ether, pivaloyl, tert-butyl ether, tetrahydropyranyl, tetrahydrofuran, trityl, trimethylsilyl, tert-butyldimethylsilyl, and the like.

[0023] Preferably, the compound is any one selected from the group consisting of the following: (3aR,4R,6aR)-1-(tert-Butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-5-((Benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate, 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-4-((E)-but-2-en-1-yl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate, 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate, (4-((3aS,4R,6aR)-4,5-Bis((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, and (3aS,4R,6aR)-5-(Benzyloxycarbonyl)-4-(4-boronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

[0024] In addition, the compound represented by the chemical formula 1, or a pharmaceutically acceptable salt thereof, has an arginase inhibitory effect, suppresses arginase, restores the arginine level in the tumor microenvironment, and can promote the tumor-killing activity of cytotoxic T-cells. Therefore, the present invention provides a pharmaceutical composition for preventing or treating cancer or a tumor containing the compound represented by the chemical formula 1, or a pharmaceutically acceptable salt thereof.

[0025] The term "prevention" in the present invention means all acts of suppressing or delaying the occurrence, spread, and recurrence of the disease by administration of the composition of the present invention, and "treatment" means all acts of improving or favorably changing the symptoms of the disease by administration of the composition of the present invention.

[0026] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms by standard pharmaceutical practices. These dosage forms can contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, adjuvants, or diluents.

[0027] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, but are not limited thereto. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the manufacture of injection solutions. Further, for local action, the compounds of the present invention can be formulated into ointments or creams.

[0028] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the degree of the disease, the form of the drug, the administration route, and the period, but can be appropriately selected by those skilled in the art. However, for a preferable effect, it is good to administer the compound of the present invention at 0.0001 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg (body weight). The administration can be carried out once a day or dividedly through oral or parenteral routes.

[0029] Depending on the administration method, the pharmaceutical composition can contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.

[0030] The pharmaceutical composition according to the present invention can be administered to mammals such as mice, rats, livestock, and humans through various routes. Although all modes of administration can be anticipated, for example, it can be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine dural, or intracerebroventricular injection.

Effect of the Invention

[0031] The compound represented by Chemical Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, can be usefully used for the prevention or treatment of cancer or tumors.

Mode for Carrying Out the Invention

[0032] Hereinafter, preferred examples are presented for the understanding of the present invention. However, the following examples merely illustrate the present invention, and the scope of the present invention is not limited to the following examples.

[0033] Example 1: Production of (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride JPEG2025523364000010.jpg3837

[0034] Step 1) Production of dibenzyl (R)-4-oxopyrrolidine-1,2-dicarboxylate After cooling methylene chloride (1.5 L) to -78 °C, oxalyl chloride (90.0 mL) and dimethyl sulfoxide (92.7 mL) were slowly added dropwise. After stirring at -78 °C for 10 minutes, dibenzyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (186.0 g) was dissolved in methylene chloride (700 mL) and then slowly added dropwise at -78 °C. After stirring for 30 minutes, triethylamine (255 mL) was slowly added dropwise at -78 °C. The reaction was stirred at -78 °C for 1 hour to complete the reaction. The reaction solution was poured into a 1N-HCl solution at 0 - 5 °C, and then the organic layer was separated. The aqueous layer was extracted twice with methylene chloride (1 L) to separate the organic layer. The organic layer was dried over MgSO4 and then concentrated. Column separation was performed using ethyl acetate (in Hexane 30%) to obtain Compound 1-1 (117 g, yield 63%).

[0035] MS: [M+H] + = 354 1 H NMR(500 MHz, CDCl3) 7.38 - 7.25 (m, 10H), 5.26 - 5.09 (m, 4H), 4.96 - 4.86 (m, 1H), 4.05 - 3.95 (m, 2H), 3.01 - 2.92 (m, 1H), 2.63 - 2.59 (m, 1H)

[0036] Step 2) Production of 4,5-dibenzyl 1-(tert-butyl) (R)-4,6-dihydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate Compound 1-1 (67 g) was dissolved in tetrahydrofuran (300 ml), and then cooled to -78 °C under nitrogen. 2.5 N n-BuLi (84 ml) was slowly added dropwise at -78 °C under nitrogen. After stirring at -50 to -55 °C for 1 hour, it was cooled to -78 °C. tert-Butyl (2-oxoethyl) carbamate (34 g) was dissolved in tetrahydrofuran (100 ml), and then slowly added dropwise at -78 °C under nitrogen. The reaction was completed by stirring at -50 to -55 °C for 1 hour. The reaction solution was poured into a saturated NH4Cl solution at 0 to 5 °C, and then liquid separation was carried out using ethyl acetate (1.4 L), and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (670 ml) to separate the organic layer. The organic layer was dried over MgSO4 and then concentrated. After dissolving in methylene chloride (1 L), conc-HCl solution (8.1 ml) was slowly added dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0 to 5 °C, 3% aqueous NaHCO3 solution (500 ml) was added, then the organic layer was separated, dried over MgSO4 and then concentrated. Column separation was carried out using ethyl acetate (in Hexane 30%) to obtain Compound 1-2 (24 g, yield 30%).

[0037] MS: [M+H] + = 477 1 H NMR(500 MHz,CDCl3) 7.42 - 7.31 (m, 9H), 7.28 - 7.24 (m, 1H), 6.09 (m, 1H), 5.41 - 5.03 (m, 5H), 4.82 - 4.73 (m, 2H), 1.59 (m, 9H)

[0038] Step 3) Preparation of (3aR,4R,6aR)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid Compound 1-2 (24 g) was dissolved in tetrahydrofuran (500 ml) and methanol (500 ml). After adding Pd(OH)2 (12 g), the reaction was stirred for 4 hours under a hydrogen balloon to complete the reaction. The reaction solution was washed with methanol, filtered through celite, concentrated, and then dried under reduced pressure to obtain Compound 1-3 (12.8 g, yield 100%).

[0039] MS: [M+H] + = 257 1 H NMR (500 MHz, MeOD) 4.91 (m, 1H), 4.25 - 4.15 (m, 1H), 3.74 (m, 1H), 3.50 - 3.48 (m, 2H), 3.44 - 3.39 (m, 1H), 2.03 - 1.95 (m,2H), 1.89 (m, 1H) 1.49 (s, 9H)

[0040] Step 4) Preparation of (3aS,4R,6aR)-5-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid Compound 1-3 (12.8 g) was dissolved in 1N aqueous KOH solution (100 ml), and then benzyl carbonochloridate (8.5 ml) was slowly added dropwise. After stirring at room temperature for 12 hours, the reaction was completed. After cooling the reaction solution to 0 - 5°C, ethyl acetate (150 ml) and H2O (100 ml) were added. After adjusting the pH to 2 - 3 using 6N aqueous HCl solution, layer separation was performed to separate the organic layer. Ethyl acetate (100 ml) was added to the aqueous layer twice, layer separation was performed to separate the organic layer, which was dried over MgSO4 and then concentrated. After drying under reduced pressure, Compound 1-4 (20 g, yield 100%) was obtained. The obtained compound was used in the next reaction without purification.

[0041] MS: [M+H] + = 391 11H NMR (500 MHz, CDCl3) δ 7.38 - 7.28 (m, 5H), 5.20 - 5.10 (m, 2H), 4.61 (m, 1H), 4.58 - 4.30 (m, 1H), 4.16 - 4.05 (m, 1H), 3.58 - 3.50 (m, 1H), 3.49 - 3.32 (m, 2H), 3.22 - 3.15 (m, 1H), 1.95 - 1.94 (m, 2H), 1.53 (s, 9H)

[0042] Step 5) Synthesis of 4,5 - dibenzyl 1 - (tert - butyl) (3aS,4R,6aR) - hexahydropyrrolo[3,4 - b]pyrrole - 1,4,5 - tricarboxylate Compound 1 - 4 (20 g) was dissolved in N,N - dimethylformamide (100 ml). Potassium carbonate (10.42 g), sodium iodide (753 mg), and benzyl bromide (8.9 ml) were added, and the mixture was stirred at room temperature for 12 hours to complete the reaction. Ethyl acetate (400 ml) and 0.5 N aqueous HCl solution (200 ml) were added, and the layers were separated. After concentrating the organic layer, column separation was performed with an ethyl acetate (in hexane 30%) solution to obtain Compound 1 - 5 (20 g, yield 83%).

[0043] MS: [M + H] + = 481 1 1H NMR (500 MHz, CDCl3) δ 7.37 - 7.27 (m, 10H), 5.29 - 5.06 (m, 4H), 4.63 - 4.61 (m, 1H), 4.37 - 4.27 (m, 1H), 4.16 - 4.11 (m, 1H), 3.50 - 3.20 (m, 3H), 3.19 - 3.16 (m, 1H), 1.84 (m, 1H), 1.75 (m, 1H), 1.45 (m, 9H)

[0044] Step 6) Synthesis of 4,5-dibenzyl 1-(tert-butyl) (3aS,4R,6aR)-4-((E)-but-2-en-1-yl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate JPEG2025523364000016.jpg3129Compound 1-5 (20 g) was dissolved in tetrahydrofuran (200 ml), and then cooled to -78 °C under nitrogen. Crotyl bromide (8.1 ml) was added dropwise, and 1N potassium bis(trimethylsilyl)amide (80 ml) was slowly added dropwise. The reaction was stirred at -78 °C for 30 minutes to complete the reaction. The reaction solution was added dropwise to 1N HCl aqueous solution (200 ml) at 0 - 5 °C, and extracted with ethyl acetate (200 ml). The aqueous solution was extracted twice with ethyl acetate (200 ml), and the organic layer was concentrated. Column separation was performed with ethyl acetate (in hexane 30%) to obtain compound 1-6 (10.4 g, yield 65%).

[0045] MS: [M+H] + = 335 1 H NMR (500 MHz, CDCl3) 5.6 - 4.90 (m, 6H), 4.35 - 3.85 (m, 2H), 3.55 - 3.30 (m, 1H), 3.25 - 3.15 (m, 2H), 2.95 - 2.65 (m, 3H), 1.95 - 2.85 (m, 1H), 1.75 - 1.55 (m, 4H), 1.46 - 1.44 (m, 9H)

[0046] Step 7) Preparation of 4,5-dibenzyl 1-(tert-butyl) (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate JPEG2025523364000017.jpg 4044 Chloroiridium(I) dimer (1.7 g) and 1,2-bis(diphenylphosphino)ethane (2.1 g) were added to methylene chloride (100 ml) under nitrogen. After adding 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.66 ml), the mixture was stirred for 20 minutes under nitrogen. Compound 1-6 (14 g) was dissolved in methylene chloride (50 ml) and then slowly added dropwise. The mixture was stirred at room temperature for 20 hours under nitrogen. H2O (50 ml) was added to the reaction solution for extraction, and the organic layer was separated. The organic layer was concentrated and then separated by column chromatography with ethyl acetate (in hexane 30%) to obtain Compound 1-7 (8.5 g, yield 49%).

[0047] MS: [M+H] + = 663 1 H NMR (500 MHz, CDCl3) 7.34 - 7.21 (m, 10H), 5.20 - 4.90 (m. 4H), 3.90 - 3.55 (m, 3H), 3.50 - 3.40 (m, 2H), 2.85 - 2.80 (m, 3H), 1.90 - 1.80 (m,4H), 1.42 (s, 9H), 1.35 - 1.30 (m, 2H), 1.20 (s, 12H), 0.6 - 0.8 (m, 2H)

[0048] Step 8) Preparation of (4-((3aS,4R,6aR)-4,5-bis((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid Compound 1-7 (8.5 g) was dissolved in acetone (128 ml), and then methylboronic acid (7.66 g) was added. After adding 0.1 N aqueous NaOH solution (128 ml), the mixture was stirred at room temperature for 12 hours. After adding a saturated NH4Cl solution (100 ml), extraction was performed using ethyl acetate (170 ml). The aqueous solution was extracted twice with ethyl acetate (100 ml). The organic layer was concentrated and then separated by column chromatography with methylene chloride:methanol = 20:1 (v:v) to obtain Compound 1-8 (5.5 g, yield 74%).

[0049] MS: [M+H] + = 581 1 H NMR (500 MHz, CDCl3) 7.39 - 7.24 (m, 10H), 5.19 - 4.89 (m, 4H), 4.75 - 4.35 (m, 1H), 4.20 - 4.00 (m, 2H), 3.6 - 3.45 (m, 1H), 3.43 - 3.30 (m, 1H), 3.28 - 3.15 (m, 1H), 2.90 - 2.70 (m, 1H), 2.65 - 2.20 (m, 1H), 2.0 - 1.8 (m, 2H), 2.75 - 2.65 (m, 1H), 1.60 - 1.40 (m, 9H), 1.35 - 1.30 (m, 2H), 1.25 - 1.10 (m, 1H), 0.95 - 0.65 (m, 2H)

[0050] Step 9) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid Compound 1-8 (5.5 g) was dissolved in methanol (50 ml). 10% Pd / C (2 g) was added, and the reaction was completed by stirring at room temperature for 4 hours using a hydrogen balloon. The product was immediately used in the following Step 10.

[0051] MS: [M+H] + = 357

[0052] Step 10) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride JPEG2025523364000020.jpg3937The product of Step 9 was washed with methanol, filtered through celite, and concentrated. 6N aqueous HCl solution was added, and after stirring at room temperature for 2 hours, it was concentrated. After dissolving in H2O (5 ml), extraction was performed 3 times using diethyl ether (5 ml) to remove the organic layer. The aqueous solution was concentrated and then dried under reduced pressure to obtain Compound 1 (2.5 g, yield 80% (Steps 9 and 10)).

[0053] MS: [M+H] + = 257 1 H NMR (500 MHz, MeOD) 4.73-4.73 (m, 1H), 3.97-3.85 (m, 2H), 3.52-3.41 (m, 1H), 3.39-3.36 (m, 2H), 2.41-2.39 (m, 1H), 2.16-2.11 (m, 2H), 2.01-1.95 (m, 1H), 1.51-1.45 (m, 3H), 1.32 (m, 1H), 0.9-0.8 (m, 2H)

[0054] Example 2: Preparation of (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride JPEG2025523364000021.jpg4151

[0055] Step 1) Preparation of dibenzyl (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-4,5(1H)-dicarboxylate HCl Compound 1-7 (800 mg) was dissolved in 1,4-dioxane (10 ml), and then 4N HCl (in dioxane; 12 ml) was added. The reaction was stirred at 50 °C for 1 hour to complete the reaction. It was concentrated and dried under reduced pressure to obtain Compound 2-1 (723 mg, yield 100%).

[0056] MS: [M+H] + = 563 1 H NMR (500 MHz, MeOD) 7.2 - 7.3 (m, 10H), 5.3 - 5.2 (m, 4H), 3.65 - 3.40 (m, 2H), 2.85 - 2.70 (m, 3H), 2.15 - 2.05 (m, 1H), 1.95 - 1.70 (m, 4H), 1.65 - 1.40 (m, 2H), 1.35 - 1.25 (m, 2H), 1.20 m, 2H), 0.6~0.8 (m, 2H)

[0057] Step 2) Preparation of dibenzyl (3aS,4R,6aR)-1-((tert-butoxycarbonyl)-L-alanyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-4,5(1H)-dicarboxylate Compound 2-1 (54 mg) was dissolved in methylene chloride (1 ml). After adding trimethylamine (36 uL) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-alaninate (37 mg), the reaction was stirred at room temperature for 12 hours to complete the reaction. After adding a saturated aqueous solution of NH4Cl, extraction was carried out to separate the organic layer. The organic layer was concentrated and then separated by column using ethyl acetate (in hexane 40~50%) to obtain Compound 2-2 (47 mg, yield 74%).

[0058] MS: [M+H] + = 734 11H NMR (500 MHz, CDCl3) 7.3 - 7.2 (m, 10H), 5.3 - 5.3 (m, 4H), 4.6 - 4.5 (m, 1H), 4.0 - 3.5 (m, 3H), 3.4 - 3.35 (m, 2H), 3.2 - 3.1 (m, 1H), 2.1 - 2.0 (m, 2H), 1.8 - 1.7 (m, 2H), 1.42 (s, 9H), 1.45 (m, 3H), 1.35 - 1.25 (m, 4H), 1.20 (s, 12H), 0.7 - 0.9 (m, 2H)

[0059] Step 3) Preparation of (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Using compound 2-2, compound 2 was obtained in the same manner as in Steps 8 to 10 of Example 1.

[0060] MS: [M+H] + = 328, [M - H2O + H] + = 310 1 1H NMR (500 MHz, MeOD) 4.73 (m, 1H), 4.32 - 4.28 (m, 1H), 3.95 - 3.91 (m, 1H), 3.83 - 3.79 (m, 1H), 3.61 - 3.50 (m, 2H), 3.25 - 3.23 (1H), 2.30 - 2.29 (m, 1H), 2.13 - 2.07 (m, 2H), 1.98 - 1.96 (m, 1H), 1.33 (m, 3H), 1.31 (s, 3H), 1.30 (m, 1H), 0.84 (m, 2H)

[0061] Example 3: Preparation of (3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Compound 3 was obtained in the same manner as in Steps 2 and 3 of Example 2 using 4751 Compound 2-1 (100 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-phenylalaninate (97.8 mg).

[0062] MS: [M+H] + = 368 [M-H2O+H] + = 386 1 H NMR(500 MHz, MeOD) 7.40-7.29 (m, 5H), 4.89 (m, 1H), 4.64 (m, 1H), 3.81-3.79 (m, 2H), 3.55 (m, 1H), 3.12 (m, 2H), 2.99 (m, 1H), 2.58 (m, 1H), 2.06 (m, 1H), 1.95-1.90 (m, 3H), 1.48-1.44 (m, 3H), 1.44 (m, 2H)

[0063] Example 4: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Compound 4 was obtained in the same manner as in Steps 2 and 3 of Example 2 using 4049 Compound 2-1 (60 mg) and 1-(tert-butyl) 2-(2,5-dioxopyrrolidin-1-yl) (S)-pyrrolidine-1,2-dicarboxylate (40 mg).

[0064] MS: [M+H] + = 354 [M-H2O+H] + = 336 11H NMR (500 MHz, MeOD) 3.70 - 3.60 (m, 1H), 3.55 - 3.30 (m, 3H), 3.10 - 2.70 (m, 4H), 2.20 - 2.0 (m, 4H), 1.95 - 1.70 (m, 2H), 1.70 - 1.50 (m, 3H), 1.30 - 1.20 (m, 4H), 0.80 - 0.70 (m, 2H)

[0065] Example 5: Preparation of (3aS,4R,6aR)-1-((2R,3S)-2-amino-3-hydroxybutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Using compound 2-1 (60 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-threoninate (40 mg), compound 5 was obtained in the same manner as in steps 2 and 3 of Example 2.

[0066] MS: [M+H] + = 358 [M - H2O + H] + = 340 1 1H NMR (500 MHz, MeOD) 3.94 - 3.40 (m, 1H), 3.50 - 3.40 (m, 3H), 3.40 - 3.30 (m, 1H), 3.10 - 2.85 (m, 2H), 2.05 - 1.80 (m, 3H), 1.60 - 1.50 (m, 2H), 1.40 - 1.20 (m, 4H), 1.20 - 1.15 (m, 3H), 0.9 - 0.8 (m, 2H)

[0067] Example 6: Preparation of (3aS,4R,6aR)-1-((S)-2-amino-3-methylbutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Compound 6 was obtained in the same manner as in Steps 2 and 3 of Example 2 using Compound 2-1 (60 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate (40 mg).

[0068] MS: [M+H] + = 356 [M-H2O+H] + = 338 1 H NMR(500 MHz, MeOD) 4.74 (m, 1H), 4.1 (m, 1H), 4.05 (m, 1H), 3.81 - 3.80 (m, 1H), 3.56 (m, 2H), 3.22 (m, 1H), 2.24 (m, 2H), 2.09 - 2.07 (m, 2H), 1.96 (m, 1H), 1.52 - 1.44 (m, 3H), 1.30 (m, 1H), 1.09 - 1.04 (m, 6H), 0.81 (m, 2H)

[0069] Example 7: Preparation of (3aS,4R,6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Compound 7 was obtained in the same manner as in Steps 2 and 3 of Example 2 using Compound 2-1 (83 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-leucinate (56 mg).

[0070] MS: [M+H] + = 370,[M-H2O+H] + = 352 11H NMR (500 MHz, MeOD) 4.71 (m, 1H), 4.25 (m, 1H), 3.95 (m, 1H), 3.80 (m, 1H) 3.55 (m, 2H), 3.24 (m, 1H), 2.25 (m, 1H), 2.05 - 2.20 (m, 2H), 1.95 (m, 1H), 1.75 (m, 1H), 1.70 (m, 2H), 1.70 - 1.60 (m, 3H), 1.25 (m, 1H), 1.00 - 1.02 (m, 6H), 0.81 - 0.78 (m, 2H)

[0071] Example 8: Preparation of (3aS,4R,6aR)-1-((2S,3S)-2-amino-3-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Using compound 2-1 (83 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-isoleucinate (56 mg), compound 8 was obtained in the same manner as in steps 2 and 3 of Example 2.

[0072] MS: [M+H] + = 370, MS: [M - H2O + H] + = 352 1 1H NMR (500 MHz, MeOD) 4.72 (m, 1H), 4.09 - 3.95 (m, 2H), 3.76 (m, 1H), 3.57 - 3.54 (m, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.95 (m, 2H), 2.70 - 2.40 (m, 4H), 2.20 (m, 1H), 2.15 (m, 2H), 1.07 (m, 3H), 0.96 (m, 3H), 0.81 (m, 2H)

[0073] Example 9: Preparation of (3aS,4R,6aR)-1-((R)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride Compound 9 (15 mg) was obtained in the same manner as in Steps 2 and 3 of Example 2 using 4151 Compound 2-1 (167 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-D-alaninate (134 mg).

[0074] MS: [M+H] + = 328 1 H NMR (500 MHz, MeOD) 4.8 (1H, m), 4.2 (1H, m), 3.8 (1H, m), 3.7 (2H, m), 3.4 (1H, m), 3.2 (1H, m), 2.3 (1H, m), 2.2 (2H, m), 2.0 - 1.9 (1H, m), 1.6 - 1.4 (6H, m), 1.3 (1H, m), 0.8 (2H, m)

[0075] Example 10: Preparation of dihydrochloride of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid JPEG2025523364000032.jpg4137

[0076] Step 1) Preparation of (3aS,4R,6aR)-5-((benzoyloxy)carbonyl)-1-(tert-butoxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid Compound 1-7 (1.0 g) was dissolved in methanol (20.0 ml). 10% Pd / C (100.0 mg) was added, and the reaction was completed by stirring at room temperature for 4 hours using a hydrogen balloon. The reaction solution was washed with methanol, filtered through celite, and concentrated. After dissolving in THF (20.0 ml), 1N-KOH (5.7 ml) was added, and benzyl carbonochloridate (0.43 ml) was slowly added dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0-5 °C, ethyl acetate (10.0 ml) and H2O (5.0 ml) were added. After adjusting the pH to 2-3 using 6N HCl aqueous solution, layer separation was performed to separate the organic layer. Ethyl acetate (10 ml) was added to the aqueous layer twice, layer separation was performed to separate the organic layer, which was dried over MgSO4 and then concentrated. Drying under reduced pressure gave compound 9-1 (1.21 g, yield 70%). The obtained compound was used in the next reaction without purification.

[0077] MS: [M+H] + = 573

[0078] Step 2) Preparation of 5-benzyl 1-(tert-butyl) 4-ethyl (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate Compound 10-1 (100.0 mg) was dissolved in N,N-dimethylformamide (2.0 ml). Cesium carbonate (114.0 mg) and ethyl iodide (70.0 μL) were added, and the mixture was stirred at 50 °C for 4 hours. After cooling to 0-10 °C, saturated ammonium chloride aqueous solution (1.0 ml) and ethyl acetate (5.0 ml) were added to separate the organic layer. The organic layer was dried over magnesium sulfate, concentrated, and column separated using ethyl acetate:hexane = 1:2 to obtain compound 9-2 (80.0 mg, yield 76%).

[0079] MS: [M+H] + = 601

[0080] Step 3) Preparation of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid dihydrochloride Using compound 10-2, compound 10 (12.0 mg) was obtained in the same manner as in Steps 8 to 10 of Example 1.

[0081] MS: [M+H] + = 285 1 H NMR(500 MHz, MeOD) : 4.7 (1H, m), 4.4(2H, m), 3.9(1H, m), 3.8(1H, m), 3.6(1H, m), 3.5(1H, m), 3.4(1H, m), 2.3(1H, m), 2.1(1H, m), 2.0(2H, m), 1.5(3H,m), 1.4(3H, m), 1.2(1H, m), 0.8(2H, m)

[0082] Example 11: Preparation of 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid dihydrochloride Using compound 9-1 (100.0 mg), compound 11 (17.7 mg) was obtained in the same manner as in Steps 2 and 3 of Example 9.

[0083] MS: [M+H] + = 299 1 H NMR(500 MHz, MeOD) 5.2(1H, m), 4.8(1H, m),3.9-3.8(2H, m), 3.7-3.6(2H, m), 3.5(1H, m), 3.4(1H, m), 2.3(1H, m), 2.2-2.1(1H, m), 2.1-2.0(2H, m), 1.5(3H, m), 1.4(6H, m), 0.8(2H, m)

[0084] Example 12: Preparation of 4-((3aS,4R,6aR)-4-(((Isopropoxycarbonyl)oxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride Using compound 9-1 (100.0 mg) and chloromethyl isopropyl carbonate (35.0 μL), compound 12 (40.0 mg) was obtained in the same manner as in Example 9.

[0085] MS: [M+H] + = 373 1 H NMR(500 MHz, MeOD): 6.0(2H, m), 4.7(1H, m), 3.9 - 3.8(2H, m), 3.5 - 3.4(3H,m), 3.4(1H, m), 2.4(1H, m), 2.1(3H,m), 1.5(3H, m), 1.25(1H,m), 1.2(6H, d), 0.8(2H, m)

[0086] Example 13: Preparation of 4-((3aS,4R,6aR)-4-(((tert-Butoxycarbonyl)oxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride Using compound 9-1 (100.0 mg) and tert-butyl (chloromethyl) carbonate (37.8 μL), compound 13 (10.0 mg) was obtained in the same manner as in Example 9.

[0087] MS: [M+H] + = 387 1 H NMR(500 MHz, MeOD) 6.0(2H, m), 4.7(1H, m), 3.9 - 3.8(2H, m), 3.5 - 3.4(2H, m), 3.4(1H, m), 2.4 - 2.3(1H, m), 2.1 - 2.0(3H, m), 1.5 - 1.4(3H, m), 1.25(1H, m), 1.2(9H, s), 0.8(2H,m)

[0088] Example 14: Preparation of 4-((3aS,4R,6aR)-4-((1-(Ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride Using compound 9-1 (100.0 mg) and 1-chloroethyl ethyl carbonate (34.7 μL), compound 14 (15.0 mg) was obtained in the same manner as in Example 9.

[0089] MS: [M+H] + = 373 1 H NMR (500 MHz, MeOD) δ 6.9 (1H, m), 4.7 (1H, m), 3.9 - 3.8 (2H, q), 3.7 - 3.5 (2H, m), 3.5 - 3.4 (3H, m), 2.3 (1H, m), 2.2 - 2.1 (3H, m), 1.6 (3H d), 1.6 - 1.5 (4H, m), 1.4 - 1.3 (6H, d), 0.8 (2H, m)

[0090] Example 15: Preparation of 4-((3aS,4R,6aR)-4-((1-(Cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride Using compound 9-1 (100.0 mg) and 1-chloroethyl cyclohexyl carbonate (48.0 μL), compound 15 (12.0 mg) was obtained in the same manner as in Example 9.

[0091] MS: [M+H] + = 427 11H NMR (500 MHz, MeOD) δ 6.9 (1H, m), 4.7 (1H, m), 3.9 - 3.8 (2H, m), 3.5 (2H, m), 3.4 (1H, m), 2.3 (1H, m), 2.2 - 2.0 (3H, m), 1.9 (2H, m), 1.7 - 1.6 (2H, m), 1.5 (3H, m), 1.5 - 1.3 (11H, m), 0.8 (2H, m)

[0092] Example 16: Preparation of 4 - ((3aS,4R,6aR) - 4 - ((1 - (Isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid dihydrochloride JPEG2025523364000041.jpg4747 Compound 9 - 1 (150.0 mg) and 1 - chloroethyl isopropyl carbonate (60.0 μL) were used to obtain Compound 16 (15.0 mg) in the same manner as in Example 9.

[0093] MS: [M + H] + = 387 1 1H NMR (500 MHz, MeOD) δ 6.9 (1H, m), 4.7 (1H, m), 3.9 - 3.8 (2H, m), 3.7 - 3.5 (2H,m), 3.5 - 3.4 (2H, m), 2.4 - 2.3 (1H, m), 2.2 - 2.0 (3H, m), 1.6 (3H, m), 1.6 - 1.5 (4H, m), 1.4 - 1.3 (6H, d), 0.8 (2H, m)

[0094] Example 17: Preparation of 4 - ((3aS,4R,6aR) - 4 - ((1 - (Pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid dihydrochloride JPEG2025523364000042.jpg4443 Compound 9 - 1 (100.0 mg) and 1 - chloroethyl 1 - chloroethyl pivalate (47.0 μL) were used to obtain Compound 17 (20.0 mg) in the same manner as in Example 9.

[0095] MS: [M+H] + = 385 1 H NMR(500 MHz, MeOD) 7.0(1H, m), 4.8(1H, m), 4.0 - 3.8(2H, m), 3.6 - 3.5(2H, m), 3.4(1H, m), 2.3 - 2.1(1H, m), 2.2 - 2.0(4H, m), 1.6(3H, m), 1.5(3H, m), 1.3 - 1.2(9H, s), 0.8(2H, m)

[0096] Example 18: Preparation of 4 - ((3aS,4R,6aR) - 4 - ((2 - (pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4 - b]pyrrol - 4 - yl)butylboronic acid dihydrochloride JPEG2025523364000043.jpg4347

[0097] Step 1) Preparation of 5 - benzyl 1 - (tert - butyl) 4 - (2 - hydroxyethyl) (3aS,4R,6aR) - 4 - (4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)butyl)hexahydropyrrolo[3,4 - b]pyrrole - 1,4,5 - tricarboxylate JPEG2025523364000044.jpg4044 Compound 9 - 1 (200.0 mg) and 2 - bromoethanol (125.0 μL) were used to obtain Compound 18 - 1 (197.0 mg, yield 91%) in the same manner as in Example 9.

[0098] MS: [M+H] + = 617

[0099] Step 2) Preparation of 5 - benzyl 1 - (tert - butyl) 4 - (2 - (pivaloyloxy)ethyl) (3aS,4R,6aR) - 4 - (4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)butyl)hexahydropyrrolo[3,4 - b]pyrrole - 1,4,5 - tricarboxylate After dissolving compound 18-1 (200.0 mg) in tetrahydrofuran (3.0 ml), triethylamine (136.0 μL) and pivaloyl chloride (90.8 μL) were added. After reacting at room temperature for 12 hours, it was concentrated and separated by column chromatography with ethyl acetate:hexane = 1:1 to obtain compound 18-2 (60.0 mg).

[0100] MS: [M+H] + = 701

[0101] Step 3) Preparation of 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride Compound 18-2 (60.0 mg) was used to obtain compound 18 (14.0 mg) in the same manner as in steps 8 to 10 of Example 1.

[0102] MS: [M+H] + = 385 1 H NMR (500 MHz, MeOD) 4.7 (1H, m), 4.6 - 4.5 (2H, m), 4.4 (2H, m), 4.0 - 3.8 (3H, m), 3.8 - 3.6 (2H, m), 2.4 (1H, m), 2.1 - 2.0 (3H, m), 1.4 - 1.4 (3H, m), 1.3 (1H, m), 1.3 - 1.2 (9H, m), 0.8 (2H, m)

[0103] Example 19: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((cyclohexanecarbonyl)oxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride JPEG2025523364000047.jpg4461

[0104] Step 1) Preparation of 4,5-dibenzyl 1-(1-chloroethyl) (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate Compound 2-1 (431.1 mg) was dissolved in dimethyl chloride (5.0 ml). After cooling to 0 - 10°C, triethylamine (300.0 μL) was added. 1-Chloroethyl carbonochloridate (118.0 μl) was slowly added dropwise, and then the mixture was stirred at room temperature for 12 hours to complete the reaction. After cooling to 0 - 10°C, saturated ammonium chloride aqueous solution was added to separate the organic layer. The organic layer was dried over MgSO4, concentrated, and dried under reduced pressure to obtain Compound 19-1 (455.0 mg).

[0105] MS: [M+H] + = 670

[0106] Step 2) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(((1-((cyclohexanecarbonyl)oxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Compound 19-1 (235.4 mg) was dissolved in dimethyl chloride (3.0 ml). Cesium carbonate (234.0 mg), sodium iodide (5.4 mg), and cyclohexanecarboxylic acid (67.0 μL) were added. The mixture was stirred at 50°C for 2 hours to complete the reaction. After cooling to 0 - 10°C, ethyl acetate (5.0 ml) and saturated ammonium chloride aqueous solution (5.0 ml) were added for layer separation, and the organic layer was concentrated. Column separation was performed with ethyl acetate:hexane = 3:7, and Compound 19 (20.0 mg) was obtained in the same manner as in Steps 8 - 10 of Example 1.

[0107] MS: [M+H] + = 455 11H NMR (500 MHz, MeOD) δ 6.7 (1H, m), 4.8 - 4.7 (1H, m), 3.8 - 3.7 (1H, m), 3.6 - 3.5 (1H, m), 3.4 (2H, m), 3.2 (1H, m), 2.3 (1H, m), 2.2 (1H, m), 2.1 (1H, m), 1.9 - 1.8 (4H, m), 1.7 (2H, m), 1.6 (1H, m), 1.4 (8H, m), 1.3 (4H, m), 0.8 (2H, m)

[0108] Example 20: Preparation of (3aS,4R,6aR)-4-(4-Boronobutyl)-1-((1-(pentyloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Using compound 19-1 (100.0 mg) and pentanoic acid (35.0 μL), compound 20 (7.0 mg) was obtained in the same manner as in Example 19.

[0109] MS: [M + H] + = 429 1 1H NMR (500 MHz, MeOD) δ 6.5 (1H, m), 4.5 - 4.4 (1H, m), 3.6 (2H, m), 3.5 - 3.4 (2H, m), 3.0 (1H, m), 2.4 (2H, m), 2.2 (1H, m), 2.1 - 2.0 (2H, m), 1.9 - 1.8 (1H, m), 1.7 (1H, m), 1.6 (2H, m), 1.5 - 1.3 (5H, m), 1.0 - 0.9 (9H, m), 0.8 - 0.6 (2H, m)

[0110] Example 21: Preparation of (3aS,4R,6aR)-4-(4-Boronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride Compound 21 (15.0 mg) was obtained in the same manner as in Example 19 using Compound 19-1 (200.0 mg) and pivalic acid (70.0 μL).

[0111] MS: [M+H] + = 429 1 H NMR(500 MHz, MeOD) 6.7(1H, m), 4.7(1H, m), 3.8 - 3.7(1H, m), 3.6 - 3.5(1H, m), 3.5 - 3.4(2H, m), 3.2(1H, m), 2.2(1H, m), 2.1(1H, m), 2.0(2H,m), 1.5 - 1.4(6H, m), 1.3 - 1.2(1H,m), 1.2(9H, m), 0.8(2H, m)

[0112] Example 22: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Compound 22 (15.5 mg) was obtained in the same manner as in Example 19 using Compound 19-1 (240 mg) and dimethyl-L-valine (78.4 mg).

[0113] MS: [M+H] + = 472 1 H NMR(500 MHz, MeOD) 6.9(1H,m), 4.8 - 4.7(1H, m), 4.1 - 4.0(1H, m), 3.9 - 3.5(2H, m), 3.5 - 3.4(2H, m), 3.2 - 3.1(1H, m), 2.9(6H, s), 2.5(1H, m), 2.2 - 1.8(3H, m), 1.7 - 1.5(3H, m), 1.5(2H, m), 1.4(2H, m), 1.2(3H, m), 1.1(3H, m), 0.8(2H, m)

[0114] Example 23: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexanecarbonyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride JPEG2025523364000053.jpg4461

[0115] Step 1) Preparation of 4,5-dibenzyl 1-(1-chloro-2-methylpropyl) (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate JPEG2025523364000054.jpg4056Compound 2-1 (300 mg) was dissolved in dimethyl chloride (3.0 ml). After cooling to 0 - 10 °C, triethylamine (200.0 μL) was added. 1-Chloro-2-methylpropyl carbonochloridate (125.0 μL) was slowly added dropwise, and then the mixture was stirred at room temperature for 12 hours to complete the reaction. After cooling to 0 - 10 °C, saturated aqueous ammonium chloride solution was added to separate the organic layer. The organic layer was dried over MgSO4, concentrated, and dried under reduced pressure to obtain compound 23-1 (350.0 mg).

[0116] MS: [M+H] + = 698

[0117] Step 2) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexanecarbonyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Compound 23-1 (115.0 mg) was dissolved in dimethylformamide (1.0 ml). Cesium carbonate (108.0 mg), sodium iodide (3.0 mg), and cyclohexanecarboxylic acid (32.0 μL) were added. The mixture was stirred at 70 °C for 2 hours to complete the reaction. After cooling to 0 - 10 °C, ethyl acetate (5.0 ml) and saturated aqueous ammonium chloride solution (3.0 ml) were added, and the layers were separated. The organic layer was concentrated. Column separation was performed with ethyl acetate:hexane = 3:7, and compound 23 (20.0 mg) was obtained in the same manner as in steps 8 - 10 of Example 1.

[0118] MS: [M+H] + = 483 1 H NMR (500 MHz, MeOD) 6.8(1H, m), 4.8 - 4.5(1H, m), 3.6(2H,m), 3.4(2H,m), 3.1 - 2.9(2H, m) 2.3(2H, m), 2.1 - 2.0(2H,m), 1.9(3H, m), 2.8 - 2.6(4H, m), 1.5 - 1.3(4H, m), 1.3 - 1.2(3H, m), 1.0(6H, m), 0.9 - 0.8(2H, m)

[0119] Example 24: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Using compound 23-1 (115 mg) and pivalic acid (25.6 mg), compound 24 (5.6 mg) was obtained in the same manner as in Example 23.

[0120] MS: [M+H] + = 457 11H NMR (500 MHz, MeOD) δ 6.5 (1H, m), 4.5 - 4.4 (1H, m), 3.6 (1H, m), 3.5 - 3.4 (2H, m), 3.1 - 2.9 (2H, m), 2.2 - 2.0 (2H, m), 1.9 - 1.8 (1H, m), 1.7 (2H, m), 1.5 - 1.4 (3H, m), 1.2 (9H, m), 1.0 (6H, m), 0.8 - 0.6 (2H, m)

[0121] Example 25: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Using compound 2-1 (50 mg) and ethyl carbocloridate (12 μL), compound 25 (14 mg) was obtained in the same manner as in Step 1 of Example 19 and Steps 8 - 10 of Example 1.

[0122] MS: [M+H] + = 329 1 1H NMR (500 MHz, MeOD) δ 4.6 (1H, m), 4.1 (2H, m), 3.7 (1H, m), 3.6 (1H, m), 3.5 - 3.4 (2H, m), 3.2 (1H, m), 2.2 (1H, m), 2.1 (1H, m), 1.9 (2H, m), 1.5 (3H, m), 1.3 (4H, m), 0.8 (2H, m)

[0123] Example 26: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride Using compound 2-1 (50 mg) and isobutyl carbocloridate (15 μL), compound 26 (6.7 mg) was obtained in the same manner as in Step 1 of Example 19 and Steps 8 - 10 of Example 1.

[0124] MS: [M+H] += 357 1 1H NMR (500 MHz, MeOD) 4.5 (1H, m), 3.9 (2H, m), 3.7 - 3.5 (2H, m), 3.4 (2H, m), 3.2 (1H, m), 2.2 (1H, m), 2.1 (1H, m), 2.0 - 1.9 (3H, m), 1.6 - 1.5 (3H, m), 1.3 (1H, m), 1.0 (6H, m), 0.8 (2H, m)

[0125] Example 27: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-methyloctahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride JPEG2025523364000059.jpgCompound 2-1 (100 mg) was dissolved in dichloromethane (2 ml), then formaldehyde (12.3 μL) and acetic acid (40.0 μL) were added, and the mixture was stirred at 40 °C for 3 hours. Sodium acetoxyborohydride (96 mg) was added, and the mixture was stirred at 40 °C for 3 hours to complete the reaction. After cooling to 0 - 10 °C, H2O was added and the organic layer was separated. After concentration, separation was carried out with ethyl acetate:hexane = 9:1, and then compound 27 (4.0 mg) was obtained in the same manner as in steps 8 - 10 of Example 1.

[0126] MS: [M+H] + = 271 1 1H NMR (500 MHz, MeOD) 4.5 (1H, m), 4.2 (1H, m), 3.9 (1H, m), 3.8 (1H, m), 3.7 - 3.5 (2H, m), 3.1 (3H, s), 2.5 (1H, m), 2.2 - 2.1 (2H, m), 2.0 (1H, m), 1.6 (1H, m), 1.5 (2H, m), 1.3 (1H, m), 0.8 (2H, m)

[0127] Example 28: Preparation of ((3aS,4R,6aR)-4-(4-boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride After dissolving Compound 2-1 (200 mg) in dichloromethane (2 ml), tert-butylmethyl(2-oxoethyl)carbamate (115.6 μL) and acetic acid (95 μL) were added, followed by stirring at 40 °C for 3 hours. After adding sodium acetoxyborohydride (200 mg), the reaction was stirred at 40 °C for 3 hours to complete the reaction. After cooling to 0 - 10 °C, H2O was added to separate the organic layer. After concentration, separation was carried out with ethyl acetate:hexane = 5:1, and then Compound 28 (20.0 mg) was obtained in the same manner as in Steps 8 - 10 of Example 1.

[0128] MS: [M+H] + = 314 1 H NMR(500 MHz, D2O) 4.3(1H, m), 3.8(1H, m), 3.7(1H, m), 3.6 - 3.4(3H, m), 3.4 - 3.3(2H, m), 3.2(1H, m), 3.1(1H, m), 2.3(1H, m), 2.0(1H, m), 1.8(2H, m), 1.5 - 1.3(2H, m), 1.1(1H, m), 0.7 - 0.6(2H, m)

[0129] Experimental Example 1: Arginase Inhibitory Activity Test An arginase inhibitory activity test was conducted on the compounds according to the present invention. In addition to the compounds according to the present invention, for comparison, Compound CB-1158 (Numidargistat) was also tested together.

[0130] Specifically, all the reagents required for the evaluation were diluted in reaction buffer (8 mM NaHPO4, 2 mM KH2PO4, pH 7.5, 137 mM NaCl, 2.7 mM KCl, and 0.05% Tween-20). The compounds were dissolved in DMSO, diluted, and then further diluted in reaction buffer to the desired concentration. 10 μL of the compound and 10 μL of 30 nM Arginase-1 were mixed in a transparent 96-well plate (SPL) and incubated at room temperature for at least 1 hour. Then, 10 μL of 15 mM L-arginine and 3 mM MnCl2 were added to the plate and reacted at room temperature for at least 30 minutes. Finally, a 1:1 mixture of 30 μL of reagent A (10 mM o-phthaldialdehyde, 0.4% polyoxyethylene lauryl ether, and 1.8 M sulfuric acid in DW) and reagent B (1.3 mM primaquine diphosphate, 0.4% polyoxyethylene lauryl ether, and 3.6 M sulfuric acid in DW) was added to terminate the enzyme reaction, and the mixture was incubated at room temperature for at least 1 hour. The absorbance at 450 nM of the incubated plate was measured using a Flexstation3 multi-mode microplate reader (Molecular Devices).

[0131] The background control (BC) reading was subtracted from all the readings to obtain the ΔOD for each reading. After setting the ΔOD of the enzyme control (EC) to the maximum value, the following formula was used to calculate the % relative Arginase-1 activity of each compound (S), and the IC 50 value of the compound was determined using PRISM (GraphPad software).

[0132] Relative Arginase-1 activity (%) = (ΔOD of S / ΔOD of EC) × 100

[0133] In Table 1 below, the efficacy of the compounds was ranked on a scale from A to C. The efficacy value of A refers to the compound of the present invention having an IC 50 value of less than 100 nM, and the compound with an efficacy value of B shows an IC 50 value in the range of 100 nM to 1,000 nM, and a C efficacy value was assigned to the compound having an IC 50 value exceeding 1,000 nM.

[0134]

Table 1

[0135] Experimental Example 2: PBMC Activity Evaluation Test For the compound according to the present invention, a Primary Peripheral Blood Mononuclear Cells (PBMC) activity test was conducted. After inhibiting the differentiation of T cells induced by α-CD3 and α-CD28 antibodies with synthetic arginase1, it was confirmed that the compound inhibits arginase1 and induces the differentiation and proliferation of T cells. To evaluate the proliferation of T cells, the CellTiter-Glo® Luminescent Cell Viability (Promega, Catalog #G7571) evaluation method was used, which can confirm the proliferation of cells by quantifying the ATP present in the cells. In addition to the compound according to the present invention, for comparison, the compound CB-1158 (Numidargistat) was also tested together.

[0136] Specifically, a clear 96-well microplate was coated with α-CD3 antibody. 1×10 5Individual PBMC cells were placed in each well. RPMI media (10% FBS, 1% penicillin / streptomycin) was used as the cell culture medium. α-CD28 antibody and synthetic arginase1 were placed in each well. The compounds produced in the examples were treated at different concentrations (2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125 uM). After culturing for 72 hours, 50 μL of the cells in each well were transferred to a white 96-well microplate and mixed with 50 μL of CellTiter-Glo® solution. After reacting at room temperature with light blocked for 10 minutes, luminescence was measured. The measurement results for each compound were calculated using Excel, and the EC 50 value was calculated using GraphPad Prism software.

[0137] The efficacy of the compounds was ranked according to the scales of A and B in Table 2 below. The efficacy value of A refers to the compound of the present invention having an EC 50 value of less than 100 nM, and the efficacy value of B was assigned to the compound having an EC 50 value in the range of 100 nM to 500 nM.

[0138]

Table 2

Claims

1. A compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the Chemical Formula 1, R １ 、R ２ is, independently of each other, hydrogen; C １－４ alkyl which is unsubstituted or substituted by amino, (C １－４ alkyl)amino, or di(C １－４ alkyl)amino; or -L １ -R' １ wherein L １ is -CO-, -CO-O-, -(CO)-O-(C １－４ alkylene)-O-(CO)-, or -CH ２ -O-CO- and R' １ is -CH(NH ２ )-R Ａ 、-CH(N(CH ３ ))-R ２ )-R Ａ 、R Ｂ 、or R Ｃ and R ３ is hydroxy or -L ３ -R' ３ and L ３ is -NH-, -O-, or -O-(CH ２ ) ｎ３ -O-CO- and R' ３ is -CH(COOH)-R Ａ , -CH(NH ２ )-R Ａ , R Ｂ , or R Ｃ and R Ａ is, independently of one another, hydrogen; or C which is unsubstituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, C １－６ alkylthio, phenyl, hydroxyphenyl, or C containing one or two Ns ４－１０ heteroaryl-substituted C １－６ alkyl, R Ｂ is, independently of each other, C containing N ４－１０ heterocycloalkyl, R Ｃ is, independently of one another, unsubstituted or C ６－１０ aryl, or C ４－１０ heterocycloalkyl-substituted C １－６ alkyl; unsubstituted or C １－６ aryl substituted with C ６－１０ alkoxy; or C ３－６ cycloalkyl, and n3 is an integer from 1 to 3.

2. R １ and R ２ are each independently hydrogen, methyl, methylaminoethyl, or a substituent represented by any one of the following: The compound according to Claim 1, or a pharmaceutically acceptable salt thereof: In the above, R Ａ 、R Ｂ 、and R Ｃ are as defined in claim 1, n1 is an integer from 1 to 3.

3. R ３ is a hydroxy or a substituent represented by any one of the following: The compound according to Claim 1, or a pharmaceutically acceptable salt thereof: In the above, R Ａ , R Ｂ , R Ｃ and n3 are as defined in claim 1.

4. R Ａ is, independently of one another, hydrogen; or C １－６ alkyl which is unsubstituted or substituted by hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, methylthio, phenyl, hydroxyphenyl, indole, or imidazole The compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

5. R Ａ are each independently a residue of a natural amino acid, The residue of the natural amino acid means a structure excluding the terminal -CH(NH ２ )(COOH). The compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

6. R Ｂ is pyrrolidinyl, The compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

7. R Ｃ is, independently of each other, unsubstituted or C substituted with phenyl or piperidinyl １－６ alkyl; unsubstituted or C substituted with methoxy ６－１０ aryl; or C ３－６ cycloalkyl, The compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

8. R １ is hydrogen, and R ２ is hydrogen or R １ is hydrogen, and R ３ is hydroxy, or R ２ is hydrogen, and R ３ is hydroxy, The compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

9. The Chemical Formula 1 is represented by any one of the following Chemical Formulas 2 to 5, The compound according to Claim 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] In the Chemical Formulas 2 to 5, R Ａ is as defined in claim 1.

10. The compound represented by the Chemical Formula 1 is 1) (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, 2) (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 3) (3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 4) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 5) (3aS,4R,6aR)-1-((2R,3S)-2-amino-3-hydroxybutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 6) (3aS,4R,6aR)-1-((S)-2-amino-3-methylbutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 7) (3aS,4R,6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 8) (3aS,4R,6aR)-1-((2S,3S)-2-amino-3-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 9) (3aS,4R,6aR)-1-((R)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 10) 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrole-4-yl)carboxylic acid, 11) 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrole-4-yl)carboxylic acid, 12) 4-((3aS,4R,6aR)-4-(((isopropoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 13) 4-((3aS,4R,6aR)-4-(((tert-butoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 14) 4-((3aS,4R,6aR)-4-(((1-(ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 15) 4-((3aS,4R,6aR)-4-(((1-(cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 16) 4-((3aS,4R,6aR)-4-(((1-(isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 17) 4-((3aS,4R,6aR)-4-(((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 18) 4-((3aS,4R,6aR)-4-(((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butylboronic acid, 19) (3aS,4R,6aR)-4-(4-boronobutyl)-1-(((1-(cyclohexanecarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(pentyloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((1-(cyclohexanecarbonyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-methyloctahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-4-(4-Boronobutyl)-1-(butyryloxymethyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (3aS,4R,6aR)-1-(((acetoxymethoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, (S)-2-(((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)propanoic acid, (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylbutanoic acid (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxamide)-4-methylpentanoic acid (2S,3R)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylpentanoic acid (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-phenylpropanoic acid 4-((3aS,4R,6aR)-4-(((2-((S)-2-aminopropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl))carboxylic acid 4-((3aS,4R,6aR)-4-(((2-((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl))butylboronic acid 4-((3aS,4R,6aR)-4-(((2-((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl))carboxylic acid 4-((3aS,4R,6aR)-4-(((2-((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl))carboxylic acid 4-((3aS,4R,6aR)-4-(((2-((S)-2-amino-3-phenylpropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl))carboxylic acid 4-((3aS,4R,6aR)-4-(((2-((S)-pyrrolidine-2-carbonyl-oxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl))butylboronic acid 4-((3aS,4R,6aR)-4-(((propionyloxymethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl))carboxylic acid 43) 4-(((3aS,4R,6aR)-4-((isobutyryloxymethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, 44) 4-(((3aS,4R,6aR)-4-(benzyloxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, 45) 4-(((3aS,4R,6aR)-4-((piperidin-4-ylmethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, 46) 4-(((3aS,4R,6aR)-4-(phenoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, 47) 4-(((3aS,4R,6aR)-4-((2-methoxyphenoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, 48) (3aS,4R,6aR)-1-((((S)-2-amino-3-phenylpropanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 49) (3aS,4R,6aR)-1-((((S)-2-aminopropanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 50) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((((S)-pyrrolidine-2-carbonyl)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 51) (3aS,4R,6aR)-1-((((2S,3R)-2-amino-3-hydroxybutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 52) (3aS,4R,6aR)-1-((((S)-2-amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 53) (3aS,4R,6aR)-1-((((S)-2-amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, or (3aS,4R,6aR)-1-((((2S,3S)-2-Amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for preventing or treating cancer or tumor, comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Any one compound selected from the group consisting of the following: In the above, PG1 and PG2 each independently represent the same or different protecting groups.

13. The compound is any one selected from the group consisting of the following: Compound: (3aR,4R,6aR)-1-(tert-Butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid (3aS,4R,6aR)-5-((Benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-4-((E)-but-2-en-1-yl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate 4,5-Dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate (4-((3aS,4R,6aR)-4,5-bis((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-yl)butyl)boronic acid, and (3aS,4R,6aR)-5-(benzyloxycarbonyl)-4-(4-boronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

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