GCL inhibitor

Abstract

To provide an agent comprising a compound having a GCL inhibitory activity as an active ingredient, in inhibiting the progression of, inhibiting the reoccurrence of, and / or treating GCL-related diseases such as cancer.SOLUTION: A compound represented by general formula (I) (all symbols in the formula are as defined in the description) or a salt thereof has GCL inhibitory activity, making it useful for inhibiting the progression of, inhibiting the reoccurrence of, and / or treating GCL-related diseases such as cancer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a compound or a salt thereof having glutamate cysteine ​​ligase (hereinafter referred to as "GCL") inhibitory activity, and a pharmaceutical composition containing the compound or a salt thereof as an active ingredient. More specifically, the compound is represented by the general formula (I):

[0002] [ka]

[0003] (wherein all symbols have the same meaning as described below) or a salt thereof (hereinafter referred to as the disclosed compound), and pharmaceutical compositions containing them as active ingredients, etc. [Background technology]

[0004] GCL is a rate-limiting enzyme in glutathione (GSH) synthesis, composed of a glutamate cysteine ​​ligase catalytic subunit (GCLC) and a glutamate cysteine ​​ligase modifying subunit (GCLM).

[0005] The relationship between this enzyme and cancer has been reported. For example, it has been reported that GCLC inhibitors are useful for treating ARID1A-deficient cancers (Patent Document 1) and that knocking out GCLC suppresses tumor growth in acute myeloid leukemia (AML) (Non-Patent Document 1).

[0006] L-buthionine sulfoximine (hereinafter referred to as BSO) is known as a GCLC inhibitor, and BSO derivatives and low molecular weight compounds have been reported as GCLC inhibitors (Patent Document 2, Non-Patent Documents 2 to 4). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2020 / 138385 Brochure [Patent Document 2] International Publication No. 1989 / 009205 Brochure [Non-patent literature]

[0008] [Non-Patent Document 1] American Journal of Cancer Research, p. 2911, vol. 11, no. 6, 2021(American Journal of Cancer Research, p. 2911, 11(6), 2021) [Non-Patent Document 2] Bioscience, Biotechnology, and Biochemistry 1500, 66(7), 2002 [Non-Patent Document 3] Bioorganic & Medicinal Chemistry 1935, No. 6, 1998 [Non-Patent Document 4] MOLECULAR PHARMACOLOGY 1140, 71, 2007 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a compound having inhibitory activity against GCL. [Means for solving the problem]

[0010] Means for Solving the Problems The present inventors have conducted intensive research to solve the above problems and have found that a compound represented by the general formula (I) described below has inhibitory activity against GCL.

[0011] That is, in one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: [1] General formula (I):

[0012] [ka]

[0013] (In the formula, R 1 represents a hydrogen atom, a methyl group, or a hydroxyl group, and R 2 is (1)-C(R 3 R 4 )-R 5 or (2) 1 to 9 R 6 represents a C3-C5 cycloalkyl group which may be substituted by 3 or R 4 each represents (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom, or (4) a methyl group which may be substituted by 1 to 3 halogen atoms; R 5 represents (1) a trifluoromethyl group or (2) a tert-butyl group, R 6 represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted with 1 to 3 halogen atoms; R 6 If there are multiple, multiple R 6 may be the same or different, and R 7 represents a hydrogen atom or a C1-C4 alkyl group, and n represents 0 or 1, or a salt thereof, [2] A pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof according to [1] above. [3] The present invention provides an embodiment of the pharmaceutical composition etc. described in [2] above, which is a GCL inhibitor. Effect of the Invention

[0014] The disclosed compound has inhibitory activity against GCL and can therefore be used as an active ingredient in an agent for inhibiting the progression, inhibiting recurrence and / or treating diseases associated with GCL (GCL-associated diseases) such as cancer. [Brief description of the drawings]

[0015] [Figure 1] 4 shows the amount of GSH in the tumor 24 hours after administration of BSO and the compound prepared in Example 2. [Diagram 2] The amount of GSH in the tumor 24 hours after administration of BSO and each of the compounds prepared in Example 2 and Example 3 is shown. [Diagram 3] The change in tumor volume over time in each group after administration of BSO and each compound prepared in Example 2 and Example 3 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present disclosure will be described in detail below.

[0017] In the present disclosure, examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms, etc. A fluorine or chlorine atom is preferred, and a fluorine atom is more preferred.

[0018] In the present disclosure, a methyl group optionally substituted with 1 to 3 halogen atoms means, for example, a methyl group optionally substituted with 1, 2 or 3 halogen atoms, and specific examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, and a trifluoromethyl group.

[0019] In the present disclosure, C1-C4 alkyl groups include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, and tert-butyl groups.

[0020] In the present disclosure, C3 to C5 cycloalkyl groups include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

[0021] In the present disclosure, C3-C4 cycloalkyl groups include a cyclopropyl group and a cyclobutyl group.

[0022] In the present disclosure, C4 to C5 cycloalkyl groups include a cyclobutyl group and a cyclopentyl group. etc.

[0023] In this disclosure, R 1 is preferably a hydrogen atom.

[0024] In the present disclosure, n is preferably 1.

[0025] In this disclosure, R 5 is preferably a trifluoromethyl group.

[0026] In this disclosure, R 2 Preferably, (1)-C(R 3 R 4 )-CF3 or (2) 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R 6 and R 1 to R 2 are each independently substituted with a C3 to C5 cycloalkyl group (the C3 to C5 cycloalkyl group is preferably a C3 to C4 cycloalkyl group or a C4 to C5 cycloalkyl group, and more preferably a cyclobutyl group).

[0027] In this disclosure, R 3 is preferably a hydrogen atom, a halogen atom or a hydroxyl group, more preferably a hydrogen atom or a hydroxyl group, and even more preferably a hydroxyl group.

[0028] In this disclosure, R 4 is preferably a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and more preferably a hydrogen atom, a methyl group or a trifluoromethyl group.

[0029] In this disclosure, R 6 is preferably a hydroxyl group, a halogen atom, a methyl group or a trifluoromethyl group, and more preferably a hydroxyl group or a halogen atom.

[0030] In this disclosure, R 2 A preferred embodiment of the present invention is

[0031] [ka]

[0032] (In the formula, the wavy line indicates the bond position with the adjacent group (CH2(CHR 1 ) n The other symbols have the same meanings as above.

[0033] In this disclosure, R 2 A preferred embodiment of the present invention is

[0034] [ka]

[0035] (In the formula, m represents an integer of 1 to 3, p represents an integer of 0 to 3, and R 6a represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted with 1 to 3 halogen atoms, and when p is 2 or 3, a plurality of R 6a may be the same or different. The other symbols have the same meanings as above.

[0036] In this disclosure, R 2 A preferred embodiment of the present invention is

[0037] [ka]

[0038] (wherein m-1 represents 1 or 2, and the other symbols have the same meanings as defined above), or

[0039] [ka]

[0040] (In the formula, m-2 represents 1 or 2, and the other symbols have the same meanings as defined above.)

[0041] In this disclosure, R 2 A preferred embodiment of the present invention is

[0042] [ka]

[0043] (wherein all symbols have the same meaning as above).

[0044] In this disclosure, R 6a is preferably a halogen atom, a methyl group or a trifluoromethyl group, and more preferably a halogen atom.

[0045] In the present disclosure, m is preferably 2.

[0046] In the present disclosure, m-1 is preferably 2.

[0047] In the present disclosure, m-2 is preferably 1.

[0048] In the present disclosure, p is preferably 0 to 2, more preferably 0 or 1, and further preferably 0. In this disclosure, R 7 is preferably a hydrogen atom, an ethyl group or an isopropyl group, and more preferably a hydrogen atom.

[0049] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (I-1)

[0050] [ka]

[0051] (wherein all symbols have the same meanings as defined above).

[0052] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (I-2)

[0053] [ka]

[0054] (wherein all symbols have the same meanings as defined above).

[0055] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (II)

[0056] [ka]

[0057] (wherein all symbols have the same meanings as defined above).

[0058] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (II-1)

[0059] [ka]

[0060] (wherein all symbols have the same meanings as defined above).

[0061] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (II-2)

[0062] [ka]

[0063] (wherein the symbols have the same meanings as defined above).

[0064] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (II-3):

[0065] [ka]

[0066] (In the formula, R 2a teeth

[0067] [ka]

[0068] (wherein the symbols have the same meanings as defined above), or

[0069] [ka]

[0070] (wherein the symbols have the same meanings as defined above), and the other symbols have the same meanings as defined above.)

[0071] In the present disclosure, the compound represented by the general formula (I) is preferably a combination of the preferred definitions of each group including the general formula described above.

[0072] In the present disclosure, another embodiment of the compound represented by general formula (I) is most preferably a compound of the examples described later in the Examples section or a salt thereof.

[0073] The disclosed compound has GCL inhibitory activity. In one embodiment, the GCL inhibitory activity in the disclosed compound is GCLC inhibitory activity. In one embodiment, the disclosed compound has GCL inhibitory activity equal to or greater than that of BSO. In one embodiment, the disclosed compound has a stronger GCL inhibitory effect in cells than BSO. In one embodiment, the disclosed compound has a stronger GCL inhibitory effect in cells than BSO, about 2 times or more, about 3 times or more, about 4 times or more, about 5 times or more, or about 10 times or more. The GCL inhibitory effect in cells can be confirmed using a general measurement method, and can be measured, for example, by the method described in Pharmacological Example 2 below.

[0074] In one embodiment, the compound of the present disclosure has excellent pharmacokinetics. Each parameter related to pharmacokinetics (AUC, CLtotal, T1 / 2, and / or BA, etc.) can be confirmed by a general measurement method.

[0075] In one embodiment, the compound of the present disclosure has a stronger in vivo effect than BSO, and exerts its effectiveness at a lower concentration than BSO. The in vivo effect (effectiveness, etc.) can be confirmed, for example, by a general measurement method, and can be measured, for example, by the method described in Pharmacological Example 3 below.

[0076] In this disclosure, all isomers are included unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include straight-chain and branched-chain isomers. In addition, isomers (E, Z, cis, trans) in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbons (R, S, α, β, enantiomers, diastereomers), isomers due to the presence of sulfur atoms (asymmetric) in sulfoximine (R, S, enantiomers, diastereomers), optically active isomers having optical rotation (D, L, d, l), polar isomers (high polarity, low polarity) obtained by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any ratio, and racemic mixtures are all included in this disclosure. In addition, in this disclosure, all isomers due to tautomerism are also included.

[0077] In this disclosure, unless otherwise specified, the symbols

[0078] [ka]

[0079] represents bonding to the other side of the paper (i.e., α-configuration),

[0080] [ka]

[0081] indicates that the molecule is bonded to the front side of the paper (i.e., the β-configuration),

[0082] [ka]

[0083] represents any mixture of α- and β-configurations. [salt] The compound represented by the general formula (I) etc. can be converted into a salt by a known method.

[0084] The salt is preferably a pharma- ceutically acceptable salt.

[0085] The salt is preferably water-soluble.

[0086] Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts or amine salts.

[0087] Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate salts, or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and gluconate.

[0088] Examples of the alkali metal salt include potassium salts and sodium salts.

[0089] Alkaline earth metal salts include, for example, calcium salts and magnesium salts.

[0090] The ammonium salt includes, for example, tetramethylammonium salt.

[0091] Examples of the amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris(hydroxymethyl)aminomethane salt, lysine salt, arginine salt, and N-methyl-D-glucamine salt.

[0092] The compounds of the present disclosure can be converted into N-oxides by any method. The term "N-oxides" refers to compounds in which the nitrogen atom of a compound represented by general formula (I) or the like is oxidized.

[0093] The compound represented by the general formula (I) and its salt may be present in a non-solvated form or in a solvated form with a pharma- ceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compound represented by the general formula (I) and its salt may be converted into a solvate.

[0094] The compound represented by the general formula (I) etc. can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharma- ceutically acceptable one formed with a pharma- ceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules with intermolecular interactions other than ionic bonds. A co-crystal may also be a complex of a neutral molecule and a salt. A co-crystal can be prepared by known methods, for example, by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO2006 / 007448.

[0095] In this disclosure, all references to the disclosed compounds include a compound represented by general formula (I) or the like, a salt thereof, an N-oxide thereof, a solvate (e.g., hydrate) thereof, or a cocrystal thereof, or an N-oxide of a salt of a compound represented by general formula (I) or the like, a solvate (e.g., hydrate) thereof, or a cocrystal thereof. [Prodrug] A prodrug of a compound represented by the general formula (I) or the like refers to a compound that is converted into a compound represented by the general formula (I) or the like in vivo by a reaction caused by an enzyme, gastric acid, or the like. Examples of the prodrug of a compound represented by the general formula (I) or the like include, when the compound represented by the general formula (I) or the like has an amino group, a compound in which the amino group has been acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of a compound represented by the general formula (I) or the like has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by the general formula (I) or the like has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group of a compound represented by the general formula (I) or the like has been acetylated, palmitoylated, propanoylated, or the like). yl, pivaloyl, succinyl, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by the general formula (I) etc. has a carboxy group, the carboxy group is esterified or amidated (for example, the carboxy group of the compound represented by the general formula (I) etc. is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidated compounds, etc.). These compounds can be produced by known methods. In addition, the prodrug of the compound represented by the general formula (I etc.) may be either a hydrate or a non-hydrate. In addition, the prodrug of the compound represented by general formula (I) etc. may be one that changes into the compound represented by general formula (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, published by Hirokawa Shoten in 1990.

[0096] Furthermore, each atom constituting the compound represented by the general formula (I) etc. may contain its isotope (e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 16 N, 17 O. 18 O. 18 F, 35 S, 36 Cl, 77 Br, 125 I, etc.) may be substituted. [Method of producing the disclosed compound] The disclosed compound can be produced by appropriately improving and combining known methods, such as the methods shown below, methods similar thereto, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C.Larock, John Wiley & Sons Inc, 2018), or the methods shown in the examples. The starting material may be a salt. The order of carrying out each reaction can be appropriately changed depending on the protective group introduced and the reaction conditions.

[0097] Furthermore, a compound having an amino group, a carboxyl group, or a hydroxyl group can be produced, as necessary, by using a compound protected with a protecting group commonly used for these groups, for example, a protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and carrying out a known deprotection reaction after an appropriate reaction step.

[0098] Examples of carboxyl-protecting groups include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0099] Examples of the protecting group for an amino group include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, and a 2-(trimethylsilyl)ethoxymethyl (SEM) group.

[0100] Examples of hydroxyl-protecting groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like.

[0101] The deprotection reaction is known and can be carried out by the following method. For example, (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) deprotection by hydrogenolysis, (4) deprotection reaction of the silyl group, (5) Deprotection reaction using metals, (6) Deprotection reaction using a metal complex, etc.

[0102] To explain these methods in detail, (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter, THF), dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C.

[0103] (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C.

[0104] (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., an ether (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol (e.g., methanol, ethanol, etc.), a benzene (e.g., benzene, toluene, etc.), a ketone (e.g., acetone, methyl ethyl ketone, etc.), a nitrile (e.g., acetonitrile, etc.), an amide (e.g., N,N-dimethylformamide (hereinafter, DMF), etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) under a hydrogen atmosphere under normal or increased pressure or in the presence of ammonium formate at 0 to 200°C.

[0105] (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) at 0 to 40° C. Also, for example, it is carried out in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C.

[0106] (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution having a pH of 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as THF) in the presence of zinc powder at 0 to 40° C., if necessary, with ultrasonication.

[0107] (6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, in the presence of a trapping reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.), at 0 to 40°C.

[0108] The compounds of formula (I) can be prepared according to reaction scheme 1.

[0109] [ka]

[0110] (In reaction scheme 1, PG represents an amino-protecting group, X represents a leaving group, CO2Me represents a methoxycarbonyl group, and the other symbols have the same meanings as above.) In reaction scheme 1, reaction 1-1 is an S-alkylation reaction. The S-alkylation reaction is known, and is carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof, or a mixture thereof, at 0 to 100°C.

[0111] In reaction scheme 1, reaction 1-2 is an oxidation reaction from sulfide to sulfoximine. For example, it is carried out in an organic solvent (methanol (MeOH)) in the presence of iodobenzene diacetate and ammonium carbamate at 0°C to room temperature.

[0112] In reaction scheme 1, reactions 1-3 are deprotection reactions, which can be carried out in the same manner as described above.

[0113] In reaction scheme 1, reactions 1-4 are deprotection reactions, which can be carried out in the same manner as described above.

[0114] In each reaction in the present specification, the compounds represented by general formula 1a and general formula 1b used as starting materials are publicly known or can be easily produced by using a combination of publicly known methods, for example, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or methods in which the publicly known methods have been partially modified.

[0115] Among the compounds used in the present invention, optically active compounds can be produced by using optically active starting materials or reagents, by optically resolving a racemic production intermediate and then leading to the compound of the present disclosure, or by optically resolving a racemic compound of the present disclosure.

[0116] This optical resolution is well known, and examples of the method include forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly separating it using a chiral column.

[0117] In each reaction in the present specification, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

[0118] In each reaction herein, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0119] In each reaction in the present specification, the reaction product can be purified by a conventional purification method, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of some reactions. [toxicity] The compounds of the present disclosure have low toxicity and can therefore be safely used as pharmaceuticals. [Application to pharmaceuticals] Since the compounds disclosed herein have inhibitory activity against GCL, they can be prescribed as effective agents for suppressing the progression, suppressing recurrence, or treating diseases associated with GCL (GCL-associated diseases), such as cancer.

[0120] Cancers that the disclosed compounds are intended to inhibit progression, inhibit recurrence and / or treat include any solid cancer and blood cancer, but one example includes ARID1A-deficient cancer and / or cancer sensitive to GCL (GCL-sensitive cancer).

[0121] As used herein, ARID1A deficiency refers to ARID1A gene deficiency or ARID1A protein deficiency caused by ARID1A gene mutation. ARID1A-deficient cancer refers to cancer with ARID1A deficiency. Examples of ARID1A-deficient cancer include ovarian cancer, uterine cancer, gastric cancer, bladder cancer, bile duct cancer, liver cancer, esophageal cancer, lung cancer, colon cancer, pancreatic cancer, breast cancer, neuroblastoma, glioma, skin cancer, B-cell lymphoma and renal cancer.

[0122] GCL-sensitive cancers include, for example, acute myeloid leukemia and B-cell lymphoma.

[0123] In this specification, the term "cancer treatment" includes, for example, treatments performed to (a) reduce the proliferation of cancer cells, (b) reduce symptoms caused by cancer, improve the quality of life of cancer patients, (c) reduce the dose of other anticancer drugs or cancer treatment adjuvant drugs already administered, and / or (d) extend the survival time of cancer patients. "Suppression of cancer progression" means delaying the progression of cancer, stabilizing symptoms associated with cancer, and reversing the progression of symptoms. "Suppression of recurrence" means preventively suppressing cancer recurrence in patients whose cancer lesions have completely or substantially disappeared or been removed by cancer treatment or cancer surgical resection.

[0124] In order to use the disclosed compound for the purpose of suppressing the progression, suppressing recurrence and / or treating the above-mentioned disease, the substance as an active ingredient is usually formulated together with a pharma- ceutically acceptable carrier such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, the pharma- ceutically acceptable carrier means a substance other than the active ingredient that is generally used in the formulation of a pharmaceutical product. The pharma- ceutically acceptable carrier is preferably one that does not exhibit a pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, the pharma- ceutically acceptable carrier can also be used for the purpose of increasing the usefulness of the active ingredient and the formulation, facilitating formulation, stabilizing the quality, or improving usability. Specifically, a substance such as that described in "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nipposha in 2000, may be appropriately selected according to the purpose.

[0125] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, gargles, etc.), injectable preparations (e.g., injectables, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enteral injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.).

[0126] [Combination or combination drug] The disclosed compound or a pharmaceutical composition containing the disclosed compound as an active ingredient (hereinafter abbreviated as "the disclosed compound, etc.") may be formulated in combination with one or more other drugs for the purposes of (a) suppressing the progression, suppressing recurrence, and / or enhancing the therapeutic effect of cancer, (b) reducing the dosage of other drugs prescribed in combination, (c) reducing the side effects of other drugs prescribed in combination, and / or (d) enhancing the immune enhancing effect of other drugs prescribed in combination, i.e., as an adjuvant. In the present disclosure, when the compound is formulated in combination with other drugs (e.g., other anticancer drugs), the dosage form may be a combination drug in which both components are formulated in one formulation, or may be a separate formulation. By using the compound in combination, it is possible to complement the preventive, symptom progression suppressive, recurrence suppressive, and / or therapeutic effect of the other drug, or to maintain or reduce the dosage or number of administrations. When the disclosed compound, etc. and the other drug are formulated separately, they may be administered simultaneously for a certain period of time, and then only the disclosed compound, etc. or only the other drug may be administered. In addition, the compound disclosed herein may be administered first, and then the other drug may be administered, or the other drug may be administered first, and then the compound disclosed herein may be administered, or in the above administration, there may be a period during which both drugs are administered simultaneously for a certain period. In addition, the administration method of each drug may be the same or different. Depending on the nature of the drug, it may be provided as a kit of a formulation containing the compound disclosed herein and a formulation containing the other drug. Here, the dosage of the other drug may be appropriately selected based on the dose used in clinical practice. In addition, any two or more kinds of other drugs may be administered in combination at an appropriate ratio. In addition, the other drugs include not only those that have been discovered so far, but also those that will be discovered in the future. [Prescription] To use the disclosed compounds or combinations of the disclosed compounds and other drugs for the above purposes, they are usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1ng to 2,000mg per dose per adult, or parenterally administered once to several times a day in the range of 0.1ng to 200mg per dose per adult, or continuously administered intravenously for 30 minutes to 24 hours a day. Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a dosage less than the above dosage is sufficient, and in other cases it is necessary to administer beyond the range.

[0127] The disclosed compounds are administered to a mammal, preferably a human, more preferably a human patient, in a pharma- ceutical effective amount.

[0128] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0129] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0130] In one aspect, the present disclosure provides the following embodiments. [1] General formula (I)

[0131] [ka]

[0132] (In the formula, R 1 represents a hydrogen atom, a methyl group, or a hydroxyl group, R 2 is (1)-C(R 3 R 4 )-R 5 or (2) 1 to 9 R6 represents a C3-C5 cycloalkyl group optionally substituted by R 3 or R 4 each represents (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom, or (4) a methyl group which may be substituted by 1 to 3 halogen atoms, R 5 represents (1) a trifluoromethyl group or (2) a tert-butyl group; R 6 represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted with 1 to 3 halogen atoms; R 6 If there are multiple, multiple R 6 may be the same or different, R 7 represents a hydrogen atom or a C1-C4 alkyl group, n represents 0 or 1, or a salt thereof. [2] R 2 However, (1)-C(R 3 R 4 )-CF3 or (2) 1 to 4 R 6 A C3-C5 cycloalkyl group optionally substituted with (preferably, 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R 6 a cyclobutyl group optionally substituted by [3] R 3 is a hydrogen atom, a halogen atom or a hydroxyl group (more preferably a hydrogen atom or a hydroxyl group), [4] R 6 is a hydroxyl group, a halogen atom, a methyl group or a trifluoromethyl group (more preferably a hydroxyl group or a halogen atom), [5] R 2 but,

[0133] [ka]

[0134] (wherein the symbols have the same meanings as in [1] above), or

[0135] [ka]

[0136] (In the formula, m represents an integer of 1 to 3, p represents an integer of 0 to 3 (preferably 0 to 2), and R 6a represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted with 1 to 3 halogen atoms, and when p is 2 or 3, a plurality of R 6a may be the same or different.) The compound or salt thereof according to the above [1] or [2], [6] R 2 but,

[0137] [ka]

[0138] (wherein the symbols have the same meanings as in the above [1]), [7] R 4 is a hydrogen atom, a halogen atom, a methyl group, or a trifluoromethyl group (more preferably a hydrogen atom, a methyl group, or a trifluoromethyl group), [8] R 2 but,

[0139] [ka]

[0140] (wherein the symbols have the same meanings as in the above [5]) or a salt thereof, [9] R 6ais a halogen atom, a methyl group or a trifluoromethyl group (more preferably a halogen atom), or a salt thereof.

[10] The compound or salt thereof according to [5], [8] or [9] above, wherein m is 2.

[11] The compound or salt thereof according to any one of the above [1] to

[10] , wherein n is 1.

[12] R 1 is a hydrogen atom,

[13] The compound represented by general formula (I) is represented by general formula (II-3)

[0141] [ka]

[0142] (In the formula, R 2a teeth

[0143] [ka]

[0144] (wherein the symbols have the same meanings as in [1] above), or

[0145] [ka]

[0146] (wherein the symbols are as defined in the above [5]), and the other symbols are as defined in the above [1], or a salt thereof,

[14] R 4 is a hydrogen atom, a halogen atom, a methyl group, or a trifluoromethyl group (more preferably a hydrogen atom, a methyl group, or a trifluoromethyl group),

[15] R 6ais a halogen atom, a methyl group or a trifluoromethyl group (more preferably a halogen atom), and p is 0 or 1.

[16] R 7 is a hydrogen atom, an ethyl group, or an isopropyl group (more preferably a hydrogen atom),

[17] The compound represented by formula (I), (1) (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid, (2) (2S)-2-amino-4-[S-(2-cyclopentylethyl)sulfonimidoyl]butanoic acid, (3) (2S)-2-amino-4-[S-(2-cyclobutylethyl)sulfonimidoyl]butanoic acid, (4) (2S)-2-amino-4-[S-(2-cyclopropylethyl)sulfonimidoyl]butanoic acid, (5) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-methylbutyl)sulfonimidoyl]butanoic acid, (6) (2S)-2-amino-4-{S-[2-(3,3-difluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (7) (2S)-2-amino-4-[S-(4,4-dimethylpentyl)sulfonimidoyl]butanoic acid, (8) (2S)-2-amino-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (9) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoic acid, (10) (2S)-2-amino-4-{S-[2-(1-fluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (11) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)sulfonimidoyl]butanoic acid, (12) (2S)-2-amino-4-{S-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]sulfonimidoyl}butanoic acid, (13) (2S)-2-amino-4-[S-(3,3,4,4,4-pentafluorobutyl)sulfonimidoyl]butanoic acid, (14) (S)-2-amino-4-((R,3R)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid, (15) (S)-2-amino-4-((R,3S)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid, (16) (S)-2-amino-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid, (17) (S)-2-amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoic acid, (18) Ethyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate, and (19) Isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate The compound according to the above [1] or a salt thereof,

[18] A pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof according to [1].

[19] The pharmaceutical composition according to the above

[18] , which is a GCL inhibitor.

[20] The pharmaceutical composition according to

[18] or

[19] above, which is an agent for inhibiting progression, inhibiting recurrence and / or treating a GCL-related disease (e.g., cancer).

[21] A method for inhibiting progression, suppressing recurrence and / or treating cancer, comprising administering an effective amount of the compound represented by the general formula (I) described in [1] above or a salt thereof to a patient in need of such inhibition, suppression of recurrence and / or treatment of cancer.

[22] A compound represented by the general formula (I) or a salt thereof according to [1] above, which is used for inhibiting the progression, inhibiting the recurrence and / or treating cancer, and

[23] Use of a compound represented by the general formula (I) or a salt thereof described in [1] above for the manufacture of an agent for inhibiting the progression, inhibiting the recurrence and / or treating cancer.

[0147] In one aspect, the present disclosure provides the following embodiments, but the scope of the present invention is not limited thereto. Based on the description of the present disclosure, various changes or modifications can be made by those skilled in the art, and these changes or modifications are also included in the present invention. [Synthesis Example] The solvents in parentheses shown in the chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume.

[0148] The solvent in parentheses in the NMR section indicates the solvent used in the measurement.

[0149] The names of compounds used in this specification were generated using ACD / Name (registered trademark), a computer program that generally performs naming according to the IUPAC rules, or ChemDraw Professional (Version 18.0, PerkinElmer), or in accordance with the IUPAC nomenclature method.

[0150] LC-MS / ELSD was performed under the following conditions. Condition A; Column: YMC triart C 18 (Particle size: 1.9 x 10 -6 m, column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 30 °C; mobile phase (A): 0.1% trifluoroacetic acid in water; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (ratio of mobile phase (A):mobile phase (B) is listed): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; detector: UV (PDA), ELSD, MS. Condition B: Column: YMC triart C18 (particle size: 1.9 x 10 -6m, column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 30 °C; mobile phase (A): 0.1% trifluoroacetic acid in water; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (ratio of mobile phase (A):mobile phase (B) is listed): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:50; [1.21 min] 5:95; [1.6 min] 5:95; detector: UV (PDA), ELSD, MS.

[0151] HPLC retention times are shown under condition A for synthetic intermediates and under condition B for compounds of the present disclosure.

[0152] SFC fractionation was performed under one of the following conditions: Condition C; Column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250x20 mm ID); Flow rate: 100 mL / min; Column temperature: 35 °C; Pressure: 120 bar; Mobile phase (A): CO2; Mobile phase (B): MeOH; Isocratic (Mobile phase (A): Mobile phase (B) = 95:5); Detector: UV 220 nm. Condition D; Column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250x20 mm ID); Flow rate: 100 mL / min; Column temperature: 35 °C; Pressure: 120 bar; Mobile phase (A): CO2; Mobile phase (B): MeOH; Isocratic (Mobile phase (A): Mobile phase (B) = 90:10); Detector: UV 210 nm. Condition E; Column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250x20 mm ID); Flow rate: 100 mL / min; Column temperature: 35 °C; Pressure: 120 bar; Mobile phase (A): CO2; Mobile phase (B): EtOH; Isocratic (Mobile phase (A): Mobile phase (B) = 92:8); Detector: UV 220 nm. Reference Example 1: Methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[(4,4,4-trifluorobutyl)thio]butanoate Potassium carbonate (415 mg) and 4,4,4-trifluorobutyl methanesulfonate (CAS: 164523-19-7) (806 mg) were added to a solution of methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (750 mg) in DMF (10 mL), and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to give the title compound (1.08 g) having the following physical properties. TLC: Rf 0.5 (hexane:ethyl acetate=3:1) Reference Example 2: Methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate To a solution of the compound (1.08 g) produced in Reference Example 1 in methanol (10 mL), iodobenzene diacetate (2.03 g) and ammonium carbamate (351 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (820 mg) having the following physical properties. TLC: Rf 0.6 (ethyl acetate) Reference Example 3: (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid A solution (3 mL) of lithium hydroxide monohydrate (176 mg) was added to a solution of the compound (820 mg) produced in Reference Example 2 in THF (6 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (764 mg) having the following physical properties. HPLC retention time (min): 0.845 Example 1: (2S)-2-Amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid

[0153] [ka]

[0154] A 5N aqueous hydrochloric acid solution (5 mL) was added to the compound (764 mg) produced in Reference Example 3, and the mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added to the reaction solution, and an ion exchange resin (trade name: DOWEX (H + The ninhydrin-reactive fraction was collected and concentrated to give the compound of the present disclosure (473 mg) having the following physical properties: MS(ESI,Pos.):293(M+H) + ; 1 H-NMR(D2O): δ 2.02, 2.20 - 2.38, 3.23 - 3.43, 3.77. Examples 1-1 to 1-4 By carrying out the same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 using the corresponding methanesulfonate instead of 4,4,4-trifluorobutyl methanesulfonate, the presently disclosed compound having the following physical properties was obtained. Example 1-1: (2S)-2-amino-4-[S-(2-cyclopentylethyl)sulfonimidoyl]butanoic acid

[0155] [ka]

[0156] The compound of the present disclosure (23 mg) having the following physical properties was obtained. HPLC retention time (min): 0.683; MS(ESI,Pos.):263(M+H) + ; 1 H-NMR(D2O): δ 1.00 - 1.14, 1.37 - 1.60, 1.64 - 1.77, 1.77 - 1.86, 2.14 - 2.34, 3.16 - 3.39, 3.75. Example 1-2: (2S)-2-amino-4-[S-(2-cyclobutylethyl)sulfonimidoyl]butanoic acid

[0157] [ka]

[0158] The compound of the present disclosure (75 mg) having the following physical properties was obtained. HPLC retention time (min): 0.567; MS(ESI,Pos.):249(M+H) + ; 1 H-NMR(D2O): δ 1.48 - 1.64, 1.68 - 1.85, 1.90 - 2.04, 2.14 - 2.37, 2.91 - 3.16, 3.17 - 3.44, 3.77. Example 1-3: (2S)-2-amino-4-[S-(2-cyclopropylethyl)sulfonimidoyl]butanoic acid

[0159] [ka]

[0160] The compound of the present disclosure (48 mg) having the following physical properties was obtained. HPLC retention time (min): 0.425; MS(ESI,Pos.):235(M+H) + ; 1 H-NMR(D2O):δ -0.05 - 0.08, 0.30 - 0.44, 0.69, 1.47 - 1.65, 2.13 - 2.27, 3.14 - 3.35, 3.71. Example 1-4: (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-methylbutyl)sulfonimidoyl]butanoic acid

[0161] [ka]

[0162] The compound of the present disclosure (22 mg) having the following physical properties was obtained. HPLC retention time (min): 0.599; MS(ESI,Pos.):291(M+H) + ; 1H-NMR(D2O): δ 1.08, 1.73 - 1.87, 1.97 - 2.18, 2.20 - 2.34, 2.36 - 2.51, 3.21 - 3.44, 3.79. Reference Example 4: 2-(3,3-difluorocyclobutyl)ethyl methanesulfonate Diisopropylethylamine (0.38mL) and mesylic anhydride (281mg) were added to a solution of 2-(3,3-difluorocyclobutyl)ethanol (CAS:1056467-54-9) (200mg) in dichloromethane (2mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (314mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Example 1-5: (2S)-2-amino-4-{S-[2-(3,3-difluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid

[0163] [ka]

[0164] Using the compound prepared in Reference Example 4 instead of 4,4,4-trifluorobutyl methanesulfonate, the same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 were carried out to obtain the disclosed compound (61 mg) having the following physical properties. HPLC retention time (min): 0.523; MS(ESI,Pos.):285(M+H) + ; 1 H-NMR(D2O): δ 1.86 - 2.00, 2.12 - 2.31, 2.57 - 2.73, 3.12 - 3.41, 3.76. Example 1-6: (2S)-2-amino-4-[S-(4,4-dimethylpentyl)sulfonimidoyl]butanoic acid

[0165] [ka]

[0166] The compound of the present disclosure (25 mg) having the following physical properties was obtained. HPLC retention time (min): 0.714; MS(ESI,Pos.):265(M+H) + ; 1 H-NMR(D2O): δ 0.81, 1.17 - 1.29, 1.64 - 1.77, 2.15 - 2.30, 3.12 - 3.20, 3.20 - 3.39, 3.74. Reference Example 5: 2-(1-hydroxycyclobutyl)ethyl methanesulfonate Diisopropylethylamine (0.4mL) and mesylic anhydride (329mg) were added to a solution of 1-(2-hydroxyethyl)cyclobutanol (CAS:83237-27-8) (200mg) in dichloromethane (2mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (335mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=2:1) Reference Example 6: Methyl (2S)-4-{[2-(1-hydroxycyclobutyl)ethyl]thio}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate Potassium carbonate (166 mg) and the compound prepared in Reference Example 5 (202 mg) were added to a solution of methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (200 mg) in DMF (4 mL), and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4) to give the title compound (236 mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=1:1) Reference Example 7: Methyl (2S)-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate To a solution of the compound (235 mg) produced in Reference Example 6 in methanol (5 mL), iodobenzene diacetate (132 mg) and ammonium carbamate (653 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5) to give the title compound (90 mg) having the following physical properties. TLC: Rf 0.2 (ethyl acetate) Reference Example 8: (2S)-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoic acid A solution (0.5 mL) of lithium hydroxide monohydrate (20 mg) was added to a solution (1 mL) of the compound (90 mg) produced in Reference Example 7 in THF at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (62 mg) having the following physical properties. HPLC retention time (min): 0.773 Example 2: (2S)-2-Amino-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}butanoic acid

[0167] [ka]

[0168] A 5N aqueous hydrochloric acid solution (1 mL) was added to the compound (62 mg) produced in Reference Example 8, and the mixture was stirred at room temperature for 1 hour. Water (1 mL) was added to the reaction solution, and the mixture was washed with ion exchange resin (trade name: DOWEX (H + The ninhydrin-reactive fraction was collected and concentrated to give the compound of the present disclosure (12 mg) having the following physical properties: MS(ESI,Pos.):265(M+H) + ; 1 H-NMR(D2O): δ 1.43 - 1.62, 1.63 - 1.77, 1.92 - 2.09, 2.20 - 2.36, 3.17 - 3.45, 3.79. Reference Example 9: Ethyl 3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutanoate Imidazole (439 mg) and tert-butyldimethylchlorosilane (632 mg) were added to a solution of ethyl 4,4,4-trifluoro-3-hydroxybutanoate (CAS: 372-30-5) (600 mg) in DMF (2 mL), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound having the following physical properties. TLC: Rf 0.8 (hexane:ethyl acetate=5:1) Reference Example 10: 3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluoro-1-butanol Lithium borohydride (140 mg) and methanol (0.52 mL) were added to a solution of the residue obtained in Reference Example 9 in THF (10 mL) under ice cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to give the title compound (510 mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Reference Example 11: 3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutyl methanesulfonate To a solution of the compound (200 mg) produced in Reference Example 10 in dichloromethane (2 mL), diisopropylethylamine (0.2 mL) and mesylic anhydride (162 mg) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (260 mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Reference Example 12: Methyl (2S)-4-[(3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutyl)thio]-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate Potassium carbonate (100 mg) and the compound prepared in Reference Example 11 (267 mg) were added to a solution of methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (180 mg) in DMF (8 mL), and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to give the title compound (350 mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Reference Example 13: Methyl (2S)-4-[S-(3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutyl)sulfonimidoyl]-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate To a solution of the compound (350 mg) produced in Reference Example 12 in methanol (5 mL), iodobenzene diacetate (690 mg) and ammonium carbamate (140 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (270 mg) having the following physical properties. TLC: Rf 0.5 (hexane:ethyl acetate=1:1) Reference Example 14: (2S)-4-[S-(3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutyl)sulfonimidoyl]-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoic acid A solution (1 mL) of lithium hydroxide monohydrate (44 mg) was added to a solution (2 mL) of the compound (270 mg) produced in Reference Example 13 in THF (2 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound (200 mg) having the following physical properties. HPLC retention time (min): 1.114 Example 3: (2S)-2-Amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoic acid

[0169] [ka]

[0170] A 5N aqueous hydrochloric acid solution (2 mL) was added to the compound (200 mg) produced in Reference Example 14 and stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction solution, and an ion exchange resin (trade name: DOWEX (H + The ninhydrin-reactive fraction was collected and concentrated to give the title compound of the present disclosure (47 mg) having the following physical properties: MS(ESI,Pos.):293(M+H) + ; 1 H-NMR(D2O): δ 1.95 - 2.07, 2.15 - 2.34, 3.25 - 3.46, 3.77 - 3.82, 4.17. Example 3-1: (2S)-2-amino-4-{S-[2-(1-fluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid

[0171] [ka]

[0172] The compound of the present disclosure (95 mg) having the following physical properties was obtained by carrying out the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3 using the corresponding methanesulfonate instead of the compound prepared in Reference Example 11. HPLC retention time (min): 0.596; MS(ESI,Pos.):267(M+H) + ; 1 H-NMR(D2O): δ 1.41 - 1.54, 1.67 - 1.81, 2.03 - 2.12, 2.14 - 2.34, 3.23 - 3.45, 3.75 - 3.85. Reference Example 15: 4,4,4-trifluoro-3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate Borane-THF complex (0.92M, 3.9mL) was added to a solution of 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (CAS: 338-03-4) (200mg) in THF (2mL) under ice cooling, and the mixture was stirred overnight at room temperature. Methanol was added to the reaction solution under ice cooling, and the mixture was concentrated under reduced pressure. Paratoluenesulfonyl chloride (266mg) was added to a solution of the obtained residue in pyridine (2mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (244mg) having the following physical properties. TLC: Rf 0.5 (hexane:ethyl acetate=3:1) Example 3-2: (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)sulfonimidoyl]butanoic acid

[0173] [ka]

[0174] The compound of the present disclosure (62 mg) having the following physical properties was obtained by carrying out the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3 using the compound prepared in Reference Example 15 instead of the compound prepared in Reference Example 11. HPLC retention time (min): 0.329; MS(ESI,Pos.):307(M+H) + ; 1 H-NMR(D2O): δ 1.32, 2.01 - 2.21, 2.24 - 2.34, 3.25 - 3.46, 3.76 - 3.84. Reference Example 16: 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl 4-methylbenzenesulfonate Paratoluenesulfonyl chloride (149 mg) was added to a pyridine (2 mL) solution of 4,4,4-trifluoro-3-(trifluoromethyl)-1,3-butanediol (CAS: 21379-33-9) (139 mg) and stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (244 mg) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Example 3-3: (2S)-2-amino-4-{S-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]sulfonimidoyl}butanoic acid

[0175] [ka]

[0176] The compound of the present disclosure (66 mg) having the following physical properties was obtained by carrying out the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3 using the compound prepared in Reference Example 16 instead of the compound prepared in Reference Example 11. HPLC retention time (min): 0.746; MS(ESI,Pos.):361(M+H) + ; 1 H-NMR(D2O): δ 2.20 - 2.39, 2.39 - 2.49, 3.27 - 3.52, 3.80. Example 3-4: (2S)-2-amino-4-[S-(3,3,4,4,4-pentafluorobutyl)sulfonimidoyl]butanoic acid

[0177] [ka]

[0178] Using the corresponding iodide (CAS: 40723-80-6) instead of the compound produced in Reference Example 11, the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3 were carried out to obtain the disclosed compound (110 mg) having the following physical properties. HPLC retention time (min): 0.637; MS(ESI,Pos.):313(M+H) + ; 1 H-NMR(D2O): δ 2.28, 2.58 - 2.80, 3.26 - 3.44, 3.44 - 3.62, 3.77. Reference Example 17: Benzyl (3R)-4,4,4-trifluoro-3-hydroxybutanoate Potassium carbonate (1.75 g) and benzyl bromide (826 mL) were added to a solution of (3R)-4,4,4-trifluoro-3-hydroxybutanoic acid (CAS: 108211-36-5) (1 g) in DMF (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.57 g) having the following physical properties. Reference Example 18: Benzyl (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butanoate Imidazole (861 mg) and TESCl (1.37 mL) were added to a solution of the residue (1.57 g) obtained in Reference Example 17 in DMF (8 mL), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (2.3 g) having the following physical properties. TLC: Rf 0.8 (hexane:ethyl acetate=5:1) Reference Example 19: (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]-1-butanol Lithium borohydride (276 mg) and methanol (1.0 mL) were added to a solution of the compound (2.3 g) obtained in Reference Example 18 in THF (20 mL) under ice cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (1.32 g) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=5:1) Reference Example 20: (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butyl methanesulfonate To a solution of the compound (1.32 g) produced in Reference Example 19 in dichloromethane (10 mL), diisopropylethylamine (1.3 mL) and mesylic anhydride (1 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.7 g) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=5:1) Reference Example 21: Methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-({(3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butyl}thio)butanoate Potassium carbonate (554 mg) and the compound prepared in Reference Example 20 (1.62 g) were added to a solution of methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (1 g) in DMF (15 mL), and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain the title compound (1.9 g) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=3:1) Reference Example 22: Methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-(S-{(3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butyl}sulfonimidoyl)butanoate To a solution of the compound (1.9 g) produced in Reference Example 21 in methanol (19 mL), iodobenzene diacetate (2.6 g) and ammonium carbamate (450 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (1.65 g) having the following physical properties. TLC: Rf 0.5 (hexane:ethyl acetate=1:1) Reference Example 23: Methyl (S)-4-((R,3R)-N-((benzyloxy)carbonyl)-4,4,4-trifluoro-3-((triethylsilyl)oxy)butylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate Pyridine (1.28 mL) and benzyl chloroformate (0.67 mL) were added to a solution of the compound (1.65 g) produced in Reference Example 22 in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3). The resulting compound was separated by SFC (condition E) to give the title compound (680 mg) having the following physical properties. HPLC retention time (min): 1.418 Reference Example 24: Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((R,3R)-4,4,4-trifluoro-3-((triethylsilyl)oxy)butylsulfonimidoyl)butanoate Palladium carbon (68 mg) was added to a solution of the compound (680 mg) produced in Reference Example 23 in methanol (8 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Ethyl acetate (8 mL) was added to the reaction solution, and the mixture was filtered through Celite (trade name) to obtain the title compound (540 mg) having the following physical properties. HPLC retention time (min): 1.202 Reference Example 25: (S)-2-((tert-butoxycarbonyl)amino)-4-((R,3R)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid A solution (1 mL) of lithium hydroxide monohydrate (78 mg) was added to a solution (2 mL) of the compound (540 mg) prepared in Reference Example 24 at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (360 mg) having the following physical properties. HPLC retention time (min): 0.792 Example 4: (S)-2-Amino-4-((R,3R)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid

[0179] [ka]

[0180] A 5N aqueous hydrochloric acid solution (3 mL) was added to the compound (360 mg) produced in Reference Example 25, and the mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the mixture was washed with ion exchange resin (trade name: DOWEX (H +The column was supported on a silica gel column (formula 1). After washing with a sufficient amount of water, it was eluted with 8% aqueous ammonia. The fractions reacting with ninhydrin were collected and concentrated to obtain the compound of the present disclosure (236 mg) having the following physical properties. MS(ESI,Pos.):293(M+H) + ; 1 H-NMR(D2O): δ 1.95 - 2.10, 2.16 - 2.36, 3.26 - 3.48, 3.75 - 3.82, 4.18. Reference Example 26: (3S)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butyl methanesulfonate Instead of (3R)-4,4,4-trifluoro-3-hydroxybutanoic acid, (3S)-4,4,4-trifluoro-3-hydroxybutanoic acid (CAS: 128899-79-6) was used, and the same operations as in Reference Example 17 → Reference Example 18 → Reference Example 19 → Reference Example 20 were carried out to obtain the title compound (1.78 g) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=5:1) Example 5: (S)-2-Amino-4-((R,3S)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid

[0181] [ka]

[0182] Using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 20, the same operations as in Reference Example 21 → Reference Example 22 → Reference Example 23 → Reference Example 24 → Reference Example 25 → Example 4 were carried out to obtain the title compound (185 mg) having the following physical properties. MS(ESI,Pos.):293(M+H) + ; 1 H-NMR(D2O): δ 1.95 - 2.07, 2.15 - 2.35, 3.25 - 3.46, 3.79, 4.17. Reference Example 27: Methyl (2S)-4-{[2-(1-hydroxycyclobutyl)ethyl]thio}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate Potassium carbonate (3.5 g) and 1-(2-bromoethyl)cyclobutanol (CAS: 1909309-61-0) (5 g) were added to a solution of methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (6.3 g) in DMF (100 mL), and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate and hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4) to give the title compound (8.7 g) having the following physical properties. TLC: Rf 0.3 (hexane:ethyl acetate=2:1) Reference Example 28: Methyl (2S)-4-{[2-(1-acetoxycyclobutyl)ethyl]thio}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate To a solution of the compound (8.7 g) produced in Reference Example 27 in dichloromethane (150 mL), diisopropylethylamine (10 mL), acetic anhydride (4.3 mL) and 4-dimethylaminopyridine (CAS: 1122-58-3) (610 mg) were added and stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain the title compound (9.35 g) having the following physical properties. TLC: Rf 0.6 (hexane:ethyl acetate=2:1) Reference Example 29: Methyl (2S)-4-{S-[2-(1-acetoxycyclobutyl)ethyl]sulfonimidoyl}-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate To a solution of the compound (9.35 g) produced in Reference Example 28 in methanol (100 mL), iodobenzene diacetate (16.2 g) and ammonium carbamate (2.8 g) were added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (8.35 g) having the following physical properties. TLC: Rf 0.5 (ethyl acetate) Reference Example 30: Methyl (S)-4-((R)-2-(1-acetoxycyclobutyl)-N-((benzyloxy)carbonyl)ethylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate Pyridine (1 mL) and benzyl chloroformate (0.25 mL) were added to a solution of the compound (500 mg) produced in Reference Example 29 in dichloromethane (4 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3). The resulting compound was separated by SFC (condition D) to give the title compound (250 mg) having the following physical properties. HPLC retention time (min): 1.208 Reference Example 31: Methyl (S)-4-((R)-2-(1-acetoxycyclobutyl)ethylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate Palladium carbon (25 mg) was added to a solution of the compound (250 mg) produced in Reference Example 30 in methanol (4 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Ethyl acetate (4 mL) was added to the reaction solution, and the mixture was filtered through Celite (trade name) to obtain the title compound (180 mg) having the following physical properties. HPLC retention time (min): 0.967 Reference Example 32: (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid A solution (1 mL) of lithium hydroxide monohydrate (54 mg) was added to a solution (2 mL) of the compound (180 mg) produced in Reference Example 31 in THF at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (156 mg) having the following physical properties. HPLC retention time (min): 0.837 Example 6: (S)-2-Amino-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid

[0183] [ka]

[0184] A 5N aqueous hydrochloric acid solution (2 mL) was added to the compound (156 mg) produced in Reference Example 32, and the mixture was stirred at room temperature for 2 hours. Water (2 mL) was added to the reaction solution, and the mixture was washed with ion exchange resin (trade name: DOWEX (H +The ninhydrin-reactive fraction was collected and concentrated to give the compound of the present disclosure (60 mg) having the following physical properties: MS(ESI,Pos.):265(M+H) + ; 1 H-NMR(D2O): δ 1.44 - 1.59, 1.62 - 1.77, 1.93 - 2.08, 2.21 - 2.34, 3.15 - 3.31, 3.31 - 3.44, 3.75 - 3.82. Reference Example 33: Methyl (S)-4-((S)-N-((benzyloxy)carbonyl)-4,4,4-trifluorobutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate Pyridine (1 mL) and benzyl chloroformate (0.17 mL) were added to a solution of methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate (215 mg) in dichloromethane (10 mL) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1). The resulting compound was separated by SFC (condition C) to give the title compound (87 mg) having the following physical properties. MS(ESI,Pos.):547(M+Na) + . Reference Example 34: Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoate Palladium carbon (35 mg) was added to a solution of the compound (79 mg) prepared in Reference Example 33 in methanol (4 mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Ethyl acetate (4 mL) was added to the reaction solution, which was then filtered through Celite and concentrated to give the title compound (60 mg) having the following physical properties. MS(ESI,Pos.):391(M+H) + . Reference Example 35: Methyl (S)-2-amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoate A 4N hydrochloric acid / ethyl acetate solution (1mL) was added to a methanol (1mL) solution of the compound (60mg) produced in Reference Example 34, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and then supported on an ion exchange resin (trade name: DOWEX (H+form)). After washing with a sufficient amount of methanol, it was eluted with a 2N ammonia / methanol solution. The fractions reacting with ninhydrin were collected and concentrated to obtain the title compound (39mg) having the following physical properties. MS(ESI,Pos.):291(M+H) + . Example 7: (S)-2-Amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoic acid

[0185] [ka]

[0186] Water (0.5 mL) was added to the compound (39 mg) produced in Reference Example 35, and the mixture was cooled to 0°C. 1N aqueous sodium hydroxide solution (0.14 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was then washed with ion exchange resin (trade name: DOWEX (NH4 + The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (33 mg) having the following physical properties: MS(ESI,Pos.):277(M+H) + ; 1 H-NMR(D2O): δ 1.98 - 2.06, 2.23 - 2.36, 3.23 - 3.41, 3.77. Reference Example 36: (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[(4,4,4-trifluorobutyl)thio]butanoic acid A solution (0.5 mL) of lithium hydroxide monohydrate (16 mg) was added to a solution (1 mL) of the compound (70 mg) produced in Reference Example 1 in THF at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with a 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (67 mg) having the following physical properties. HPLC retention time (min): 1.162 Reference Example 37: Ethyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[(4,4,4-trifluorobutyl)thio]butanoate To a solution of the compound (67 mg) produced in Reference Example 36 in dichloromethane (1 mL), ethanol (0.057 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (CAS: 25952-53-8) (56 mg) and 4-dimethylaminopyridine (CAS: 1122-58-3) (5 mg) were added and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain the title compound (57 mg) having the following physical properties. HPLC retention time (min): 1.288 Reference Example 38: Ethyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate To a solution of the compound (57 mg) produced in Reference Example 37 in methanol (3 mL), iodobenzene diacetate (123 mg) and ammonium carbamate (24 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:8) to obtain the title compound (61 mg) having the following physical properties. HPLC retention time (min): 1.05 Example 8: Ethyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate

[0187] [ka]

[0188] A 4N hydrochloric acid-dioxane solution (1 mL) was added to the compound (61 mg) produced in Reference Example 38, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by aminosilica gel column chromatography (ethyl acetate:methanol=2:1) ​​to obtain the disclosed compound (45 mg) having the following physical properties. MS(ESI,Pos.):305(M+H) + ; 1H-NMR(CDCl3): δ 1.24 - 1.33, 1.90, 1.94 - 2.07, 2.09 - 2.22, 2.22 - 2.38, 3.07 - 3.16, 3.16 - 3.32, 3.58, 4.21. Example 8-1: Isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate

[0189] [ka]

[0190] The same procedures as in Reference Example 37→Reference Example 38→Example 8 were carried out using 2-propanol instead of ethanol to give the compound of the present disclosure (43 mg) having the following physical properties. MS(ESI,Pos.):319(M+H) + ; 1 H-NMR (CDCl3): δ 1.27, 1.83 - 2.06, 2.09 - 2.22, 2.22 - 2.39, 3.11, 3.14 - 3.32, 3.53, 5.05. [Pharmacological Examples] In the following pharmacological examples, BSO (Toronto Research Chemicals) (CAS number: 83730-53-4) and compound number Ic ((2S)-2-Amino-4-[(2R,S)-2-carboxybutyl-(R,S)-sulfonimidoyl]butanoic acid) described in Non-Patent Document 2 were used as comparative examples, and these were designated as Comparative Example 1 and Comparative Example 2, respectively. [Pharmacological Example 1] Evaluation of GCL enzyme inhibitory activity (GCL-compound pre-incubation enzyme inhibitory activity evaluation system (substrate start)) Using an assay buffer containing 200mmol / L Tris-HCl (pH 8.0), 20mmol / L MgCl2, 150mmol / L KCl, and 0.1% BSA, recombinant human GCLC and recombinant human GCLM were mixed at a molar concentration ratio of 1:2, and allowed to stand at 37°C for 60 minutes to form a complex, which was used as a human GCL enzyme solution. Next, ATP was added to a human GCL enzyme complex solution equivalent to a final concentration of 5nmol / L GCLC at a final concentration of 0.2mmol / L, and each compound was added to a final concentration of 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30μmol / L. This human GCL enzyme complex-ATP-compound mixed solution was pre-incubated at room temperature for 60 minutes. Furthermore, the substrates L-glutamic acid (Nacalai Tesque) and L-cysteine ​​(Nacalai Tesque) were added to final concentrations of 1.2 and 0.2 mmol / L, respectively, to initiate the enzyme reaction. The recombinant human GCLC and recombinant human GCLM were His-tagged and expressed in E. coli, then purified using a nickel column and an anion exchange column. The enzyme reaction was carried out at room temperature using a 384-well polypropylene microplate, and the wells to which the enzyme was not added were used as the blank group.

[0191] One hour after the start of the enzyme reaction, a 1% formic acid solution containing 20 μmol / L ophthalmic acid as an internal standard was added to stop the enzyme reaction. The top of the enzyme reaction plate was sealed with aluminum and centrifuged at 560 g for 5 minutes at room temperature, after which the enzyme reaction product γ-glutamylcysteine ​​and the internal standard ophthalmic acid were quantified using a RapidFire-Mass Spectrometry system. The ratio of each quantitative value was calculated, and the average value of the blank group was set to 100% inhibition, and the average value of the compound-free group was set to 0% inhibition, to calculate the γ-glutamylcysteine ​​production inhibition rate at each compound concentration, and the IC 50 The value was calculated.

[0192] The compounds disclosed herein exhibited excellent GCL enzyme inhibitory activity. Table 1 shows the GCL enzyme inhibitory activity (IC 50 value).

[0193] In Non-Patent Document 2, it was reported that the compound shown as Comparative Example 2 had a binding affinity to E. coli GCLC that was approximately 500 times higher (Ki value ratio) than BSO, but in this assay system, it had the same inhibitory activity as BSO.

[0194] [Table 1]

[0195] In addition, the GCL enzyme inhibitory activity can also be evaluated by the following method. (GCL enzyme inhibitory activity evaluation system (enzyme start)) Using an assay buffer containing 200 mmol / L Tris-HCl (pH 8.0), 20 mmol / L MgCl2, 150 mmol / L KCl, and 0.1% BSA, recombinant human GCLC and recombinant human GCLM were mixed at a molar ratio of 1:2, and allowed to stand at 37°C for 60 minutes to form a complex, which was used as a human GCL enzyme solution. Next, ATP, L-glutamic acid and L-cysteine ​​as substrates were prepared to final concentrations of 0.2, 1.2 and 0.2 mmol / L, respectively, and each compound was added to a final concentration of 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 or 30 μmol / L. Next, the human GCL enzyme complex prepared in advance as described above was added to a concentration equivalent to a final concentration of 5 nmol / L GCLC, and the enzyme reaction was started. The recombinant human GCLC and recombinant human GCLM were His-tagged and expressed in E. coli and purified using a nickel column and an anion exchange column. The enzyme reaction was carried out at room temperature using a 384-well polypropylene microplate, and the wells to which the enzyme was not added were used as the blank group.

[0196] One hour after the start of the enzyme reaction, a 1% formic acid solution containing 20 μmol / L of ophthalmic acid as an internal standard was added to stop the enzyme reaction. The top of the enzyme reaction plate was sealed with aluminum and centrifuged at 560 g for 5 minutes at room temperature, after which the enzyme reaction product γ-glutamylcysteine ​​and the internal standard ophthalmic acid were quantified using a RapidFire-Mass Spectrometry system. The ratio of each quantitative value was calculated, and the average value of the blank group was set to 100% inhibition, and the average value of the compound-free group was set to 0% inhibition, to calculate the γ-glutamylcysteine ​​production inhibition rate at each compound concentration, and the IC 50 In this system as well, the compound of the present disclosure exhibited excellent GCL enzyme inhibitory activity. [Pharmacological Example 2] In vitro test (cell culture) Human ovarian cancer cell line TOV21G (hereafter referred to as cells) was purchased from ATCC. The cells were cultured in DMEM / Ham's F-12 containing 2 mmol / L L-Glutamine, 10% (vol%) FBS, and 1% (vol%) Penicillin-Streptomycin-Amphotericin B Suspension (hereafter referred to as 10%FBS-DMEM / Ham's F-12) at 37°C under 5% CO2 and 95% air conditions. [Pharmacological Example 2-1] In vitro GSH concentration measurement test (method) Cells were plated in flat-bottom 96-well plates at 2 x 10 3 After seeding at 100 μL / well, the cells were incubated overnight at 37°C, 5% CO2, and 95% air. The day after cell seeding, each compound was added to the cultured cells, and after 24 hours of culture at 37°C, 5% CO2, and 95% air, the GSH concentration was measured using GSH-Glo. TM Glutathione Assay (Promega) and ATP concentration were measured using CellTiter-Glo® Luminescent Cell Viability Assay (Promega). GSH concentration divided by ATP concentration was used as an alternative to cell number correction. Dose-response curves were created and IC 50 The value was calculated. (result) The IC of GCL inhibitory activity of each compound prepared in BSO (Comparative Example 1), Comparative Example 2, and Examples 1, 1-2, 2, 3, 8, and 8-1 50 The values ​​were 1.5, 1.3, 0.2, 0.2, 0.3, 0.1, 0.007 and 0.01 μmol / L, respectively. Comparative Example 2 had the same inhibitory activity as BSO, whereas the disclosed compound had improved GCL inhibitory activity in the cell line compared to BSO. For example, it was confirmed that the compounds produced in Example 1, Example 1-2, Example 1-5, Example 2, Example 3, Example 3-2, Example 3-3, Example 8 and Example 8-1 had improved GCL inhibitory activity by 7, 7, 3, 6, 14, 12, 10, 206 and 106 times, respectively, compared to the activity of BSO in the cell line. [Pharmacological Example 2-2] In vitro proliferation test (method) Cells were plated in flat-bottom 96-well plates at 2 x 10 3 After seeding at 100 μL / well, the cells were incubated overnight at 37°C, 5% CO2, and 95% air. The day after cell seeding, each compound was added to the cultured cells, and after 48 hours of culture at 37°C, 5% CO2, and 95% air, the ATP concentration was measured using CellTiter-Glo® Luminescent Cell Viability Assay (Promega). A dose-response curve was created and the IC 50 The value was calculated. (result) The IC of cell proliferation inhibition of BSO (Comparative Example 1) and each compound prepared in Example 1, Example 1-2, Example 2, Example 3, Example 8, and Example 8-1, respectively. 50 The values ​​were 4.8, 0.5, 0.6, 0.5, 0.2, 0.02 and 0.03 μmol / L, respectively, and it was confirmed that the proliferation inhibitory activity was improved by 11, 9, 11, 27, 292 and 166 times, respectively, compared with the activity of BSO in the cell lines.

[0197] Pharmacological Example 2-1 and Pharmacological Example 2-2 confirmed that the compounds of the present disclosure, typified by the compounds described in the above Pharmacological Examples, have improved activity in cell lines compared to BSO. [Pharmacological Example 3] In vivo test (cell culture) TOV21G cells, a human ovarian cancer cell line, were purchased from ATCC. The cells were cultured in 10% FBS-DMEM / Ham's F-12 at 37°C under 5% CO2 and 95% air conditions. (In vivo xenograft test) Female CB17 / Icr-Prkdc mice aged 7-8 weeks at the time of transplantation scid The cultured cells were mixed with equal amounts of Matrigel to prepare a cell suspension at the desired concentration, and 2.5 × 10 cells were injected subcutaneously into the right flank of the mouse. 6 Cells were transplanted at a rate of 0.1 mL / body. For individuals in which tumors were found, the long and short diameters of the tumors were measured with electronic calipers, and the tumor volume was calculated according to the following formula. Tumor volume (mm 3 ) = tumor long axis (mm) × (tumor short axis (mm)) 2 ×0.5 The compound was dissolved in water for injection and orally administered once a day using a sonde. (In vivo GSH concentration measurement test) The average tumor volume on the day before or on the day of compound administration was 140-180 mm 3 The mice were used in the experiment, and tumors were subjected to concentration measurement 24 hours after administration. After measuring the tumor weight, 10 times the amount of 5% 5-Sulfosalicylic acid was added, and the tumors were crushed with a homogenizer under ice cooling. The supernatant after centrifugation was used to measure GSH / GSSG-Glo. TM Total GSH concentration was measured using the Promega GSH Assay. Protein amounts in the supernatant were measured using the Pierce TM Quantification was performed using the BCA Protein Assay Kit and used for correction. [Pharmacological Example 3-1] Pharmacokinetic (PD) evaluation in a TOV21G cell subcutaneous transplantation model PD evaluation was performed using the amount of GSH in the tumor after a single administration as an index. The mice were divided into groups on the 19th day after subcutaneous implantation of TOV21G cells, and on the following day, BSO (Comparative Example 1) and the compound prepared in Example 2 were each orally administered in a single dose. The average tumor volume of each group at the time of grouping was 141 to 158 mm. 3The doses of BSO were 100, 300 and 750 mg / kg, and the compound prepared in Example 2 was 30, 100 and 300 mg / kg. The evaluation time point was 24 hours after a single administration (Figure 1). BSO dose-dependently reduced GSH in the tumor, and at the highest dose of 750 mg / kg, it reduced GSH to 21%. The compound prepared in Example 2 dose-dependently reduced GSH in the tumor, and at the highest dose of 300 mg / kg, it reduced GSH to 20% of the control.

[0198] Next, PD evaluation was performed on the compound produced in Example 3 using the amount of GSH in the tumor after a single administration as an index. 19 days after subcutaneous implantation of TOV21G, the mice were divided into groups, and three days later, the compound was orally administered in a single dose. The average tumor volume of each group on the day of administration was 141 to 177 mm. 3 The doses of the compound prepared in Example 3 were 30, 100 and 300 mg / kg, and the evaluation time point was 24 hours. In order to confirm the reproducibility and maximum effect of the compound prepared in Example 2, the compound was also evaluated 24 hours after administration of 300 mg / kg and 750 mg / kg. As a result, it was confirmed that the compound prepared in Example 3 reduced GSH in the tumor 24 hours after administration (Figure 2). The compound prepared in Example 2 was confirmed to have reproducibility, and was dose-responsive at 100 mg / kg and 300 mg / kg in the previous test, and was considered to have the maximum effect at 300 mg / kg based on the results of the current test.

[0199] From the above, it was confirmed that the doses showing the maximum effect were 750 mg / kg for BSO, 300 mg / kg for the compound prepared in Example 2, and 100 mg / kg for the compound prepared in Example 3, and that the compounds prepared in Examples 2 and 3 had in vivo activities that were approximately 3-fold and 7.5-fold higher than BSO in terms of dose ratio, respectively. [Pharmacological Example 3-2] Evaluation of antitumor effect in a TOV21G cell subcutaneous transplant model The in vivo antitumor effects of the compounds prepared in Examples 2 and 3 were evaluated. The average tumor volume of each group was 105 to 108 mm 3When the rats reached the age of 10, they were divided into groups, and each compound was orally administered once a day from the day of grouping until the day before the final observation day. The dose of BSO was 750 mg / kg, the dose of the compound prepared in Example 2 was 300 mg / kg, and the doses of the compounds prepared in Example 3 were 30 and 100 mg / kg. The final evaluation day of this test was Day 23.

[0200] The tumor volume of each group is shown in Figure 3. The average tumor volume of each group on day 23 was 819 mm in the vehicle group. 3 , 463 mm in the BSO 750 mg / kg group. 3 , Example 2 300 mg / kg group 396 mm 3 , Example 3 30 mg / kg group 453 mm 3 , Example 3 100 mg / kg group 414 mm 3 The mean tumor growth inhibition rate (TGI mean ) was 44%, whereas the TGI mean 52%, and TGI of the 30 mg / kg and 100 mg / kg groups in Example 3 mean From the above, it was confirmed that the doses showing the maximum effect were 750 mg / kg for BSO, 300 mg / kg for the compound prepared in Example 2, and 30 mg / kg for the compound prepared in Example 3, and that the compounds prepared in Examples 2 and 3 had in vivo activities that were approximately 3-fold and 25-fold higher than BSO in terms of dose ratio, respectively.

[0201] From the above, it was confirmed that the compounds of the present disclosure represented by Examples 2 and 3 have improved in vivo activity compared to BSO. [Formulation Examples] Formulation examples The following ingredients are mixed in a conventional manner and compressed into tablets to obtain approximately 10,000 tablets, each containing 10 mg of active ingredient. (2S)-2-Amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid ……100g Calcium carboxymethylcellulose (disintegrant) …… 20g Magnesium stearate (lubricant) …… 10g Microcrystalline cellulose ……870g [Industrial Applicability]

[0202] Since the disclosed compound has GCL inhibitory activity, a pharmaceutical comprising the disclosed compound as an active ingredient is useful as an agent for suppressing the progression, suppressing the recurrence and / or treating GCL-related diseases such as cancer.

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, R １ represents a hydrogen atom, a methyl group, or a hydroxyl group, R ２ is (1)-C(R ３ R ４ )-R ５ or (2) 1 to 9 R ６ represents a C3-C5 cycloalkyl group optionally substituted by R ３ Or R ４ each represents (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom, or (4) a methyl group which may be substituted by 1 to 3 halogen atoms, R ５ represents (1) a trifluoromethyl group or (2) a tert-butyl group; R ６ represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted with 1 to 3 halogen atoms; R ６ If there are multiple R ６ may be the same or different, R ７ represents a hydrogen atom or a C1-C4 alkyl group, n represents 0 or 1, or a salt thereof.

2. R ２ But (1)-C(R ３ R ４ )-CF ３ or (2) 1 to 4 R ６ The compound according to claim 1, which is a C4-C5 cycloalkyl group optionally substituted by, or a salt thereof.

3. R ２ but, 【Chemistry 2】 (wherein the symbols have the same meanings as in claim 1), or 【Chemistry 3】 (In the formula, m represents an integer of 1 to 3, p represents an integer of 0 to 3, R ６ａ represents (1) a hydroxyl group, (2) a halogen atom, or (3) a methyl group which may be substituted by 1 to 3 halogen atoms; when p is 2 or 3, a plurality of R ６ａ and may be the same or different. The compound or salt thereof according to claim 1 or 2,

4. R １ The compound or salt thereof according to any one of claims 1 to 3, wherein is a hydrogen atom and n is 1.

5. The compound represented by general formula (I) is represented by general formula (II-3) 【Chemistry 4】 (In the formula, R ２ａ teeth 【Chemistry 5】 (wherein the symbols have the same meanings as in claim 1), or 【Chemistry 6】 2. The compound according to claim 1, which is represented by the formula: (wherein the symbols have the same meanings as in claim 3, and the other symbols have the same meanings as in claim 1), or a salt thereof.

6. R ７ The compound or salt thereof according to any one of claims 1 to 5, wherein is a hydrogen atom, an ethyl group, or an isopropyl group.

7. The compound represented by the general formula (I) (1) (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid, (2) (2S)-2-amino-4-[S-(2-cyclopentylethyl)sulfonimidoyl]butanoic acid, (3) (2S)-2-amino-4-[S-(2-cyclobutylethyl)sulfonimidoyl]butanoic acid, (4) (2S)-2-amino-4-[S-(2-cyclopropylethyl)sulfonimidoyl]butanoic acid, (5) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-methylbutyl)sulfonimidoyl]butanoic acid, (6) (2S)-2-amino-4-{S-[2-(3,3-difluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (7) (2S)-2-amino-4-[S-(4,4-dimethylpentyl)sulfonimidoyl]butanoic acid, (8) (2S)-2-amino-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (9) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoic acid, (10) (2S)-2-amino-4-{S-[2-(1-fluorocyclobutyl)ethyl]sulfonimidoyl}butanoic acid, (11) (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)sulfonimidoyl]butanoic acid, (12) (2S)-2-amino-4-{S-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]sulfonimidoyl}butanoic acid, (13) (2S)-2-amino-4-[S-(3,3,4,4,4-pentafluorobutyl)sulfonimidoyl]butanoic acid, (14) (S)-2-amino-4-((R,3R)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid, (15) (S)-2-amino-4-((R,3S)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid, (16) (S)-2-amino-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid, (17) (S)-2-amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoic acid, (18) ethyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate, and (19) Isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate 2. The compound according to claim 1, which is a compound selected from the group consisting of:

8. A pharmaceutical composition comprising a compound represented by the formula (I) according to claim 1 or a salt thereof.

9. The pharmaceutical composition according to claim 8, which is a GCL inhibitor.

10. The pharmaceutical composition according to claim 8 or 9, which is an agent for suppressing the progression, suppressing the recurrence and / or treating cancer.

11. A method for inhibiting progression, suppressing recurrence and / or treating cancer, comprising administering an effective amount of the compound represented by the general formula (I) according to claim 1 or a salt thereof to a patient in need thereof.

12. 2. The compound represented by formula (I) according to claim 1 or a salt thereof for use in inhibiting the progression, inhibiting the recurrence and / or treating cancer.

13. 2. Use of a compound represented by formula (I) according to claim 1 or a salt thereof for producing an agent for inhibiting the progression, inhibiting the recurrence and / or treating cancer.

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