Arginase inhibitors and pharmaceutical compositions containing same

Abstract

The present disclosure relates to a compound represented by Chemical Formula 1 in the specification or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same can be advantageously used in the prevention or treatment of cancer or tumor.

Description

Technical Field

[0001] The present disclosure relates to compounds having novel structures, which can be advantageously used for preventing or treating cancer or tumors. Background Art

[0002] With regard to the development of immuno-anticancer agents currently emerging in the field of development of cancer therapeutic agents, it is a well-known fact that arginine depletion in the tumor microenvironment due to elevated arginase levels is observed in cancer patients. In fact, it is known that such a mechanism allows tumor cells of acute myeloid leukemia, breast cancer, prostate cancer, glioblastoma, esophageal cancer, renal cell carcinoma, etc. to avoid being destroyed by the body's immune system. Therefore, there is a need to develop arginase inhibitors that inhibit arginase to restore arginine levels in the tumor microenvironment and promote the tumor-killing activity of cytotoxic T cells.

[0003] As for arginase inhibitors, pyrrolidine-based arginase inhibitors have been developed and known so far, but development of arginase inhibitors having a new chemical structure is desired.

[0004] Therefore, the present inventors have studied novel compounds having a chemical structure different from arginase inhibitors reported so far, and as a result have confirmed that a compound having an octahydropyrrolo[3,4-b]pyrrole bicyclic structure as a mother core has excellent arginase inhibitory activity, thereby completing the present disclosure. Summary of the invention

[0005] [Technical issues]

[0006] An object of the present disclosure is to provide a compound having a novel structure, which can be advantageously used for preventing or treating cancer or tumors.

[0007] [Technical solution]

[0008] In order to achieve the above object, a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof is provided herein:

[0009] [Chemical formula 1]

[0010]

[0011] In Chemical Formula 1,

[0012] R1 and R2 are each independently hydrogen; unsubstituted or substituted with amino, (C 1-4 alkyl)amino or di(C 1-4 Alkyl)amino substituted C 1-4 Alkyl; or -L1-R'1,

[0013] L1 is -CO-, -CO-O-, -(CO)-O-(C 1-4 Alkylene)-O-(CO)-, or -CH2-O-CO-,

[0014] R'1 is -CH(NH2)-R A ,-CH(N(CH3)2)-R A , R B , or R C ,

[0015] R3 is hydroxyl, or -L3-R'3,

[0016] L3 is -NH-, -O-, or -O-(CH)2) n3 -O-CO-,

[0017] R'3 is -CH(COOH)-R A 、-CH(NH2)-R A , R B , or R C ,

[0018] Each R A are independently hydrogen; or unsubstituted or substituted by hydroxy, thiol, seleno, guanidinyl, amino, carboxyl, carbamoyl, C 1-6 Alkylthio, phenyl, hydroxyphenyl or C containing one or two N 4-10 Heteroaryl-substituted C 1-6 alkyl,

[0019] Each R B are independently C 4-10 Heterocycloalkyl,

[0020] Each R C are independently unsubstituted or substituted with C 6-10 Aryl or N-containing C 4-10 Heterocycloalkyl substituted C 1-6 Alkyl group; unsubstituted or substituted with C 1-6 Alkoxy substituted C 6-10 Aryl; or C 3-6 Cycloalkyl, and

[0021] n3 is an integer from 1 to 3.

[0022] Preferably, R1 and R2 are each independently hydrogen, methyl, methylaminoethyl or a substituent represented by any of the following:

[0023]

[0024] Among them, R A , R B and RC As defined above, n1 is an integer from 1 to 3.

[0025] Preferably, R3 is hydroxyl, or a substituent represented by any of the following:

[0026]

[0027] Among them, R A , R B , R C and n3 are as defined above.

[0028] Preferably, each R A independently hydrogen; or unsubstituted or substituted by hydroxy, thiol, seleno, guanidinyl, amino, carboxyl, carbamoyl, methylthio, phenyl, hydroxyphenyl, indolyl or imidazolyl. 1-6 More preferably, each R A and 1-2-butyl, 1-hydroxy-1-ethyl, 1-propyl, 1-isopropyl, 1-butyl, 1-isobutyl, 1-tert-butyl or 1-benzyl.

[0029] Preferably, each R A The residue of the natural amino acid is independently a residue of a natural amino acid, wherein the residue of the natural amino acid refers to a structure excluding the terminal -CH(NH2)(COOH). For example, if A is an alanine residue, it represents a methyl group. 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.

[0030] Preferably, R B It is pyrrolidyl.

[0031] Preferably, each R C is independently unsubstituted or substituted by phenyl or piperidinyl. 1-6 Alkyl; or unsubstituted or methoxy-substituted C 6-10 More preferably, each R C and cyclohexyl.

[0032] Preferably, R1 is hydrogen, and R2 is hydrogen, or

[0033] R1 is hydrogen, and R3 is hydroxy, or

[0034] R2 is hydrogen, and R3 is hydroxy.

[0035] Preferably, Chemical Formula 1 is represented by any one of the following Chemical Formulas 2 to 5:

[0036] [Chemical formula 2]

[0037]

[0038] [Chemical formula 3]

[0039]

[0040] [Chemical formula 4]

[0041]

[0042] [Chemical formula 5]

[0043]

[0044] In Chemical Formulae 2 to 5, R A As defined above.

[0045] Representative examples of the compound represented by Chemical Formula 1 are shown below:

[0046] 1)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0047] 2)(3aS,4R,6aR)-1-((S)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0048] 3)(3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0049] 4)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0050] 5)(3aS,4R,6aR)-1-((2R,3S)-2-amino-3-hydroxybutyryl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0051] 6)(3aS,4R,6aR)-1-((S)-2-amino-3-methylbutanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0052] 7)(3aS,4R,6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0053] 8) (3aS, 4R, 6aR)-1-((2S, 3S)-2-amino-3-methylpentanoyl)-4-(4-dihydroxyboronobutyl) octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0054] 9)(3aS,4R,6aR)-1-((R)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0055] 10) 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0056] 11) 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0057] 12) 4-((3aS,4R,6aR)-4-(((isopropoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0058] 13) 4-((3aS,4R,6aR)-4-(((tert-butoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0059] 14) 4-((3aS,4R,6aR)-4-((1-(ethoxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0060] 15) 4-((3aS,4R,6aR)-4-((1-(cyclohexyloxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0061] 16) 4-((3aS,4R,6aR)-4-((1-(isopropoxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0062] 17) 4-((3aS,4R,6aR)-4-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0063] 18) 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0064] 19) (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0065] 20)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0066] 21)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0067] 22)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0068] 23)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0069] 24)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0070] 25)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0071] 26)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0072] 27)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-methyl-octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0073] 28)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0074] 29)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(butyryloxymethyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0075] 30)(3aS,4R,6aR)-1-((acetoxymethoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0076] 31)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)propanoic acid,

[0077] 32)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylbutanoic acid,

[0078] 33)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxamide)-4-methylpentanoic acid,

[0079] 34)(2S,3R)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylpentanoic acid,

[0080] 35)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-phenylpropionic acid,

[0081] 36) 4-((3aS,4R,6aR)-4-((2-((S)-2-aminopropionyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0082] 37) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0083] 38) 4-((3aS,4R,6aR)-4-((2-((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0084] 39) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0085] 40) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-phenylpropionyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0086] 41) 4-((3aS,4R,6aR)-4-((2-((S)-pyrrolidine-2-carbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0087] 42) 4-((3aS,4R,6aR)-4-((propionyloxymethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid,

[0088] 43) 4-((3aS,4R,6aR)-4-((isobutyryloxymethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0089] 44) 4-((3aS,4R,6aR)-4-(benzyloxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0090] 45) 4-((3aS,4R,6aR)-4-((piperidin-4-ylmethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0091] 46) 4-((3aS,4R,6aR)-4-(phenoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0092] 47) 4-((3aS,4R,6aR)-4-((2-methoxyphenoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0093] 48) (3aS, 4R, 6aR)-1-(((S)-2-amino-3-phenylpropionyloxy) methoxy) carbonyl-4-(4-dihydroxyboronobutyl) octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0094] 49) (3aS, 4R, 6aR)-1-(((S)-2-aminopropionyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0095] 50)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((((S)-pyrrolidine-2-carbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0096] 51)(3aS,4R,6aR)-1-((((2S,3R)-2-amino-3-hydroxybutyryloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0097] 52)(3aS,4R,6aR)-1-((((S)-2-amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0098] 53)(3aS,4R,6aR)-1-((((S)-2-amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, and

[0099] 54)(3aS,4R,6aR)-1-((((2S,3S)-2-amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

[0100] In addition, the compounds of the present disclosure may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art, such as acid addition salts formed from pharmaceutically acceptable free acids, may be used without restriction. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of a compound represented by Chemical Formula 1, which is relatively non-toxic and harmless to the patient at a concentration, and is effectively activated, and its side effects do not reduce the beneficial effects of the above-mentioned compounds.

[0101] Furthermore, when preparing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically unacceptable salt or solvate of the compound represented by Chemical Formula 1 may be used as an intermediate.

[0102] In addition, the compound of Chemical Formula 1 according to the present disclosure includes not only its pharmaceutically acceptable salt, but also solvates prepared therefrom, such as hydrates, and includes but is not limited to all possible stereoisomers. The solvates and stereoisomers of the compound of Chemical Formula 1 can be prepared from the compound of Chemical Formula 1 using common methods known in the art.

[0103] In addition, the compound of Chemical Formula 1 according to the present invention can be prepared in a crystalline form or a non-crystalline form, and when the compound of Chemical Formula 1 is prepared in a crystalline form, it can be optionally hydrated or solvated. In the present disclosure, the compound of Chemical Formula 1 can include not only stoichiometric hydrates, but also compounds containing different amounts of water. The solvate of the compound of Chemical Formula 1 according to the present disclosure includes both stoichiometric solvates and non-stoichiometric solvates.

[0104] In addition, as an example, the compound represented by Chemical Formula 1 according to the present disclosure may be prepared by the following Reaction Scheme 1.

[0105] [Reaction Scheme 1]

[0106]

[0107] Reaction Scheme 1 shows a case where R1 is -L1-R'1, R2 is hydrogen, and R3 is hydroxyl, and can be used to prepare the remaining compounds represented by Chemical Formula 1 other than the above. The first reaction of Reaction Scheme 1 is a -L1-R'1 substitution reaction, and the second reaction is a protecting group removal reaction. The preparation method can be more specifically implemented in the preparation examples provided below.

[0108] In addition, the present disclosure provides any one compound selected from the group consisting of the following compounds, wherein the following compounds may be used as intermediates in preparing the compound represented by Chemical Formula 1 according to the present disclosure.

[0109]

[0110] wherein PG1 and PG2 are each independently the same or different and represent a protecting group.

[0111] As a protecting group, there is no particular limitation, as long as it is widely used in the technical field to which the present disclosure belongs. Preferably, PG1 is an amine protecting group and PG2 is a carboxylic acid protecting group. Representative examples of PG1 include benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzylcarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl, etc., but are not limited thereto. Representative examples of PG2 include 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, tetrahydrofuranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, etc.

[0112] Preferably, the compound is selected from any one of the group consisting of:

[0113] (3aR,4R,6aR)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0114] (3aS,4R,6aR)-5-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0115] 4,5-dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate,

[0116] 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,

[0117] 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,

[0118] (4-((3aS,4R,6aR)-4,5-bis((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, and

[0119] (3aS,4R,6aR)-5-(Benzyloxycarbonyl)-4-(4-dihydroxyboronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

[0120] In addition, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has an arginase inhibitory effect, and can inhibit arginase to restore arginine levels in the tumor microenvironment and promote the tumor killing activity of cytotoxic T cells. Therefore, the present disclosure provides a pharmaceutical composition for preventing or treating cancer or tumors, including a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0121] As used herein, the term "prevention" refers to any action of delaying or inhibiting the occurrence, spread or recurrence of the above-mentioned diseases by administering the composition of the present disclosure, and "treatment" refers to any action of better improving or changing the symptoms of the above-mentioned diseases by administering the composition of the present disclosure.

[0122] The pharmaceutical compositions according to the present disclosure can be formulated for oral or parenteral administration according to standard pharmaceutical practice. In addition to the active ingredients, these preparations may contain additives such as pharmaceutically acceptable carriers, adjuvants or diluents.

[0123] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate, etc. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, etc., but are not limited thereto. In addition, the compounds of the present disclosure can be dissolved in oil, propylene glycol or other solvents that are commonly used to prepare injection solutions. In addition, the compounds of the present disclosure can be formulated into ointments or creams for topical application.

[0124] The preferred dosage of the compound of the present disclosure can be changed according to the patient's condition and body weight, the severity of the disease, the type of drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compound of the present disclosure can be administered daily at a dosage of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration can be performed once a day or daily in divided doses by oral or parenteral routes.

[0125] The pharmaceutical composition may contain the compound of the present disclosure in an amount of 0.001 to 99% by weight, preferably 0.01 to 60% by weight, depending on the administration method.

[0126] The pharmaceutical composition according to the present disclosure can be administered to mammals, such as rats, mice, livestock, humans, by various routes. Administration can be carried out by all possible methods, such as oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, intraventricular injection.

[0127] [Beneficial Effects]

[0128] The compound represented by Chemical Formula 1 of the present disclosure or a pharmaceutically acceptable salt thereof may be advantageously used for preventing or treating cancer or tumor. DETAILED DESCRIPTION

[0129] Hereinafter, preferred examples are given to help understand the present disclosure. However, the following examples are only for illustrative purposes and should not be construed as limiting the scope of the present disclosure to these examples.

[0130] Example 1: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0131]

[0132] Step 1) Preparation of (R)-4-oxopyrrolidine-1,2-dicarboxylic acid dibenzyl ester

[0133]

[0134] Dichloromethane (1.5L) was cooled to -78°C, and then oxalyl chloride (90.0ml) and dimethyl sulfoxide (92.7ml) were slowly added dropwise. The mixture was stirred at -78°C for 10 minutes, and then (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester (186.0g) was dissolved in dichloromethane (700mL) and slowly added dropwise at -78°C. The solution was stirred for 30 minutes, and then triethylamine (255mL) was slowly added dropwise at -78°C. Stirring at -78°C for 1 hour to complete the reaction. The reaction solution was added to 1N-HCl solution at 0°C to 5°C, and then the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (1L), and the organic layer was separated. The organic layer was dried over MgSO4 and concentrated. The product was subjected to column separation with ethyl acetate (30% content in hexane) to obtain compound 1-1 (117 g, yield: 63%).

[0135] MS: [M+H] + =354.

[0136] 1 H NMR (500MHz, 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).

[0137] Step 2) Preparation of 4,5-dibenzyl 1-(tert-butyl)(R)-4,6-dihydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0138]

[0139] Compound 1-1 (67g) is dissolved in tetrahydrofuran (300mL), then cooled to -78°C under nitrogen. 2.5N n-BuLi (84mL) is slowly added dropwise at -78°C under nitrogen. The solution is stirred for 1 hour at -50°C to -55°C, then cooled to -78°C. (2-oxoethyl) tert-butyl carbamate (34g) is dissolved in tetrahydrofuran (100mL), then slowly added dropwise at -78°C under nitrogen. It is stirred for 1 hour at -50°C to -55°C to complete the reaction. At 0-5°C, the reaction solution is added to saturated NH4Cl solution, then ethyl acetate (1.4L) is used to separate the layers, and the organic layer is separated. The aqueous layer is extracted twice with ethyl acetate (670mL), and the organic layer is separated. The organic layer is dried and concentrated over MgSO4. It is dissolved in dichloromethane (1L), and then concentrated hydrochloric acid solution (8.1ml) is slowly added dropwise. Stir at room temperature for 12 hours to complete the reaction. The reaction solution is cooled to 0-5 ℃, and then 3%NaHCO3 aqueous solution (500mL) is added thereto. The organic layer is then separated, and dried and concentrated through MgSO4. The product is subjected to column separation with ethyl acetate (content in hexane is 30%) to obtain compound 1-2 (24g, yield: 30%).

[0140] MS: [M+H] + =477.

[0141] 1 H NMR (500MHz, 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).

[0142] Step 3: Preparation of (3aR, 4R, 6aR)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid

[0143]

[0144] Compound 1-2 (24 g) was dissolved in tetrahydrofuran (500 mL) and methanol (500 mL). Pd(OH)2 (12 g) was added thereto, and then stirred under a hydrogen balloon for 4 hours to complete the reaction. The reaction solution was washed with methanol, filtered through diatomaceous earth, concentrated, and dried under reduced pressure to obtain compound 1-3 (12.8 g, yield: 100%).

[0145] MS: [M+H] + =257.

[0146] 1H NMR(500MHz,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).

[0147] Step 4: Preparation of (3aS, 4R, 6aR)-5-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid

[0148]

[0149] Compound 1-3 (12.8 g) was dissolved in 1N KOH aqueous solution (100 mL), and then benzyl chloroformate (8.5 ml) was slowly added dropwise thereto. The solution was stirred at room temperature for 12 hours to complete the reaction. After the reaction solution was cooled to 0-5°C, ethyl acetate (150 mL) and H2O (100 mL) were added. The resulting mixture was adjusted to a pH of 2-3 using a 6N HCl aqueous solution, and the layers were separated and the organic layer was separated. Ethyl acetate (100 mL) was added to the aqueous layer twice, the organic layer was separated, and it was dried and concentrated over MgSO4. The product was dried under reduced pressure to obtain compound 1-4 (20 g, yield: 100%). The resulting compound was used for the next reaction without purification.

[0150] MS: [M+H] + =391.

[0151] 1 H NMR(500MHz, CDCl3)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).

[0152] Step 5) Synthesis of 4,5-dibenzyl 1-(tert-butyl)(3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0153] 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 then stirred at room temperature for 12 hours to complete the reaction. Ethyl acetate (400 mL) and 0.5 N HCl aqueous solution (200 mL) were added to separate the layers. The organic layer was concentrated, and then column separation was performed with ethyl acetate (30% in hexane) solution to obtain compound 1-5 (20 g, yield: 83%).

[0154] MS:[M+H] + =481.

[0155] 1 H NMR(500MHz, CDCl3)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).

[0156] 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

[0157]

[0158] Compound 1-5 (20 g) was dissolved in tetrahydrofuran (200 mL) and then cooled to -78 ° C under nitrogen. Crotonyl bromide (8.1 ml) was added dropwise and 1N bis(trimethylsilyl) amide potassium (80 mL) was slowly added dropwise. It was stirred at -78 ° C for 30 minutes to complete the reaction. At 0-5 ° C, the reaction solution was added dropwise to 1N HCl aqueous solution (200 mL) and extracted with ethyl acetate (200 mL). The aqueous solution was extracted twice with ethyl acetate (200 mL) and the organic layer was concentrated. The product was separated by column with ethyl acetate (30% in hexane) to obtain compound 1-6 (10.4 g, yield: 65%).

[0159] MS:[M+H] + =335.

[0160] 1H NMR(500MHz, CDCl3)5.6-4.90(m,6H),4.35-3.85(m,2H),3.55-3.30(m,1H),3.25-3.1 5(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).

[0161] 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

[0162]

[0163] Under nitrogen, chloro(1,5-cyclooctadiene)iridium(I) dimer (1.7 g) and 1,2-bis(diphenylphosphino)ethane (2.1 g) were added to dichloromethane (100 mL). 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.66 ml) was added thereto, and then stirred under nitrogen for 20 minutes. Compound 1-6 (14 g) was dissolved in dichloromethane (50 mL) and then slowly added dropwise. It was stirred at room temperature under nitrogen for 20 hours. The reaction solution was extracted with H2O (50 mL) and the organic layer was separated. The organic layer was concentrated and then column separated with ethyl acetate (30% in hexane) to obtain compound 1-7 (8.5 g, yield: 49%).

[0164] MS:[M+H] + =663.

[0165] 1 H NMR(500MHz, 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).

[0166] 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

[0167]

[0168] Compound 1-7 (8.5 g) was dissolved in acetone (128 mL), and then methylboric acid (7.66 g) was added thereto. A 0.1 N NaOH aqueous solution (128 mL) was added thereto, and then stirred at room temperature for 12 hours. A saturated NH4Cl solution (100 mL) was added, and then extracted with ethyl acetate (170 mL). The aqueous solution was extracted twice by adding ethyl acetate (100 mL). The organic layer was concentrated, and then column separation was performed with a solution of dichloromethane: methanol = 20: 1 (v: v) to obtain compound 1-8 (5.5 g, yield: 74%).

[0169] MS:[M+H] + =581.

[0170] 1 H NMR(500MHz, CDCl3)7.39-7.24(m,10H),5.19-4.89(m,4H),4.75-4.35(m,1 H),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).

[0171] Step 9: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid

[0172]

[0173] Compound 1-8 (5.5 g) was dissolved in methanol (50 mL). 10% Pd / C (2 g) was added thereto, and then stirred at room temperature for 4 hours using a hydrogen balloon to complete the reaction. The product was directly used in the following step 10.

[0174] MS:[M+H] + =357.

[0175] Step 10: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0176]

[0177] The product of step 9 was washed with methanol, filtered through diatomaceous earth and concentrated. A 6N HCl aqueous solution was added thereto, stirred at room temperature for 2 hours, and then concentrated. The mixture was dissolved in H2O (5mL) and extracted three times with ether (5mL) to remove the organic layer. The aqueous solution was concentrated and dried under reduced pressure to obtain compound 1 (2.5g, yield: 80% (steps 9 and 10)).

[0178] MS:[M+H] + =257.

[0179] 1 H NMR(500MHz,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).

[0180] Example 2: Preparation of (3aS, 4R, 6aR)-1-((S)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0181]

[0182] 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.

[0183]

[0184] Compound 1-7 (800 mg) was dissolved in 1,4-dioxane (10 mL), and then 4N HCl (in dioxane; 12 mL) was added thereto. The mixture was stirred at 50° C. for 1 hour to complete the reaction. The product was concentrated and dried under reduced pressure to obtain compound 2-1 (723 mg, yield: 100%).

[0185] MS:[M+H] + =563.

[0186] 1H NMR(500MHz,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).

[0187] Step 2 Preparation of (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)-dicarboxylic acid dibenzyl ester

[0188]

[0189] Compound 2-1 (54 mg) was dissolved in dichloromethane (1 mL). Trimethylamine (36 μL) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-alanine ester (37 mg) were added thereto, and then stirred at room temperature for 12 hours to complete the reaction. After adding saturated NH4Cl aqueous solution, the mixture was extracted and the organic layer was separated. The organic layer was concentrated and then column separated with ethyl acetate (40-50% in hexane) to obtain compound 2-2 (47 mg, yield: 74%).

[0190] MS:[M+H] + =734.

[0191] 1 H NMR(500MHz, 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).

[0192] Step 3: Preparation of (3aS, 4R, 6aR)-1-((S)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0193]

[0194] Compound 2 was obtained in the same manner as in Steps 8 to 10 of Example 1 using Compound 2-2.

[0195] MS:[M+H] + =328,[M-H2O+H] + =310.

[0196] 1 H NMR(500MHz,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).

[0197] Example 3: Preparation of (3aS, 4R, 6aR)-1-((S)-2-amino-3-phenylpropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0198]

[0199] Compound 3 was obtained in the same manner as in Steps 2 and 3 of Example 2 using Compound 2-1 (100 mg) and 2,5-dioxopyrrolidin-1-yl(tert-butoxycarbonyl)-L-phenylalaninate (97.8 mg).

[0200] MS:[M+H] + =368,[M-H2O+H] + =386.

[0201] 1 H NMR(500MHz,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),3.1 2(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).

[0202] Example 4: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0203]

[0204] Compound 4 was obtained in the same manner as in Steps 2 and 3 of Example 2 using Compound 2-1 (60 mg) and 1-(tert-butyl) 2-(2,5-dioxopyrrolidin-1-yl) (S)-pyrrolidine-1,2-dicarboxylate (40 mg).

[0205] MS:[M+H] + =354,[M-H2O+H] + =336.

[0206] 1 H NMR(500MHz,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).

[0207] Example 5: Preparation of (3aS, 4R, 6aR)-1-((2R, 3S)-2-amino-3-hydroxybutyryl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0208]

[0209] Compound 5 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-threonate (40 mg).

[0210] MS:[M+H] + =358,[M-H2O+H] + =340.

[0211] 1 H NMR(500MHz,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).

[0212] Example 6: Preparation of (3aS, 4R, 6aR)-1-((S)-2-amino-3-methylbutyryl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0213]

[0214] 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-valine ester (40 mg).

[0215] MS:[M+H] + =356,[M-H2O+H] + =338.

[0216] 1 H NMR(500MHz,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),2.2 4(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).

[0217] Example 7: Preparation of (3aS, 4R, 6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0218]

[0219] 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-leucine ester (56 mg).

[0220] MS:[M+H] + =370,[M-H2O+H] + =352.

[0221] 1H NMR(500MHz,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).

[0222] Example 8: Preparation of (3aS, 4R, 6aR)-1-((2S, 3S)-2-amino-3-methylpentanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0223]

[0224] Compound 8 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-isoleucinate (56 mg).

[0225] MS:[M+H] + =370,MS:[M-H2O+H] + =352.

[0226] 1 H NMR(500MHz,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).

[0227] Example 9: Preparation of (3aS, 4R, 6aR)-1-((R)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0228]

[0229] Using Compound 2-1 (167 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-D-alaninate (134 mg), Compound 9 (15 mg) was obtained in the same manner as in Steps 2 and 3 of Example 2.

[0230] MS:[M+H] + =328.

[0231] 1 H NMR(500MHz,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).

[0232] Example 10: Preparation of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid dihydrochloride

[0233]

[0234] 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

[0235]

[0236] Compound 1-7 (1.0 g) was dissolved in methanol (20.0 mL). 10% Pd / C (100.0 mg) was added thereto and stirred at room temperature for 4 hours using a hydrogen balloon to complete the reaction. The reaction solution was washed with methanol, filtered through diatomaceous earth and concentrated. It was dissolved in THF (20.0 ml), then 1N KOH (5.7 ml) was added, and benzyl chloroformate (0.43 ml) was slowly added dropwise, and then stirred at room temperature for 12 hours to complete the reaction. After the reaction solution was cooled to 0-5°C, ethyl acetate (10.0 ml) and H2O (5.0 ml) were added. After adjusting the pH to 2-3 with 6N HCl aqueous solution, the layers were separated and the organic layer was separated. Ethyl acetate (10 mL) was added to the aqueous layer twice, the layers were separated, and the organic layer was separated, dried with MgSO4, and then concentrated. The product was dried under reduced pressure to obtain compound 9-1 (1.21 g, yield: 70%). The obtained compound was used for the next reaction without purification.

[0237] MS:[M+H] + =573.

[0238] 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

[0239]

[0240] 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 stirred at 50°C for 4 hours. After the reaction solution was cooled to 0-10°C, saturated aqueous ammonium chloride solution (1.0 ml) and ethyl acetate (5.0 ml) were added and the organic layer was separated. 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%).

[0241] MS:[M+H] + =601.

[0242] Step 3) Preparation of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid dihydrochloride

[0243]

[0244] Compound 10 (12.0 mg) was obtained in the same manner as in Steps 8 to 10 of Example 1 using Compound 10-2.

[0245] MS:[M+H] + =285.

[0246] 1 H NMR(500MHz,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).

[0247] Example 11: Preparation of 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid dihydrochloride

[0248]

[0249] Using compound 9-1 (100.0 mg), compound 11 (17.7 mg) was obtained in the same manner as in steps 2 to 3 of example 9.

[0250] MS:[M+H] + =299.

[0251] 1 H NMR(500MHz,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).

[0252] Example 12: Preparation of 4-((3aS,4R,6aR)-4-(((isopropoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0253]

[0254] Compound 12 (40.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and chloromethyl isopropyl carbonate (35.0 μL).

[0255] MS:[M+H] + =373.

[0256] 1 H NMR(500MHz,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).

[0257] Example 13: Preparation of 4-((3aS,4R,6aR)-4-(((tert-butoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0258]

[0259] 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.

[0260] MS:[M+H] + =387.

[0261] 1 H NMR(500MHz,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).

[0262] Example 14: Preparation of 4-((3aS,4R,6aR)-4-((1-(ethoxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0263]

[0264] Compound 14 (15.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and 1-chloroethyl ethyl carbonate (34.7 μL).

[0265] MS:[M+H] + =373.

[0266] 1 H NMR(500MHz,MeOD)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).

[0267] Example 15: Preparation of 4-((3aS,4R,6aR)-4-((1-(cyclohexyloxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0268]

[0269] Compound 15 (12.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and 1-chloroethylcyclohexyl carbonate (48.0 μL).

[0270] MS:[M+H] + =427.

[0271] 1 H NMR(500MHz,MeOD)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).

[0272] Example 16: Preparation of 4-((3aS,4R,6aR)-4-((1-(isopropoxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0273]

[0274] Compound 16 (15.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (150.0 mg) and 1-chloroethylcyclopropyl carbonate (60.0 μL).

[0275] MS:[M+H] + =387.

[0276] 1 H NMR(500MHz,MeOD)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).

[0277] Example 17: Preparation of 4-((3aS,4R,6aR)-4-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0278]

[0279] Compound 17 (20.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and 1-chloroethyl pivalate (47.0 μL).

[0280] MS:[M+H] + =385.

[0281] 1H NMR(500MHz,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).

[0282] Example 18: Preparation of 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0283]

[0284] 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

[0285]

[0286] Compound 18-1 (197.0 mg, yield: 91%) was obtained in the same manner as in Example 9 using compound 9-1 (200.0 mg) and 2-bromoethane-1-ol (125.0 μL).

[0287] MS:[M+H] + =617.

[0288] 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

[0289]

[0290] Compound 18-1 (200.0 mg) was dissolved in tetrahydrofuran (3.0 ml), and triethylamine (136.0 μL) and pivaloyl chloride (90.8 μL) were added thereto. The mixture was reacted at room temperature for 12 hours, and then concentrated and subjected to column separation using ethyl acetate: hexane = 1: 1 to obtain compound 18-2 (60.0 mg).

[0291] MS:[M+H] + =701.

[0292] Step 3) Preparation of 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0293]

[0294] Using compound 18-2 (60.0 mg), compound 18 (14.0 mg) was obtained in the same manner as in steps 8 to 10 of Example 1.

[0295] MS:[M+H] + =385.

[0296] 1 H NMR(500MHz,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).

[0297] Example 19: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexane acyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0298]

[0299] Step 1) Preparation of 4,5-dibenzyl 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

[0300]

[0301] Compound 2-1 (431.1 mg) was dissolved in dichloromethane (5.0 ml). The solution was cooled to 0-10°C, and triethylamine (300.0 μL) was added. 1-Chloroethyl chloroformate (118.0 μL) was slowly added dropwise, and then stirred at room temperature for 12 hours to complete the reaction. After the reaction solution was cooled to 0-10°C, a saturated aqueous ammonium chloride solution was added, and the organic layer was separated. The organic layer was dried over MgSO4, concentrated, and dried under reduced pressure to obtain compound 19-1 (455.0 mg).

[0302] MS:[M+H] + =670.

[0303] Step 2: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexane acyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0304]

[0305] Compound 19-1 (235.4 mg) was dissolved in dichloromethane (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 the reaction solution was cooled to 0-10° C., ethyl acetate (5.0 ml) and saturated aqueous ammonium chloride solution (5.0 ml) were added, the layers were separated, and the organic layer was concentrated. The product was separated by column with ethyl acetate: hexane = 3: 7, and compound 19 (20.0 mg) was obtained in the same manner as steps 8 to 10 of Example 1.

[0306] MS:[M+H] + =455.

[0307] 1 H NMR(500MHz,MeOD)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).

[0308] Example 20: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0309]

[0310] Compound 20 (7.0 mg) was obtained in the same manner as in Example 19 using compound 19-1 (100.0 mg) and valeric acid (35.0 μL).

[0311] MS:[M+H] + =429.

[0312] 1H NMR(500MHz,MeOD)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).

[0313] Example 21: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride

[0314]

[0315] 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).

[0316] MS:[M+H] + =429.

[0317] 1 H NMR(500MHz,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(1 H,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).

[0318] Example 22: Preparation of (3aS,4R,6aR)-4-(4-dihydroxyborylbutyl)-1-((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0319]

[0320] 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).

[0321] MS:[M+H] + =472.

[0322] 1 H NMR(500MHz,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).

[0323] Example 23: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexane acyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0324]

[0325] 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

[0326]

[0327] Compound 2-1 (300 mg) was dissolved in dichloromethane (3.0 ml). The solution was cooled to 0-10°C, and triethylamine (200.0 μL) was added. 1-Chloro-2-methylpropyl chloroformate (125.0 μL) was slowly added dropwise, and then stirred at room temperature for 12 hours to complete the reaction. After the reaction solution was cooled to 0-10°C, a saturated aqueous ammonium chloride solution was added, and the organic layer was separated. The organic layer was dried over MgSO4, concentrated, and dried under reduced pressure to obtain compound 23-1 (350.0 mg).

[0328] MS:[M+H] + =698.

[0329] Step 2: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexane acyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0330]

[0331] 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 thereto. The mixture was stirred at 70°C for 2 hours to complete the reaction. After the reaction solution was cooled to 0-10°C, ethyl acetate (5.0 ml) and saturated aqueous ammonium chloride solution (3.0 ml) were added, the layers were separated, and the organic layer was concentrated. The product was separated by column with ethyl acetate: hexane = 3: 7, and compound 23 (20.0 mg) was obtained in the same manner as steps 8 to 10 of Example 1.

[0332] MS:[M+H] + =483.

[0333] 1 H NMR(500MHz,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).

[0334] Example 24: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyborylbutyl)-1-((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0335]

[0336] Compound 24 (5.6 mg) was obtained in the same manner as in Example 23 using compound 23-1 (115 mg) and pivalic acid (25.6 mg).

[0337] MS:[M+H] + =457.

[0338] 1 H NMR(500MHz,MeOD)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).

[0339] Example 25: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyborylbutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0340]

[0341] Using compound 2-1 (50 mg) and ethyl chloroformate (12 μL), compound 25 (14 mg) was obtained in the same manner as in step 1 of example 19 and steps 8 to 10 of example 1.

[0342] MS:[M+H] + =329.

[0343] 1 H NMR(500MHz,MeOD)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).

[0344] Example 26: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyborylbutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0345]

[0346] Using compound 2-1 (50 mg) and isobutyl chloroformate (15 μL), compound 26 (6.7 mg) was obtained in the same manner as in step 1 of example 19 and steps 8 to 10 of example 1.

[0347] MS:[M+H] + =357.

[0348] 1 H NMR(500MHz,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).

[0349] Example 27: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-methyloctahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0350]

[0351] After compound 2-1 (100 mg) was dissolved in dichloromethane (2 mL), formaldehyde (12.3 μL) and acetic acid (40.0 μL) were added, followed by stirring at 40° C. for 3 hours. Sodium acetoxyborohydride (96 mg) was added thereto, followed by stirring at 40° C. for 3 hours to complete the reaction. After the reaction solution was cooled to 0 to 10° C., H 2 O was added to separate the organic layer. The product was concentrated and separated with ethyl acetate: hexane = 9: 1, and then compound 27 (4.0 mg) was obtained in the same manner as steps 8 to 10 of Example 1.

[0352] MS:[M+H] + =271.

[0353] 1 H NMR(500MHz,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).

[0354] Example 28: Preparation of (3aS, 4R, 6aR)-4-(4-dihydroxyboronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride

[0355]

[0356] After compound 2-1 (200 mg) was dissolved 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. Sodium acetoxyborohydride (200 mg) was added thereto, followed by stirring at 40° C. for 3 hours to complete the reaction. After the reaction solution was cooled to 0 to 10° C., H 2 O was added, and the organic layer was separated. The product was concentrated and separated with ethyl acetate: hexane = 5: 1, and compound 28 (20.0 mg) was obtained in the same manner as steps 8 to 10 of Example 1.

[0357] MS:[M+H] + =314.

[0358] 1H NMR(500MHz,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).

[0359] Experimental Example 1: Arginase Inhibitory Activity Test

[0360] Compounds according to the present disclosure were tested for arginase inhibitory activity. In addition to the compounds according to the present disclosure, compound CB-1158 (Numidargistat) was also tested for comparison.

[0361] Specifically, all reagents required for the evaluation were diluted in reaction buffer (8mM NaHPO4, 2mM KH2PO4, pH7.5, 137mM NaCl, 2.7mM KCl and 0.05% Tween-20), and the compound was dissolved in DMSO, then diluted, and then diluted in reaction buffer to meet the required concentration. 10μL of compound and 10μL of 30nM arginase-1 were mixed in a transparent 96-well plate (SPL) and incubated at room temperature for more than 1 hour. After that, 10μL of 15mM L-arginine and 3mM MnCl2 were added to the plate, and then reacted at room temperature for 30 minutes or more. Finally, 30 μL of a 1:1 mixture of reagent A (10 mM o-phthalaldehyde, 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 complete the enzyme reaction and incubated at room temperature for 1 hour or more. The absorbance of the incubated plate at 450 nm was measured using a Flexstation3 multi-mode microplate reader (Molecular Devices).

[0362] The background control (BC) readings were subtracted from all readings to obtain the ΔOD for each reading. The ΔOD of the enzyme control (EC) was set to the maximum value, and the relative arginase-1 activity (%) of each compound was calculated using the following formula, and the IC of the compound was determined using PRISM (GraphPad software): 50 value.

[0363] Relative arginase-1 activity (%) = (ΔOD of S / ΔOD of EC) * 100

[0364] Table 1 below lists the efficacy of the compounds on a scale from A to C. The efficacy value A refers to the IC50 Compounds of the present disclosure having a value of less than 100 nM, compounds having a potency value B exhibit an IC in the range of 100 nM to 1000 nM 50 Value, IC 50 Compounds with values ​​greater than 1000 nM were assigned a potency value of C.

[0365] [Table 1]

[0366] Compound <![CDATA[IC 50 ]]> CB-1158 (Numidargistat) A Example 1 A Example 2 B Example 3 B Example 4 B Example 5 B Example 6 C Example 7 C Example 9 C Embodiment 27 A Embodiment 28 B

[0367] Experimental Example 2: PBMC activity evaluation test

[0368] The compounds according to the present disclosure were tested for primary peripheral blood mononuclear cell (PBMC) activity. It was confirmed that the synthetic arginase 1 inhibited T cell differentiation induced by α-CD3 and α-CD28 antibodies, and then the compounds inhibited arginase 1 and induced T cell differentiation and proliferation. The proliferation of T cells was assessed by luminescent cell viability (Promega, catalog # G7571), which can confirm the proliferation of cells by quantifying the ATP present in the cells. In addition to the compounds according to the present disclosure, compound CB-1158 (Numidargistat) was also tested for comparison.

[0369] Specifically, α-CD3 antibody was coated on a transparent 96-well microplate. 1×10 5 PBMC cells. RPMI medium (10% FBS, 1% penicillin / streptomycin) was used as the cell culture medium. α-CD28 antibody and synthetic arginase 1 were added to each well. The compounds prepared in the examples were treated at different concentrations (2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125 μM). After incubation for 72 hours, 50 μL of cells from each well were transferred to a white 96-well microplate and incubated with 50 μL The solution was mixed.

[0370] After the reaction was carried out at room temperature in a light-shielded state for 10 minutes, luminescence was measured. The measurement results for each compound were calculated using Excel, and the EC was calculated using GraphPad Prism software. 50 value.

[0371] Table 2 below lists the efficacy of the compounds as grades A and B. Efficacy value A refers to the EC 50 The compounds of the present disclosure have a value less than 100 nM, while the EC 50 Compounds with values ​​in the range of 100 nM to 500 nM were assigned a potency value of B.

[0372] [Table 2]

[0373] In vitro activity CB-1158 Example 1 <![CDATA[EC 50 ]]> B A

Claims

1. A compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In Chemical Formula 1, R1 and R2 are each independently hydrogen; unsubstituted or substituted with amino, (C 1-4 alkyl)amino or di(C 1-4 Alkyl)amino substituted C 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 , R3 is hydroxyl, or -L3-R'3, L3 is -NH-, -O- or -O-(CH)2) n3 -O-CO-, R'3 is -CH(COOH)-R A 、-CH(NH2)-R A , R B , or R C , Each R A are independently hydrogen; or unsubstituted or substituted by hydroxy, thiol, seleno, guanidinyl, amino, carboxyl, carbamoyl, C 1-6 Alkylthio, phenyl, hydroxyphenyl or C containing one or two N 4-10 Heteroaryl-substituted C 1-6 alkyl, Each R B are independently C 4-10 Heterocycloalkyl, Each R C are independently unsubstituted or substituted with C 6-10 Aryl or N-containing C 4-10 Heterocycloalkyl substituted C 1-6 Alkyl group; unsubstituted or substituted with C 1-6 Alkoxy substituted C 6-10 Aryl; or C 3-6 Cycloalkyl, and n3 is an integer from 1 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently hydrogen, methyl, methylaminoethyl, or a substituent represented by any of the following: in, R A , R B and R C As defined in claim 1, and n1 is an integer from 1 to 3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is hydroxyl, or a substituent represented by any of the following: in, R A , R B , R C and n3 as defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R A are independently hydrogen; or C unsubstituted or substituted by hydroxy, thiol, seleno, guanidinyl, amino, carboxyl, carbamoyl, methylthio, phenyl, hydroxyphenyl, indolyl or imidazolyl 1-6 alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R A are independently the residues of natural amino acids, The natural amino acid residue refers to a structure excluding the terminal -CH(NH)2(COOH).

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R B It is pyrrolidyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R C is independently unsubstituted or substituted by phenyl or piperidinyl. 1-6 Alkyl; unsubstituted or methoxy-substituted C 6-10 Aryl; or C 3-6 Cycloalkyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, and R2 is hydrogen, or R1 is hydrogen, and R3 is hydroxy, or R2 is hydrogen, and R3 is hydroxy.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Chemical formula 1 is represented by any one of the following Chemical formulas 2 to 5: [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] [Chemical formula 5] Among them, in Chemical Formula 2 to Chemical Formula 5, R A As defined in claim 1.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by Chemical Formula 1 is any one selected from the group consisting of: 1)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, 2)(3aS,4R,6aR)-1-((S)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 3)(3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 4)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 5)(3aS,4R,6aR)-1-((2R,3S)-2-amino-3-hydroxybutyryl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 6)(3aS,4R,6aR)-1-((S)-2-amino-3-methylbutanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 7)(3aS,4R,6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 8) (3aS, 4R, 6aR)-1-((2S, 3S)-2-amino-3-methylpentanoyl)-4-(4-dihydroxyboronobutyl) octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 9)(3aS,4R,6aR)-1-((R)-2-aminopropionyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 10) 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid, 11) 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid, 12) 4-((3aS,4R,6aR)-4-(((isopropoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 13) 4-((3aS,4R,6aR)-4-(((tert-butoxyacyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 14) 4-((3aS,4R,6aR)-4-((1-(ethoxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 15) 4-((3aS,4R,6aR)-4-((1-(cyclohexyloxyacyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 16) 4-((3aS,4R,6aR)-4-((1-(isopropoxyacyloxy)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-dihydroxyboronobutyl)-1-((1-(cyclohexyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 20)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 21)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, 22)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 23)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((1-(cyclohexyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 24)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 25)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 26)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 27)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-methyl-octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 28)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, 29)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-(butyryloxymethyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 30)(3aS,4R,6aR)-1-((acetoxymethoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 31)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)propanoic acid, 32)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylbutanoic acid, 33)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxamide)-4-methylpentanoic acid, 34)(2S,3R)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-methylpentanoic acid, 35)(S)-2-((3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamide)-3-phenylpropionic acid, 36) 4-((3aS,4R,6aR)-4-((2-((S)-2-aminopropionyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid, 37) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid, 38) 4-((3aS,4R,6aR)-4-((2-((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid, 39) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic acid, 40) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-phenylpropionyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)butylboronic 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)butylboronic 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-phenylpropionyloxy) methoxy) carbonyl-4-(4-dihydroxyboronobutyl) octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 49) (3aS, 4R, 6aR)-1-(((S)-2-aminopropionyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 50)(3aS,4R,6aR)-4-(4-dihydroxyboronobutyl)-1-((((S)-pyrrolidine-2-carbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 51)(3aS,4R,6aR)-1-((((2S,3R)-2-amino-3-hydroxybutyryloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 52)(3aS,4R,6aR)-1-((((S)-2-amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid, 53)(3aS,4R,6aR)-1-((((S)-2-amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, and 54)(3aS,4R,6aR)-1-((((2S,3S)-2-amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-dihydroxyboronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

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 as an active ingredient.

12. A compound, the compound being any one selected from the group consisting of: in, PG1 and PG2 are each independently the same or different and represent a protecting group.

13. Among them, The compound is any one selected from the group consisting of the following compounds: (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-dihydroxyboronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

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