Arginase inhibitors and pharmaceutical components containing them.

Abstract

The present invention relates to a compound represented by chemical formula 1 of the present specification, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same can be effectively used in the prevention or treatment of cancer or tumors.

Description

Arginase inhibitor and pharmaceutical composition containing same

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

[0002] With the development of immunotherapy, a growing field in the field of cancer treatment, it is well known that elevated levels of arginase in cancer patients lead to arginine depletion in the tumor microenvironment. Indeed, this mechanism is known to allow tumor cells of various types, including acute myeloid leukemia, breast cancer, prostate cancer, glioblastoma, esophageal cancer, and renal cell carcinoma, to evade destruction by the body's immune system. Therefore, the need for the development of arginase inhibitors that inhibit arginase to restore arginine levels in the tumor microenvironment and promote the tumor-killing activity of cytotoxic T cells has emerged.

[0003]

[0004] Regarding arginase inhibitors, pyrrolidine-based arginase inhibitors have been developed and known to date, but there is a need for the development of arginase inhibitors with new chemical structures.

[0005]

[0006] Accordingly, the inventors of the present invention studied a novel compound having a chemical structure different from that of arginase inhibitors reported to date, and confirmed that a compound having octahydropyrrolo[3,4-b]pyrrole with a bicyclic structure as a nucleus has excellent arginase inhibitory activity, thereby completing the present invention.

[0007] The present invention provides a compound having a novel structure that can be usefully used in the treatment or prevention of cancer or tumors.

[0008] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1,

[0012] R1, 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,

[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 And,

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

[0016] L3 is -NH-, -O-, or -O-(CH2) n3 -O-CO- and,

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

[0018] R A are each independently hydrogen; or unsubstituted or substituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, C 1-6 C containing one or two alkylthio, phenyl, hydroxyphenyl, or N 4-10 C substituted with heteroaryl 1-6 It is alkyl,

[0019] R B are each independently C containing N 4-10 It is heterocycloalkyl,

[0020] R C are each independently unsubstituted, or C 6-10 C containing aryl or N 4-10 C substituted with heterocycloalkyl 1-6 Alkyl; unsubstituted or C 1-6 C substituted with alkoxy 6-10 Aryl; or C 3-6 It is cycloalkyl,

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

[0022]

[0023] Preferably, R1 and R2 are each independently hydrogen, methyl, methylaminoethyl, or a substituent represented by any one of the following:

[0024]

[0025] In the above, R A , R B , and R C is as defined above, and n1 is an integer from 1 to 3.

[0026]

[0027] Preferably, R3 is a substituent represented by hydroxy or any of the following:

[0028]

[0029] In the above, R A , R B , R C and n3 are as defined above.

[0030]

[0031] Preferably, R A are each independently hydrogen; or C unsubstituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, methylthio, phenyl, hydroxyphenyl, indole, or imidazole. 1-6 is alkyl. More preferably, R Aare each independently hydrogen, methyl, ethyl, 1-hydroxy-1-ethyl, propyl, isopropyl, normalbutyl, isobutyl, tertbutyl, or benzyl.

[0032]

[0033] Preferably, R A are each 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, if 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.

[0034]

[0035] Preferably, R B is pyrrolidinyl.

[0036]

[0037] Preferably, R C are each independently unsubstituted or substituted with phenyl or pipenidinyl. 1-6 Alkyl; or C unsubstituted or substituted with methoxy 6-10 Aryl. More preferably, R C are each independently methyl, pyrrolidinylmethyl, ethyl, propyl, isopropyl, normalbutyl, isobutyl, tertbutyl, phenyl, methoxyphenyl, benzyl, or cyclohexyl.

[0038]

[0039] Preferably, R1 is hydrogen and R2 is hydrogen, or

[0040] R1 is hydrogen, R3 is hydroxy, or

[0041] R2 is hydrogen and R3 is hydroxy.

[0042]

[0043] Preferably, the above chemical formula 1 is represented by any one of the following chemical formulas 2 to 5:

[0044] [Chemical Formula 2]

[0045]

[0046] [Chemical Formula 3]

[0047]

[0048] [Chemical Formula 4]

[0049]

[0050] [Chemical Formula 5]

[0051]

[0052] In the above chemical formulas 2 to 5,

[0053] R A is as defined above.

[0054]

[0055] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0056] 1) (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0057] 2) (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0058] 3) (3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0059] 4) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0060] 5) (3aS,4R,6aR)-1-((2R,3S)-2-amino-3-hydroxybutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0061] 6) (3aS,4R,6aR)-1-((S)-2-amino-3-methylbutanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0062] 7) (3aS,4R,6aR)-1-((S)-2-amino-4-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0063] 8) (3aS,4R,6aR)-1-((2S,3S)-2-amino-3-methylpentanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0064] 9) (3aS,4R,6aR)-1-((R)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0065] 10) 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0066] 11) 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0067] 12) 4-((3aS,4R,6aR)-4-(((isopropoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0068] 13) 4-((3aS,4R,6aR)-4-(((tert-butoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0069] 14) 4-((3aS,4R,6aR)-4-((1-(ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0070] 15) 4-((3aS,4R,6aR)-4-((1-(cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0071] 16) 4-((3aS,4R,6aR)-4-((1-(isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0072] 17) 4-((3aS,4R,6aR)-4-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0073] 18) 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0074] 19) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexanecarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0075] 20) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0076] 21) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0077] 22) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((S)-2-(dimethylamino)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0078] 23) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexanecarbonyloxy)-2-methylpropoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0079] 24) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((2-methyl-1-(pivaloyloxy)propoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0080] 25) (3aS,4R,6aR)-4-(4-boronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0081] 26) (3aS,4R,6aR)-4-(4-boronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0082] 27) (3aS,4R,6aR)-4-(4-boronobutyl)-1-methyloctahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0083] 28) (3aS,4R,6aR)-4-(4-boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid,

[0084] 29) (3aS,4R,6aR)-4-(4-boronobutyl)-1-(butyryloxymethyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0085] 30) (3aS,4R,6aR)-1-((acetoxymethoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0086] 31) (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)propanoic acid,

[0087] 32) (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-methylbutanoic acid,

[0088] 33) (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxamido)-4-methylpentanoic acid,

[0089] 34) (2S,3R)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-methylpentanoic acid,

[0090] 35) (S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxamido)-3-phenylpropanoic acid,

[0091] 36) 4-((3aS,4R,6aR)-4-((2-((S)-2-aminopropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0092] 37) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0093] 38) 4-((3aS,4R,6aR)-4-((2-((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0094] 39) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0095] 40) 4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-phenylpropanoyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0096] 41) 4-((3aS,4R,6aR)-4-((2-((S)-pyrrolidine-2-carbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0097] 42) 4-((3aS,4R,6aR)-4-((propionyloxymethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid,

[0098] 43) 4-((3aS,4R,6aR)-4-((isobutyryloxymethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0099] 44) 4-((3aS,4R,6aR)-4-(benzyloxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0100] 45) 4-((3aS,4R,6aR)-4-((piperidin-4-ylmethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0101] 46) 4-((3aS,4R,6aR)-4-(phenoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0102] 47) 4-((3aS,4R,6aR)-4-((2-methoxyphenoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid,

[0103] 48) (3aS,4R,6aR)-1-((((S)-2-amino-3-phenylpropanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0104] 49) (3aS,4R,6aR)-1-((((S)-2-aminopropanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0105] 50) (3aS,4R,6aR)-4-(4-boronobutyl)-1-((((S)-pyrrolidine-2-carbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0106] 51) (3aS,4R,6aR)-1-((((2S,3R)-2-amino-3-hydroxybutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0107] 52) (3aS,4R,6aR)-1-((((S)-2-amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0108] 53) (3aS,4R,6aR)-1-((((S)-2-amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid, or

[0109] 54) (3aS,4R,6aR)-1-((((2S,3S)-2-amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0110]

[0111] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, any salt commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids, may be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and wherein the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula 1.

[0112]

[0113] Other pharmaceutically unacceptable salts or solvates of the compound represented by chemical formula 1 can be used as intermediates in the production of the compound represented by chemical formula 1, a pharmaceutically acceptable salt, or solvate thereof.

[0114]

[0115] In addition, the compound represented by the above chemical formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts but also solvates such as possible hydrates that can be prepared therefrom and all possible stereoisomers. The solvates and stereoisomers of the compound represented by the above chemical formula 1 can be prepared from the compound represented by the chemical formula 1 using methods known in the art.

[0116]

[0117] In addition, the compound represented by the above chemical formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by the above chemical formula 1, but also compounds containing various amounts of water. The solvates of the compound represented by the above chemical formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0118]

[0119] In addition, as an example, the compound represented by the chemical formula 1 according to the present invention can be prepared as in the following reaction scheme 1:

[0120] [Reaction Formula 1]

[0121]

[0122]

[0123] The above reaction scheme 1 is an example of a case where R1 is -L1-R'1, R2 is hydrogen, and R3 is hydroxy, and can be applied to the production of compounds represented by the remaining chemical formula 1. The first reaction of the above reaction scheme 1 is a -L1-R'1 substitution reaction, the second reaction is a protecting group removal reaction, and the above production method can be further specified in the production examples described below.

[0124]

[0125] 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 an intermediate in the production of the compound represented by the chemical formula 1 according to the present invention.

[0126]

[0127] In the above,

[0128] PG1 and PG2 are each independently the same or different and represent a protecting group.

[0129]

[0130] The above protecting group is not particularly limited as long as it is widely used in the technical field to which the present invention belongs, and 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, etc. 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, tetrahydrolan, trityl, trimethylsilyl, tert-butyldimethylsilyl, etc.

[0131]

[0132] Preferably, the compound is one selected from the group consisting of:

[0133] (3aR,4R,6aR)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0134] (3aS,4R,6aR)-5-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid,

[0135] 4,5-Dibenzyl 1-(tert-butyl) (3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate,

[0136] 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,

[0137] 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,

[0138] (4-((3aS,4R,6aR)-4,5-bis((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butyl)boronic acid, and

[0139] (3aS,4R,6aR)-5-(Benzyloxycarbonyl)-4-(4-boronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid.

[0140]

[0141] In addition, the compound represented by the above chemical formula 1, or a pharmaceutically acceptable salt thereof, has an arginase inhibitory effect, and can restore arginine levels in the tumor microenvironment by inhibiting arginase and promote the tumor-killing activity of cytotoxic T cells. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer or tumors, comprising the compound represented by the above chemical formula 1, or a pharmaceutically acceptable salt thereof.

[0142]

[0143] The term "prevention" of the present invention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0144]

[0145] The pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practice. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0146]

[0147] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0148]

[0149] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be administered orally or parenterally once daily or in divided doses.

[0150]

[0151] Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99 wt%, preferably 0.01 to 60 wt%, of the compound of the present invention.

[0152]

[0153] The pharmaceutical composition according to the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebral injection.

[0154] 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.

[0155] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0156]

[0157] Example 1: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0158]

[0159] Step 1) Preparation of dibenzyl (R)-4-oxopyrrolidine-1,2-dicarboxylate

[0160]

[0161] 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 completed by stirring at -78°C for 1 hour. The reaction solution was poured into a 1 N-HCl solution at 0-5°C, and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride (1 L), and the organic layer was separated. The organic layer was dried over MgSO4 and concentrated. Compound 1-1 (117 g, yield 63%) was obtained by column separation using ethyl acetate (in Hexane 30%).

[0162] MS: [M+H] + = 354

[0163] 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)

[0164]

[0165] Step 2) Preparation of 4,5-dibenzyl 1-(tert-butyl) (R)-4,6-dihydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0166]

[0167] Compound 1-1 (67 g) was dissolved in tetrahydrofuran (300 ml) and cooled to -78°C under nitrogen. 2.5 N n-BuLi (84 ml) was slowly added dropwise at -78°C under nitrogen. The mixture was stirred at -50 to -55°C for 1 hour and then cooled to -78°C. tert-Butyl (2-oxoethyl)carbamate (34 g) was dissolved in tetrahydrofuran (100 ml) and slowly added dropwise at -78°C under nitrogen. The mixture was stirred at -50 to -55°C for 1 hour to complete the reaction. The reaction solution was poured into a saturated NH4Cl solution at 0-5°C, and the layers were separated using ethyl acetate (1.4 L) and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (670 ml) and the organic layer was separated. The organic layer was dried over MgSO4 and 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 0-5°C, 3% NaHCO3 aqueous solution (500 ml) was added, the organic layer was separated, dried over MgSO4, and concentrated. Compound 1-2 (24 g, yield 30%) was obtained by column separation using ethyl acetate (in hexane 30%).

[0168] MS: [M+H] + = 477

[0169] 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)

[0170]

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

[0172]

[0173] Compound 1-2 (24 g) was dissolved in tetrahydrofuran (500 ml) and methanol (500 ml). Pd(OH)2 (12 g) was added, and the mixture was stirred under a hydrogen balloon for 4 hours to complete the reaction. The reaction solution was washed with methanol, filtered through Celite, concentrated, and dried under reduced pressure to obtain compound 1-3 (12.8 g, yield 100%).

[0174] MS: [M+H] + = 257

[0175] 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)

[0176]

[0177] Step 4) Preparation of (3aS,4R,6aR)-5-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid

[0178]

[0179] Compound 1-3 (12.8 g) was dissolved in 1 N KOH aqueous solution (100 ml), and benzyl carbonochloridate (8.5 ml) was slowly added dropwise. The mixture was stirred at room temperature for 12 hours to complete the reaction. After cooling the reaction solution to 0 to 5°C, ethyl acetate (150 ml) and H2O (100 ml) were added. The pH was adjusted to 2 to 3 using 6 N HCl aqueous solution, and the organic layer was separated by layer separation. Ethyl acetate (100 ml) was added twice to the aqueous layer, and the organic layer was separated by layer separation, dried over MgSO4, and concentrated. Compound 1-4 (20 g, yield 100%) was obtained by drying under reduced pressure. The obtained compound was used for the next reaction without purification.

[0180] MS: [M+H] + = 391

[0181] 1 H NMR (500 MHz, 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)

[0182]

[0183] Step 5) Synthesis of 4,5-dibenzyl 1-(tert-butyl) (3aS,4R,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0184]

[0185] 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 HCl aqueous solution (200 ml) were added, and the layers were separated. The organic layer was concentrated and separated by column chromatography with ethyl acetate (30% in hexane) solution to obtain compound 1-5 (20 g, yield 83%).

[0186] MS: [M+H] + = 481

[0187] 1H NMR (500 MHz, 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)

[0188]

[0189] 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

[0190]

[0191] Compound 1-5 (20 g) was dissolved in tetrahydrofuran (200 ml) and cooled to -78°C under nitrogen. Crotyl bromide (8.1 ml) was added dropwise, and 1 N potassium bis(trimethylsilyl)amide (80 ml) was slowly added dropwise. The reaction was completed by stirring at -78°C for 30 minutes. The reaction solution was added dropwise to a 0-5°C 1 N 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. Compound 1-6 (10.4 g, yield 65%) was obtained by column separation with ethyl acetate (30% in hexane).

[0192] MS: [M+H] + = 335

[0193] 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)

[0194]

[0195] 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

[0196]

[0197] Chloro(1,5-cyclooctadiene)iridium(I) dimer (1.7 g) and 1,2-bis(diphenylphosphino)ethane (2.1 g) were added to methylene chloride (100 ml) under nitrogen. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (9.66 ml) was added, and 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 for 20 hours at room temperature under nitrogen. H2O (50 ml) was added to the reaction mixture, extracted, and the organic layer was separated. The organic layer was concentrated, purified by column chromatography with ethyl acetate (in hexane 30%), and compound 1-7 (8.5 g, yield 49%) was obtained.

[0198] MS: [M+H] + = 663

[0199] 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)

[0200]

[0201] 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

[0202]

[0203] Compound 1-7 (8.5 g) was dissolved in acetone (128 ml), and methylboronic acid (7.66 g) was added. 0.1 N NaOH aqueous solution (128 ml) was added, and the mixture was stirred at room temperature for 12 hours. 100 ml of saturated NH4Cl solution was added, and the mixture was extracted with 170 ml of ethyl acetate. The aqueous solution was extracted twice with 100 ml of ethyl acetate. 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%).

[0204] MS: [M+H] + = 581

[0205] 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)

[0206]

[0207] Step 9) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(tert-butoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid

[0208]

[0209] Compound 1-8 (5.5 g) was dissolved in methanol (50 ml). 10% Pd / C (2 g) was added, and the mixture was stirred at room temperature for 4 hours using a hydrogen balloon to complete the reaction. The product was used directly in step 10 below.

[0210] MS: [M+H] + = 357

[0211]

[0212] Step 10) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0213]

[0214] The product of Step 9 was washed with methanol, filtered through Celite, and concentrated. 6 N HCl aqueous solution was added, stirred at room temperature for 2 hours, and then concentrated. After dissolving in H2O (5 ml), the mixture was extracted three times with diethyl ether (5 ml), and the organic layer was removed. The aqueous solution was concentrated and dried under reduced pressure to obtain Compound 1 (2.5 g, yield 80% (Steps 9 and 10)).

[0215] MS: [M+H] + = 257

[0216] 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)

[0217]

[0218] Example 2: Preparation of (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0219]

[0220] 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

[0221]

[0222] Compound 1-7 (800 mg) was dissolved in 1,4-dioxane (10 ml), and 4 N HCl (in dioxane; 12 ml) was added. The reaction was completed by stirring at 50°C for 1 hour. The mixture was concentrated and dried under reduced pressure to obtain compound 2-1 (723 mg, yield 100%).

[0223] MS: [M+H] + = 563

[0224] 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)

[0225]

[0226] 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

[0227]

[0228] Compound 2-1 (54 mg) was dissolved in methylene chloride (1 ml). Trimethylamine (36 uL) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-alaninate (37 mg) were added, and the mixture was stirred at room temperature for 12 hours to complete the reaction. After adding a saturated aqueous solution of NH4Cl, extraction was performed, and the organic layer was separated. The organic layer was concentrated, and then subjected to column chromatography with ethyl acetate (40-50% in hexane) to obtain compound 2-2 (47 mg, yield 74%).

[0229] MS: [M+H] + = 734

[0230] 1 H 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)

[0231]

[0232] Step 3) Preparation of (3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0233]

[0234] Using compound 2-2, compound 2 was obtained in the same manner as steps 8 to 10 of Example 1.

[0235] MS: [M+H] + = 328, [M-H2O+H] + = 310

[0236] 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)

[0237]

[0238] 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

[0239]

[0240] Compound 3 was obtained using the same method as 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).

[0241] MS: [M+H] + = 368 [M-H2O+H] + = 386

[0242] 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)

[0243]

[0244] Example 4: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((S)-pyrrolidine-2-carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0245]

[0246] Compound 4 was obtained using the same method as 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).

[0247] MS: [M+H] + = 354 [M-H2O+H] + = 336

[0248] 1 H 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)

[0249]

[0250] 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

[0251]

[0252] Compound 5 was obtained using compound 2-1 (60 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-threoninate (40 mg) in the same manner as steps 2 and 3 of Example 2.

[0253] MS: [M+H] + = 358 [M-H2O+H] + = 340

[0254] 1 H 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)

[0255]

[0256] 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

[0257]

[0258] Compound 6 was obtained using compound 2-1 (60 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate (40 mg) in the same manner as steps 2 and 3 of Example 2.

[0259] MS: [M+H] + = 356 [M-H2O+H] + = 338

[0260] 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)

[0261]

[0262] 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

[0263]

[0264] Compound 7 was obtained using the same method as steps 2 and 3 of Example 2, using compound 2-1 (83 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-leucine (56 mg).

[0265] MS: [M+H] + = 370,[M-H2O+H] + = 352

[0266] 1 H 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)

[0267]

[0268] 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

[0269]

[0270] Compound 8 was obtained using the same method as 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).

[0271] MS: [M+H]+ = 370, MS: [M-H2O+H] + = 352

[0272] 1 H 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)

[0273]

[0274] Example 9: Preparation of (3aS,4R,6aR)-1-((R)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid dihydrochloride

[0275]

[0276]

[0277] Compound 9 (15 mg) was obtained using compound 2-1 (167 mg) and 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-D-alaninate (134 mg) in the same manner as steps 2 and 3 of Example 2.

[0278] MS: [M+H] + = 328

[0279] 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)

[0280]

[0281] Example 10: Preparation of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid dihydrochloride

[0282]

[0283] 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

[0284]

[0285] 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, and 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 6 N HCl aqueous solution, the organic layer was separated by layer separation. Ethyl acetate (10 ml) was added twice to the aqueous layer, the layers were separated, the organic layer was separated, dried over MgSO4, and concentrated. Compound 9-1 (1.21 g, yield 70%) was obtained by drying under reduced pressure. The obtained compound was subjected to the following reaction without purification.

[0286] MS: [M+H] + = 573

[0287]

[0288] 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-tricarboate

[0289]

[0290] 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 uL) were added, and the mixture was stirred at 50°C for 4 hours. After cooling 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 chromatography using ethyl acetate:hexane = 1:2 was performed to obtain compound 9-2 (80.0 mg, yield 76%).

[0291] MS: [M+H] + = 601

[0292]

[0293] Step 3) Preparation of 4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid dihydrochloride

[0294]

[0295] Compound 10 (12.0 mg) was obtained using the same method as steps 8 to 10 of Example 1 using compound 10-2.

[0296] MS: [M+H] + = 285

[0297] 1H 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)

[0298]

[0299] Example 11: Preparation of 4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrrolo[2,3-c]pyrrol-4-yl)carboxylic acid dihydrochloride

[0300]

[0301] Compound 11 (17.7 mg) was obtained using the same method as steps 2 and 3 of Example 9 using compound 9-1 (100.0 mg).

[0302] MS: [M+H] + = 299

[0303] 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)

[0304]

[0305] Example 12: Preparation of 4-((3aS,4R,6aR)-4-(((isopropoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0306]

[0307] 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 uL).

[0308] MS: [M+H] + = 373

[0309] 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)

[0310]

[0311] Example 13: Preparation of 4-((3aS,4R,6aR)-4-(((tert-butoxycarbonyloxy)methoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0312]

[0313] Compound 13 (10.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and tert-butyl(chloromethyl)carbonate (37.8 uL).

[0314] MS: [M+H] + = 387

[0315] 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)

[0316]

[0317] Example 14: Preparation of 4-((3aS,4R,6aR)-4-((1-(ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0318]

[0319] Compound 14 (15.0 mg) was obtained using the same method as Example 9 using compound 9-1 (100.0 mg) and 1-chloroethyl ethyl carbonate (34.7 uL).

[0320] MS: [M+H] + = 373

[0321] 1 H NMR (500 MHz, 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)

[0322]

[0323] Example 15: Preparation of 4-((3aS,4R,6aR)-4-((1-(cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0324]

[0325] Compound 15 (12.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (100.0 mg) and 1-chloroethyl cyclohexyl carbonate (48.0 uL).

[0326] MS: [M+H] + = 427

[0327] 1H NMR (500 MHz, 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)

[0328]

[0329] Example 16: Preparation of 4-((3aS,4R,6aR)-4-((1-(isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0330]

[0331] Compound 16 (15.0 mg) was obtained in the same manner as in Example 9 using compound 9-1 (150.0 mg) and 1-chloroethyl isopropyl carbonate (60.0 uL).

[0332] MS: [M+H] + = 387

[0333] 1 H NMR (500 MHz, 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)

[0334]

[0335] Example 17: Preparation of 4-((3aS,4R,6aR)-4-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0336]

[0337] 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 1-chloroethyl pivalate (47.0 uL).

[0338] MS: [M+H] + = 385

[0339] 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)

[0340]

[0341] Example 18: Preparation of 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0342]

[0343] 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)hexahydroprolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0344]

[0345] Compound 18-1 (197.0 mg, yield 91%) was obtained using the same method as Example 9 using compound 9-1 (200.0 mg) and 2-bromoethane-1-ol (125.0 uL).

[0346] MS: [M+H] + = 617

[0347]

[0348] 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)hexahydroprolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0349]

[0350] Compound 18-1 (200.0 mg) was dissolved in tetrahydrofuran (3.0 ml), and triethylamine (136.0 uL) and pivaloyl chloride (90.8 uL) were added. After reaction at room temperature for 12 hours, the mixture was concentrated and separated by column with ethyl acetate:hexane = 1:1 to obtain compound 18-2 (60.0 mg).

[0351] MS: [M+H] + = 701

[0352]

[0353] Step 3) Preparation of 4-((3aS,4R,6aR)-4-((2-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrol-4-yl)butylboronic acid dihydrochloride

[0354]

[0355] Compound 18-2 (60.0 mg) was prepared by the same method as steps 8 to 10 of Example 1 to obtain compound 18 (14.0 mg).

[0356] MS: [M+H] + = 385

[0357] 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)

[0358]

[0359] Example 19: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((cyclohexanecarbonyl)oxy)ethoxy)carbonyl)octahydroprolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0360]

[0361] 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

[0362]

[0363] 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 carbonchloridate (118.0 μL) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours to complete the reaction. After cooling 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).

[0364] MS: [M+H] + = 670

[0365]

[0366] Step 2) Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((cyclohexanecarbonyl)oxy)ethoxy)carbonyl)octahydroprolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0367]

[0368] 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 uL) were added. The reaction was completed by stirring at 50°C for 2 hours. After cooling 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. Compound 19 (20.0 mg) was obtained by column separation with ethyl acetate:hexane = 3:7 and in the same manner as steps 8 to 10 of Example 1.

[0369] MS: [M+H] + = 455

[0370] 1 H NMR (500 MHz, 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)

[0371]

[0372] Example 20: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pentanoyloxy)ethoxy)carbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0373]

[0374] Compound 20 (7.0 mg) was obtained using compound 19-1 (100.0 mg) and pentanoic acid (35.0 uL) in the same manner as in Example 19.

[0375] MS: [M+H] + = 429

[0376] 1H NMR (500 MHz, 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)

[0377]

[0378] Example 21: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride

[0379]

[0380] Compound 21 (15.0 mg) was obtained using the same method as Example 19 using compound 19-1 (200.0 mg) and pivaloic acid (70.0 uL).

[0381] MS: [M+H] + = 429

[0382] 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)

[0383]

[0384] 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

[0385]

[0386] Compound 22 (15.5 mg) was obtained using compound 19-1 (240 mg) and dimethyl-L-valine (78.4 mg) in the same manner as in Example 19.

[0387] MS: [M+H] + = 472

[0388] 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)

[0389]

[0390] 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

[0391]

[0392] Step 1) Preparation of 4,5-dibenzyl 1-(1-chloro-2-methylpropyl) (3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyll-1,3,2-dioxaborolan-2-yl)butyl)hexahydroprolo[3,4-b]pyrrole-1,4,5-tricarboxylate

[0393]

[0394] Compound 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 carbonchloridate (125.0 μL) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours to complete the reaction. After cooling 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).

[0395] MS: [M+H] + = 698

[0396]

[0397] 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

[0398]

[0399] 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 uL) were added. The reaction was completed by stirring at 70°C for 2 hours. After cooling 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. Compound 23 (20.0 mg) was obtained by column separation with ethyl acetate:hexane = 3:7 and the same method as steps 8 to 10 of Example 1.

[0400] MS: [M+H] + = 483

[0401] 1H 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)

[0402]

[0403] 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

[0404]

[0405] Compound 24 (5.6 mg) was obtained using compound 23-1 (115 mg) and pivaloic acid (25.6 mg) in the same manner as in Example 23.

[0406] MS: [M+H] + = 457

[0407] 1 H NMR (500 MHz, 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)

[0408]

[0409] Example 25: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(ethoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0410]

[0411] Compound 25 (14 mg) was obtained using compound 2-1 (50 mg) and ethyl carbochloridate (12 uL) in the same manner as step 1 of Example 19 and steps 8 to 10 of Example 1.

[0412] MS: [M+H] + = 329

[0413] 1 H NMR (500 MHz, 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)

[0414]

[0415] Example 26: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-(isobutoxycarbonyl)octahydropyrrolo[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0416]

[0417] Compound 26 (6.7 mg) was obtained using compound 2-1 (50 mg) and isobutyl carbochloridate (15 uL) in the same manner as step 1 of Example 19 and steps 8 to 10 of Example 1.

[0418] MS: [M+H] + = 357

[0419] 1 H 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)

[0420]

[0421] Example 27: Preparation of (3aS,4R,6aR)-4-(4-boronobutyl)-1-methyloctahydropyrrole[3,4-b]pyrrole-4-carboxylic acid hydrochloride

[0422]

[0423] Compound 2-1 (100 mg) was dissolved in dichloromethane (2 ml), formaldehyde (12.3 uL) and acetic acid (40.0 uL) 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, the mixture was separated with a ratio of ethyl acetate:hexane = 9:1, and compound 27 (4.0 mg) was obtained in the same manner as steps 8 to 10 of Example 1.

[0424] MS: [M+H] + = 271

[0425] 1 H 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)

[0426]

[0427] Example 28: Preparation of ((3aS,4R,6aR)-4-(4-boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrrolo[2,3-c]pyrrole-4-carboxylic acid hydrochloride

[0428]

[0429] Compound 2-1 (200 mg) was dissolved in dichloromethane (2 ml), and tert-butyl methyl (2-oxoethyl) carbamate (115.6 uL) and acetic acid (95 uL) were added, followed by stirring at 40°C for 3 hours. Sodium acetoxyborohydride (200 mg) was added, and the reaction was completed by stirring at 40°C for 3 hours. After cooling to 0-10°C, H2O was added, and the organic layer was separated. After concentration, the mixture was 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.

[0430] MS: [M+H] + = 314

[0431] 1 H NMR (500 MHz, DO) 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)

[0432]

[0433] Experimental Example 1: Arginase Inhibitory Activity Test

[0434] Arginase inhibitory activity tests were conducted on compounds according to the present invention. In addition to the compounds according to the present invention, compound CB-1158 (Numidargistat) was also tested for comparison.

[0435]

[0436] Specifically, all reagents required for 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), and compounds were dissolved in DMSO, diluted, and then diluted in reaction buffer to the desired concentration. 10 uL of compounds and 10 uL of 30 nM Arginase-1 were mixed in a transparent 96-well plate (SPL) and incubated at room temperature for more than 1 hour. Then, 10 uL of 15 mM L-arginine and 3 mM MnCl2 were added to the plate and reacted at room temperature for more than 30 minutes. Finally, 30 μL of a 1:1 mixture 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 plate was incubated at room temperature for more than 1 h. The absorbance of the incubated plate was measured at 450 nM using a Flexstation3 multi-mode microplate reader (Molecular Devices).

[0437]

[0438] The ΔOD for each reading was obtained by subtracting the background control (BC) reading from all readings, and the % relative Arginase-1 activity of each compound (S) was calculated using the following formula after setting the ΔOD of the enzyme control (EC) to the maximum value, and the IC of the compound was calculated using PRISM (GraphPad software). 50 The value was determined.

[0439] Relative Arginase-1 activity (%) = (ΔOD of S / ΔOD of EC)*100

[0440]

[0441] The potency of the compounds is listed in Table 1 below on a scale from A to C. Potency values ​​for A are less than 100 nM IC 50 Refers to a compound of the present invention having a value, and a compound having a potency value B has an IC ranging from 100 nM to 1,000 nM. 50 Indicates a value, IC exceeding 1000 nM 50 Compounds having a value of C were assigned an efficacy value of C.

[0442] Compound IC 50 CB-1158 (Numidargistat)A Example 1A Example 2B Example 3B Example 4B Example 5B Example 6C Example 7C Example 9C Example 27A Example 28B

[0443]

[0444] Experimental Example 2: PBMC Activity Evaluation Test

[0445] The compound according to the present invention was tested for activity in Primary Peripheral Blood Mononuclear Cells (PBMC). After inhibiting T cell differentiation induced using α-CD3 and α-CD28 antibodies with synthetic arginase1, it was confirmed that the compound induced T cell differentiation and proliferation by inhibiting arginase1. To evaluate T cell proliferation, the CellTiter-Glo® Luminescent Cell Viability (Promega, Catalog #G7571) assay was used, which can confirm cell proliferation by quantifying ATP present in cells. In addition to the compound according to the present invention, the compound CB-1158 (Numidargistat) was also tested for comparison.

[0446]

[0447] Specifically, α-CD3 antibody was coated on a clear 96-well microplate. 1x10 5 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 arginase 1 were added to each well. The compounds prepared in the example were treated at various concentrations (2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125 uM). After culturing for 72 hours, 50 uL of cells from each well were transferred to a white 96-well microplate and mixed with 50 uL of CellTiter-Glo® solution. After reacting at room temperature for 10 minutes, the luminescence was measured. The measurement results for each compound were calculated using Excel, and the EC 50 Values ​​were calculated using GraphPad Prism software.

[0448]

[0449] The potency of compounds is listed in Table 2 below on the scale of A and B. The potency value of A is less than 100 nM EC 50 Refers to a compound of the present invention having a value, and an EC in the range of 100 nM to 500 nM 50 Compounds with a value of B were assigned a potency value.

[0450] In vitro activityCB-1158Example 1EC 50 BA

Claims

DEPCT681. The compound represented by the following chemical formula 1 or its pharmaceutically acceptable salts: [Chemical Formula 1](Chemical Formula) In Chemical Formula 1, each R1 and R2 independently are hydrogen; C1-4 alkyl which is either unsubstituted or substituted with an amino, (C1-4 alkyl) amino or di(C1-4 alkyl) amino; or -L1-R'1, L1 is -CO-, -CO-O-, -(CO)-O-(C1-4 alkyl)-O-(CO)-, or -CH2-O-CO-, R'1 is -CH(NH2)-RA, -CH(N(CH3)2)-RA, RB, or RC, R3 is hydrogen. Droxy, or -L3-R'3, L3 is -NH-,-O-, or -O-(CH2)n3-O-CO-, R'3 is -CH(COOH)-RA, -CH(NH2)-RA, RB, or RC, RA each independent is hydrogen; or C1-6 alkyl which is not substituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, C1-6 alkyl thio, phenyl, hydroxyphenyl, or C4-10 heteroaryl with one or two N, RB each independent is C4-10 heterocycloalkyl with N.Each RC sample is independent, being a C1-6 alkyl group that is not substituted or substituted with C6-10 aryl or C4-10 heterocycloalkyl containing N; C6-10 aryl that is not substituted or substituted with C1-6 alkoxy; or C3-6 cycloalkyl, and n3 is an integer from 1 to 32. Its compound or salt is pharmaceutically acceptable under claim 1, where: Each R1 and R2 sample is independent, being hydrogen, methyl, methylaminoethyl, or substituent group represented by one of the following formulas: (chemical formula), where RA, RB, and RC are as specified in claim 1 and n1 is an integer. 1 to 33. Pharmaceutically acceptable compounds or their salts according to claim 1 where: R3 is a hydroxyl, or substituent group represented by one of the following formulas: (chemical formula) where RA, RB, RC and n3 are as specified in claim 14. Pharmaceutically acceptable compounds or their salts according to claim 1 where: Each individual RA is independent, hydrogen; or C1-6 alkyl which is not substituted or substituted with hydroxy, mercapto, hydroseleno, guanidino, amino, carboxy, carbamoyl, methylthio, phenyl, hydroxyphenyl, indole,or imidazole 5. Pharmaceutically acceptable compounds or salts under claim 1 where: Each independent RA is a natural amino acid residue where the natural amino acid residue means a structure excluding the terminal -CH(NH2)(COOH) 6. Pharmaceutically acceptable compounds or salts under claim 1 where: RB is pyrrolidinyl 7. Pharmaceutically acceptable compounds or salts under claim 1 where: Each independent RC is a C1-6 alkyl which is not substituted or substituted with phenyl, or piperidinyl; C6-10 aryl which is not substituted or substituted with methoxy; or C3-6 cycloalkyl 8. Pharmaceutically acceptable compounds or salts under claim 1 where: R1 is hydrogen, and R2 is hydrogen, or R1 is hydrogen, and R3 is hydroxyl, or R2 is hydrogen,And R3 is a hydroxyl 9. A pharmaceutically acceptable compound or its salt pursuant to claim 1 where: Chemical formula 1 is represented by one of the following chemical formulas 2 through 5: [Chemical formula 2](Chemical formula)[Chemical formula 3](Chemical formula)[Chemical formula 4](Chemical formula)[Chemical formula 5](Chemical formula), where in chemical formulas 2 through 5 RA is as specified in claim 1.

10. A pharmaceutically acceptable compound or its salt pursuant to claim 1 where the compound represented by chemical formula 1 is one of the compounds selected from the group consisting of: 1)(3aS,4R,6aR)-4-(4-boronobutyl)octahydroxy Dr. Pyrrol[2,3-c]pyrrol-4-carboxylic acid,2)(3aS,4R,6aR)-1-((S)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrrol[3,4-b]pyrrol-4-carboxylic acid,3)(3aS,4R,6aR)-1-((S)-2-amino-3-phenylpropanoyl)-4-(4-boronobutyl)octahydropyrrol[3 [3,4-b]Pyrol-4-Carboxylic Acid,4)(3aS,4R,6aR)-4-(4-Boronobutyl)-1-((S)-Pyrrolidine-2-Carbonyl)Octhydropyrolo[3,4-b]Pyrol-4-Carboxylic Acid,6)(3aS,4R,6aR)-1-((S)-2-Amino-3-Methylbutanoyl)-4-(4-Boronobutyl)octahydropyrolo[3,4-b]Pyrol-4-Carboxylic Acid,7)(3aS,4R,6aR)-1-((S)-2-Amino-4-Methylpentanoyl)-4-(4-Boronobutyl)octahydropyrolo[3,4-b] Pyrol-4-carboxylic acid,8)(3aS,4R,6aR)-1-((2S,3S)-2-amino-3-methylpentanoyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]Pyrol-4-carboxylic acid,9)(3aS,4R,6aR)-1-((R)-2-aminopropanoyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]Pyrol-4 -Carboxylic acid,10)4-((3aS,4R,6aR)-4-(ethoxycarbonyl)octahydropyrolo[2,3-c]pyrol-4-il)butylboronic acid,11)4-((3aS,4R,6aR)-4-(isopropoxycarbonyl)octahydropyrolo[2,3-c]pyrol-4-il)butylboronic acid,12)4-((3aS,4R,6aR)-4-(((isopropoxycarbonyl)octahydropyrolo[2,3-c]pyrol-4-il)butylboronic acid,12)4-((3aS,4R,6aR)-4-(((isopropoxycarbonyl)octahydropyrolo[2,3-c]pyrol-4-il)butylboronic acid tertiary-butoxycarbonyloxy)methoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-il)butylboronic acid,13)4-((3aS,4R,6aR)-4-(((tertiary-butoxycarbonyloxy)methoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-il)butylboronic acid,14)4-((3aS,4R,6aR)-4-((1-(ethoxycarbonyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid,15)4-((3aS,4R,6aR)-4-((1-(cyclohexyloxycarbonyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid ,16)4-((3aS,4R,6aR)-4-((1-(isopropoxycarbonyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-yl)butylboronic acid,17)4-((3aS,4R,6aR)-4-((1-(pivaloyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-yl)butylboronic acid Sid,18)4-((3aS,4R,6aR)-4-((2-(pivaloyl oxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-yl)butylboronic acid,19)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexane carbonyl oxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4- Carboxylic acid,20)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pentanoyl oxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid,21)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(pivaloyl oxy)ethoxy)carbonyl)octahydropyrolo[2,[3-c]pyrol-4-carboxylic acid,22)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-((S)-2-(dimethylaniole)-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,23)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((1-(cyclohexenca Boronyloxy)-2-methylpropoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid,24)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((2-methyl-1-(tivaloyyloxy)propoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid,25)(3aS,4R,6aR) -4-(4-boronobutyl)-1-(ethoxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,26)(3aS,4R,6aR)-4-(4-boronobutyl)-1-(isobutoxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,27)(3aS,4R,6aR)-4-(4-boronobutyl)-1-me Tiloctahydropyrolo[3,4-b]pyrol-4-carboxylic acid,28)(3aS,4R,6aR)-4-(4-boronobutyl)-1-(2-(methylamino)ethyl)octahydropyrolo[2,3-c]pyrol-4-carboxylic acid,29)(3aS,4R,6aR)-4-(4-boronobutyl)-1-(butyryloxymethyl)octahydropyrolo[3,[3,4-b]Pyrol-4-Carboxylic Acid,30)(3aS,4R,6aR)-1-((acetoxymethoxy)carbonyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]Pyrol-4-Carboxylic Acid,31)(S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrolo[3,4-b]Pyrol-4-Carboxamido)propano 32)(S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxamido)-3-methylbutanoic acid,33)(S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrolo[2,3-c]pyrol-4-carboxamido)-4-methylpentanoic acid,34)(2S,3R)-2-( (3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxamido)-3-methylpentanoic acid,35)(S)-2-((3aS,4R,6aR)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxamido)-3-phenylpropanoic acid,36)4-((3aS,4R,6aR)-4-((2-((S)-2- Aminopropanoyloxy)ethoxy)carbonyl)octahydropyrolo[2,3-c]pyrol-4-yl)butylboronic acid,37)4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-methylbutanoyloxy)ethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-yl)butylboronic acid,38)4-((3aS,4R,6aR)-4-((2-((2S,3S)-2-amino-3-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrolo[2,3-c]pyrol-4-yl)butylboronic acid,39)4-((3aS,4R,6aR)-4-((2-((S)-2-amino-4-methylpentanoyloxy)ethoxy)carbonyl)octahydropyrolo[2,3-c]pyrol-4-yl)bi Butylboronic acid,40)4-((3aS,4R,6aR)-4-((2-((S)-2-amino-3-phenylpropanoyloxy)ethoxy)carbonyl)octahydropyrolo[2,3-c]pyrrole-4-yl)butylboronic acid,41)4-((3aS,4R,6aR)-4-((2-((S)-pyrrolidine-2-carbonyloxy)ethoxy)carbonyl)octahydropyrolo [3,4-b]Pyrol-4-il)butylboronic acid,42)4-((3aS,4R,6aR)-4-((propionyl oxymethoxy)carbonyl)octahydropyrolo[2,3-c]Pyrol-4-il)butylboronic acid,43)4-((3aS,4R,6aR)-4-((isobutyryl oxymethoxy)carbonyl)octahydropyrolo[3,4-b]Pyrol-4-il )butylboronic acid,44)4-((3aS,4R,6aR)-4-(benzyloxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid,45)4-((3aS,4R,6aR)-4-((piperidin-4-ilmethoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid,46)4-((3aS,4R,6aR)-4-(phenoxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid,47)4-((3aS,4R,6aR)-4-((2-methoxyphenoxy)carbonyl)octahydropyrolo[3,4-b]pyrol-4-il)butylboronic acid,48)(3aS,4R,6aR)-1-((((S)-2-amino-3-phenyl aminopropanoyloxymethoxycarbonyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,49)(3aS,4R,6aR)-1-((((S)-2-aminopropanoyloxymethoxycarbonyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid Silicon acid,50)(3aS,4R,6aR)-4-(4-boronobutyl)-1-((((S)-pyrrolidine-2-carbonyloxy)methoxy)carbonyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid,51)(3aS,4R,6aR)-1-((((2S,3R)-2-amino-3-hydroxybutanoyloxy)methoxy)carbo (3,4-boronobutyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,52)(3aS,4R,6aR)-1-((((S)-2-amino-3-methylbutanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,53)(3aS,4R,6aR)-1-((((S)-2-amino-4-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrolo[2,3-c]pyrrole-4-carboxylic acid, and 54)(3aS,4R,6aR)-1-((((2S,3S)-2-amino-3-methylpentanoyloxy)methoxy)carbonyl)-4-(4-boronobutyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid.

11. A pharmaceutical compound for the prevention or treatment of cancer or tumors which contains any one of the compounds under claims 1 through 10 or their salts that are pharmaceutically acceptable as the active ingredient.

12. A compound which It is one of the substances chosen from a group of substances consisting of the following: (chemical formula) where each sample of PG1 and PG2 is independent, identical or different and represents the protective group13. Where the compound is one of the substances chosen from a group of substances consisting of the following: (3aR,4R,6aR)-1-(tertiary-butoxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,(3aS,4R,6aR)-5-((benzyloxy)carbonyl)-1-(tertiary-butoxycarbonyl)octahydropyrolo[3,4-b]pyrol-4-carboxylic acid,4,5-dibenzyl1-(tertiary-butyl)(3aS,4R,6aR)-hexahydropyrolo[3,4-b]pyrol-1,4,5-tricarboxylate,4,5-dibenzyl1-(tertiary-butyl)(3aS,4R,6aR)-4-((E)-but-2-ene-1-yl)hexahydropyrolo[3,4-b]pyrol-1,4,5-tricarboxylate,4,5-dibenzyl1-(tertiary-butyl)(3aS,4R,6aR)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hexahydropyrolo[3,4-b] Pyrrole-1,4,5-tricarboxylate,(4-((3aS,4R,6aR)-4,5-bis((benzyloxy)carbonyl)-1-(tertiary-butoxycarbonyl)octahydropyrolo[3,4-b]pyrrole-4-yl)butyl)boronic acid, and(3aS,4R,6aR)-5-(benzyloxycarbonyl)-4-(4-boronobutyl)-1-(tertiary-butoxycarbonyl)octahydropyrolo[3,4-b]pyrrole-4-carboxylic acid;,