JP2024178481A - Glycolipid inhibitors - Google Patents

Abstract

[Problem] To provide a drug containing as an active ingredient a compound having GCL inhibitory activity in the inhibition of progression, inhibition of recurrence and/or treatment of GCL-related diseases such as cancer. [Solution] A compound represented by general formula (I) [Chemical 1] TIFF2024178481000054.tif3993 (wherein all symbols have the same meaning as the symbols in the specification), or a salt thereof, has GCL inhibitory activity and is therefore useful in the inhibition of progression, inhibition of recurrence and/or treatment of GCL-related diseases such as cancer. [Selected Figure] None

Description

The present disclosure relates to a compound or its salt having glutamate cysteine ligase (hereinafter referred to as "GCL") inhibitory activity, and a pharmaceutical composition containing the compound or its salt as an active ingredient. In more detail, the general formula (I):

(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 an active ingredient, etc.

GCL is the rate-limiting enzyme in the synthesis of glutathione (hereinafter referred to as "GSH") and is composed of a glutamate cysteine ligase catalytic subunit (hereinafter referred to as "GCLC") and a glutamate cysteine ligase modifying subunit (hereinafter referred to as "GCLM").

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).

L-buthionine sulfoximine (hereinafter referred to as BSO) is known as a GCLC inhibitor. In addition, there have been reports of BSO derivatives and low molecular weight compounds as GCLC inhibitors (Patent Document 2, Non-Patent Documents 2 to 4).

International Publication No. 2020/138385 International Publication No. 1989/009205

American Journal of Cancer Research, p. 2911, vol. 11, no. 6, 2021 (American Journal of Cancer Research, p. 2911, 11(6), 2021) Bioscience, Biotechnology, and Biochemistry 1500, 66(7), 2002 Bioorganic & Medicinal Chemistry 1935, 6, 1998 MOLECULAR PHARMACOLOGY 1140, 71, 2007

The objective of the present invention is to provide a compound that has inhibitory activity against GCL.

As a result of intensive research aimed at solving the above problems, the present inventors have found that a compound represented by the general formula (I) described below has inhibitory activity against GCL.

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):

(wherein R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group; R ² represents (1) -C(R ³ R ⁴ )-R ⁵ or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to 9 R ⁶ ; R ³ or R ⁴ each represents (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom or (4) a methyl group optionally substituted with 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 optionally substituted with 1 to 3 halogen atoms; when there are multiple R ^6s , the multiple R ^6s may be the same or different; 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 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.

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

1 shows the amount of GSH in the tumor 24 hours after administration of BSO and the compound prepared in Example 2. 1 shows 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. 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.

This disclosure is explained in detail below.

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

In the present disclosure, a methyl group that may be substituted with 1 to 3 halogen atoms is, for example, a methyl group that may be 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.

In this disclosure, C1 to C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl groups.

In this disclosure, C3-C5 cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl groups.

In this disclosure, C3-C4 cycloalkyl groups include cyclopropyl and cyclobutyl groups.

In the present disclosure, C4 to C5 cycloalkyl groups include cyclobutyl and cyclopentyl groups.
etc.

In the present disclosure, R ¹ is preferably a hydrogen atom.

In this disclosure, n is preferably 1.

In the present disclosure, R ⁵ is preferably a trifluoromethyl group.

In the present disclosure, R ² is preferably (1) -C(R ³ R ⁴ )-CF ₃ or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R ⁶ (the C3-C5 cycloalkyl group is preferably a C3-C4 cycloalkyl group or a C4-C5 cycloalkyl group, more preferably a cyclobutyl group).

In the present disclosure, ^R3 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.

In the present 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.

In the present 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.

In the present disclosure, a preferred embodiment of ^R2 is

(In the formula, the wavy line indicates the bonding position to the adjacent group (the bonding position to CH ₂ (CHR ¹ ) _n ), and the other symbols have the same meanings as above.)

In the present disclosure, a preferred embodiment of ^R2 is

(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 with 1 to 3 halogen atoms, and when p is 2 or 3, the multiple R ^6a's may be the same or different, and the other symbols have the same meanings as defined above.)

In the present disclosure, a preferred embodiment of ^R2 is

(where m-1 represents 1 or 2, and the other symbols have the same meanings as above), or

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

In the present disclosure, a preferred embodiment of ^R2 is

(In the formula, all symbols have the same meaning as above.)

In the present disclosure, R ^6a is preferably a halogen atom, a methyl group or a trifluoromethyl group, and more preferably a halogen atom.

In this disclosure, m is preferably 2.

In this disclosure, m-1 is preferably 2.

In this disclosure, m-2 is preferably 1.

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

In this disclosure, the compound represented by general formula (I) is preferably represented by general formula (I-1)

(wherein all symbols have the same meaning as above) is a compound represented by the formula:

In this disclosure, the compound represented by general formula (I) is preferably represented by general formula (I-2)

(wherein all symbols have the same meaning as above) is a compound represented by the formula:

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

(wherein all symbols have the same meaning as above) is a compound represented by the formula:

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

(wherein all symbols have the same meaning as above) is a compound represented by the formula:

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

(wherein the symbols have the same meanings as above) is a compound represented by the formula:

In the present disclosure, the compound represented by general formula (I) is preferably represented by general formula (II-3)

(Wherein, R ^2a is

(wherein the symbols have the same meanings as above), or

(wherein the symbols have the same meanings as above), and the other symbols have the same meanings as above. ) is a compound represented by the formula:

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

In the present disclosure, another embodiment of the compound represented by general formula (I) is most preferably a compound of the examples described in the examples below, or a salt thereof.

The disclosed compound has GCL inhibitory activity. In one embodiment, the GCL inhibitory activity in the present disclosure 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.

In one embodiment, the disclosed compound has excellent pharmacokinetics. Each pharmacokinetic parameter (AUC, CLtotal, T1/2 and/or BA, etc.) can be confirmed using a common measurement method.

In one embodiment, the disclosed compound has a stronger in vivo effect than BSO and is effective at a lower concentration than BSO. The in vivo effect (effectiveness, etc.) can be confirmed, for example, using a general measurement method, and can be measured, for example, by the method described in Pharmacological Example 3 below.

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 in double bonds, rings, and condensed rings (E, Z, cis, and trans isomers), isomers due to the presence of asymmetric carbons (R, S, α, β, enantiomers, and diastereomers), isomers due to the presence of sulfur atoms (asymmetric) in sulfoximine (R, S, enantiomers, and diastereomers), optically active isomers with optical rotation (D, L, d, and l isomers), 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.

In this disclosure, unless otherwise specified, symbols that are clear to those skilled in the art

indicates that it is bonded to the other side of the paper (i.e., α-configuration),

indicates that it is bonded to the front side of the paper (i.e., β-configuration),

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

The salt is preferably a pharma- ceutically acceptable salt.

The salt is preferably water-soluble.

Examples of pharma- ceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

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

Examples of alkali metal salts include potassium salts and sodium salts.

Examples of alkaline earth metal salts include calcium salts and magnesium salts.

Examples of ammonium salts include tetramethylammonium salts.

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

The disclosed compounds can be converted into N-oxides by any method. An N-oxide refers to a compound in which the nitrogen atom of a compound represented by general formula (I) or the like is oxidized.

The compounds represented by general formula (I) and their salts may exist in a non-solvated form or in a solvated form with a pharma- ceutically acceptable solvent such as water or ethanol. The solvates are preferably hydrates. The compounds represented by general formula (I) and their salts may be converted into solvates.

The compounds of formula (I) and the like can form co-crystals 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. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO2006/007448.

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 co-crystal 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 co-crystal thereof.
[Prodrug]
The prodrug of the compound represented by the general formula (I) etc. refers to a compound which is converted into the compound represented by the general formula (I) etc. by a reaction with an enzyme, gastric acid or the like in a living body. Examples of the prodrug of the compound represented by the general formula (I) etc. include, when the compound represented by the general formula (I) etc. 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 the compound represented by the general formula (I) etc. 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) etc. 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 the compound represented by the general formula (I) etc. has been acetylated, palmitoylated or propanoylated). yl, pivaloylated, succinylated, 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. 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 the general formula (I) etc. may be one which is converted into the compound represented by the general formula (I) under physiological conditions, as described in "Drug Development", Vol. 7, "Molecular Design", pp. 163-198, published by Hirokawa Shoten in 1990.

Furthermore, each atom constituting the compound represented by general formula (I) etc. may be substituted with its isotope (e.g., ^2H , ^3H , ^11C , ^{13C , 14C , 15N} , 16N, 17O, ^18O , ^18F , ^35S , ^36Cl , ^77Br , ^125I , etc.).
[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.

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

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

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

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), etc.

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 reaction by hydrogenolysis;
(4) deprotection reaction of the silyl group,
(5) Deprotection reaction using a metal,
(6) Deprotection reaction using a metal complex, etc.

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.

(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.

(3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., ethers (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (DMF), etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under normal or elevated pressure in a hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C.

(4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. It is also carried out, for example, 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.

(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, with ultrasonication if necessary.

(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 mixture 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.

The compound represented by general formula (I) can be produced by reaction scheme 1.

(In reaction scheme 1, PG represents an amino-protecting group, X represents a leaving group, CO ₂ Me 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.

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.

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

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

In each reaction in this 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 combining publicly known methods, such as 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 that are partially modified from publicly known methods.

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 disclosed herein, or by optically resolving a racemic compound disclosed herein.

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

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

In each reaction in this specification, a solid-phase supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

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 compound of the present disclosure has an inhibitory activity against GCL, it can be prescribed as an effective agent for suppressing the progression or recurrence or for treating diseases associated with GCL (GCL-associated diseases), such as cancer.

Cancers that the disclosed compounds are intended to inhibit progression, inhibit recurrence and/or treat include any solid cancer and blood cancer, but examples include ARID1A-deficient cancers and/or cancers sensitive to GCL (GCL-sensitive cancers).

As used herein, ARID1A deficiency refers to an ARID1A gene deficiency or ARID1A protein deficiency caused by an ARID1A gene mutation. ARID1A-deficient cancer refers to a cancer having an ARID1A deficiency. Examples of ARID1A-deficient cancers 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.

Examples of GCL-sensitive cancers include acute myeloid leukemia and B-cell lymphoma.

In this specification, "cancer treatment" includes, for example, treatments performed to (a) reduce the proliferation of cancer cells, (b) reduce symptoms caused by cancer and 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 related to cancer, and reversing the progression of symptoms. "Suppression of recurrence" means preventively suppressing cancer recurrence in patients in whom cancer lesions have completely or substantially disappeared or been removed by cancer treatment or surgical resection.

To use the disclosed compound for the purpose of inhibiting the progression, inhibiting recurrence, and/or treating the above-mentioned disease, the substance, which is the active ingredient, is usually formulated 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 pharmaceuticals. A pharma- ceutically acceptable carrier is preferably one that does not exhibit pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, a 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" published by Yakuji Nipposha in 2000 (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.

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, mouthwashes, 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., solids for external use, liquids for external use, sprays, ointments, creams, gels, patches, etc.).

[Concomitant 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, the dosage form when formulated in combination with other drugs (e.g., other anticancer drugs) may be a combination drug form in which both components are formulated in one formulation, or may be an administration form as separate formulations. 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 types 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 the like or the combination of the disclosed compounds and other drugs for the above purpose, they are usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, 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.

The disclosed compounds are administered to a mammal (preferably a human, more preferably a human patient) in a pharma- tically effective amount.

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 of the present invention.

In addition, the contents of all patent and non-patent literature or references explicitly cited in this specification may be incorporated herein by reference.

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

(Wherein,
R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group;
^R2 represents (1) -C( ^R3R4 ) ^-R5 or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to ^{9 R6s} ;
^R3 and ^R4 each represent (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom, or (4) a methyl group optionally substituted with 1 to 3 halogen atoms;
^R5 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 by 1 to 3 halogen atoms, and when there are a plurality of R ^6s , the plurality of R ^6s may be the same or different;
^R7 represents a hydrogen atom or a C1-C4 alkyl group;
n represents 0 or 1; or a salt thereof,
[2] The compound according to the above [1], wherein R ² is (1) -C(R ³ R ⁴ )-CF ₃ or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to 4 R ⁶ (preferably a cyclobutyl group optionally substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R ⁶ ), or a salt thereof.
[3] The compound or salt thereof according to the above [1] or [2], wherein ^R3 is a hydrogen atom, a halogen atom or a hydroxyl group (more preferably a hydrogen atom or a hydroxyl group).
[4] The compound or salt thereof according to any one of the above [1] to [3], wherein 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] ^R2 is,

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

(wherein m represents an integer of 1 to 3, p represents an integer of 0 to 3 (preferably 0 to 2), 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, and when p is 2 or 3, a plurality of R ^6a may be the same or different from each other), or a salt thereof according to the above [1] or [2].
[6] ^R2 is,

(wherein the symbols have the same meanings as in the above [1]), or a salt thereof,
[7] The compound or salt thereof according to any one of the above [1] to [6], wherein 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] ^R2 is,

(wherein the symbols have the same meanings as in the above [5]), or a salt thereof,
[9] The compound or salt thereof according to the above [5] or [8], wherein R ^6a is a halogen atom, a methyl group or a trifluoromethyl group (more preferably a halogen atom).
[10] The compound or salt thereof according to the above [5], [8] or [9], 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] The compound or salt thereof according to any one of the above [1] to [11], wherein R ¹ is a hydrogen atom.
[13] The compound represented by general formula (I) is represented by general formula (II-3)

(Wherein, R ^2a is

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

(wherein the symbols have the same meanings as in the above [5]), and the other symbols have the same meanings as in the above [1]),
[14] The compound or salt thereof according to the above [13], wherein 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] The compound or salt thereof according to the above [13], wherein R ^6a is a halogen atom, a methyl group or a trifluoromethyl group (more preferably a halogen atom), and p is 0 or 1.
[16] The compound or salt thereof according to any one of the above [1] to [15], wherein 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) the compound according to the above-mentioned [1], which is a compound selected from the group consisting of 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, or a salt thereof.
[18] A pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof according to [1] above.
[19] The pharmaceutical composition according to the above [18], which is a GCL inhibitor.
[20] The pharmaceutical composition according to the above [18] or [19], which is an agent for inhibiting the progression, inhibiting the 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 the above [1], which is used for inhibiting the progression, inhibiting recurrence and/or treating cancer, and
[23] Use of the compound represented by the general formula (I) or a salt thereof described in the above [1] for the manufacture of an agent for inhibiting the progression, inhibiting the recurrence and/or treating cancer.

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.

The solvent in parentheses in the NMR section indicates the solvent used in the measurement.

The compound names used in this specification were created using ACD/Name (registered trademark), a computer program that generally performs naming according to IUPAC rules, or ChemDraw Professional (Version 18.0, PerkinElmer), or in accordance with the IUPAC nomenclature system.

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 I.D.); Flow rate: 1.0 mL/min; Column temperature: 30°C; Mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; Mobile phase (B): 0.1% TFA-acetonitrile solution; Gradient (ratio of mobile phase (A): mobile phase (B) is described): [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 ^10-6 m, column length: 30 x 2.0 mm I.D.); Flow rate: 1.0 mL/min; Column temperature: 30°C; Mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; Mobile phase (B): 0.1% TFA-acetonitrile solution; Gradient (ratio of mobile phase (A): mobile phase (B) is described): [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.

HPLC retention times are shown under condition A for synthetic intermediates and under condition B for the disclosed compounds.

SFC separation was performed under one of the following conditions:
Condition C; Column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250 x 20 mm I.D.); flow rate: 100 mL/min; column temperature: 35° C.; pressure: 120 bar; mobile phase (A): CO ₂ ; 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: 250 x 20 mm I.D.); flow rate: 100 mL/min; column temperature: 35° C.; pressure: 120 bar; mobile phase (A): CO ₂ ; 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: 250 x 20 mm I.D.); flow rate: 100 mL/min; column temperature: 35° C.; pressure: 120 bar; mobile phase (A): CO ₂ ; 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
To a solution of the compound (820 mg) prepared in Reference Example 2 in THF (6 mL), an aqueous solution (3 mL) of lithium hydroxide monohydrate (176 mg) was added 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

5N aqueous hydrochloric acid (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 the mixture was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, the resin was eluted with 8% aqueous ammonia. The fractions reacting with ninhydrin were collected and concentrated to obtain the compound of the present disclosure (473 mg) having the following physical properties.
MS (ESI, Pos.): 293 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): δ 2.02, 2.20 - 2.38, 3.23 - 3.43, 3.77.
Examples 1-1 to 1-4
The same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 were carried out using the corresponding methanesulfonate instead of 4,4,4-trifluorobutyl methanesulfonate to obtain the presently disclosed compound having the following physical properties.
Example 1-1: (2S)-2-amino-4-[S-(2-cyclopentylethyl)sulfonimidoyl]butanoic acid

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) ⁺ ;
^1H -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

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) ⁺ ;
^1H -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

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 (D ₂ O): 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

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 (0.38 mL) and mesylic anhydride (281 mg) were added to a solution of 2-(3,3-difluorocyclobutyl)ethanol (CAS: 1056467-54-9) (200 mg) in dichloromethane (2 mL) 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 mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (314 mg) 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

The compound of the present disclosure (61 mg) having the following physical properties was obtained by carrying out the same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1 using the compound prepared in Reference Example 4 instead of 4,4,4-trifluorobutyl methanesulfonate.
HPLC retention time (min): 0.523;
MS (ESI, Pos.): 285 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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

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) ⁺ ;
^1H -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 (0.4 mL) and mesylic anhydride (329 mg) were added to a solution of 1-(2-hydroxyethyl)cyclobutanol (CAS: 83237-27-8) (200 mg) in dichloromethane (2 mL) 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 give the title compound (335 mg) 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
To a solution of the compound (90 mg) prepared in Reference Example 7 in THF (1 mL), an aqueous solution (0.5 mL) of lithium hydroxide monohydrate (20 mg) was added 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

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 supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, the resin was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to obtain the compound of the present disclosure (12 mg) having the following physical properties.
MS (ESI, Pos.): 265 (M+H) ⁺ ;
^1H -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) prepared 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 give 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
To a solution of the compound (270 mg) prepared in Reference Example 13 in THF (2 mL), an aqueous solution (1 mL) of lithium hydroxide monohydrate (44 mg) was added 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

5N aqueous hydrochloric acid (2 mL) was added to the compound (200 mg) produced in Reference Example 14, and the mixture was stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction solution, and the mixture was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, the resin was eluted with 8% aqueous ammonia. The fractions reacting with ninhydrin were collected and concentrated to obtain the subject compound of the present disclosure (47 mg) having the following physical properties.
MS (ESI, Pos.): 293 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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

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) ⁺ ;
^1H -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 ammonium chloride solution 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

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) ⁺ ;
^1H -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
To a solution of 4,4,4-trifluoro-3-(trifluoromethyl)-1,3-butanediol (CAS: 21379-33-9) (139 mg) in pyridine (2 mL), paratoluenesulfonyl chloride (149 mg) was added 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 give 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

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 (D ₂ O): 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

The compound of the present disclosure (110 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 iodide (CAS: 40723-80-6) instead of the compound produced in Reference Example 11.
HPLC retention time (min): 0.637;
MS (ESI, Pos.): 313 (M+H) ⁺ ;
^1H -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 then concentrated under reduced pressure. The resulting residue 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 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 (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 give 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 give 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 obtain 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) prepared 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 mixture, 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
To a solution of the compound (540 mg) prepared in Reference Example 24 in THF (2 mL), an aqueous solution (1 mL) of lithium hydroxide monohydrate (78 mg) was added 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 give 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

5N aqueous hydrochloric acid (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 supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, the mixture 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 (D ₂ O): 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 to carry out the same operations as in Reference Example 17 → Reference Example 18 → Reference Example 19 → Reference Example 20 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

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) ⁺ ;
^1H -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 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 (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 give 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 obtain 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) prepared 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
To a solution of the compound (180 mg) prepared in Reference Example 31 in THF (2 mL), an aqueous solution (1 mL) of lithium hydroxide monohydrate (54 mg) was added 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

5N aqueous hydrochloric acid (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 supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, the resin was eluted with 8% aqueous ammonia. The fractions reacting with ninhydrin were collected and concentrated to obtain the compound of the present disclosure (60 mg) having the following physical properties.
MS (ESI, Pos.): 265 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 mixture, 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 (1 mL) was added to a methanol (1 mL) solution of the compound (60 mg) 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, the resin was eluted with a 2N ammonia/methanol solution. The fractions reacting with ninhydrin were collected and concentrated to give the title compound (39 mg) having the following physical properties.
MS (ESI, Pos.): 291 (M+H) ⁺ .
Example 7: (S)-2-amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoic acid

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 solution, and the mixture was stirred for 30 minutes. The reaction solution was supported on an ion exchange resin (trade name: DOWEX (NH4 ⁺ form)) and eluted with a sufficient amount of water. The fractions reacting with ninhydrin were collected and concentrated to obtain the compound of the present disclosure (33 mg) having the following physical properties.
MS (ESI, Pos.): 277 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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) prepared 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 hydrogen carbonate 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 give 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 give 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

A 4N hydrochloric acid-dioxane solution (1 mL) was added to the compound (61 mg) prepared 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 give 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

The same operations as in Reference Example 37→Reference Example 38→Example 8 were carried out using 2-propanol instead of ethanol to give the presently disclosed compound (43 mg) having the following physical properties.
MS (ESI, Pos.): 319 (M+H) ⁺ ;
^1H -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 were designated as Comparative Example 1 and Comparative Example 2, respectively.
[Pharmacological Example 1] Evaluation of GCL enzyme inhibitory activity
(GCL-compound preincubation enzyme inhibitory activity evaluation system (substrate start))
Using an assay buffer containing 200 mmol/L Tris-HCl (pH 8.0), 20 mmol/L MgCl ₂ , 150 mmol/L KCl, and 0.1% BSA, recombinant human GCLC and recombinant human GCLM were mixed at a molar concentration ratio of 1:2, and the mixture was 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 corresponding to a final concentration of 5 nmol/L GCLC at a final concentration of 0.2 mmol/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 30 μmol/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 Escherichia coli and 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 wells to which no enzyme was added were used as the blank group.

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 the plate was 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 the respective quantitative values 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 value was obtained.

The compounds of the present disclosure exhibited excellent GCL enzyme inhibitory activity. Table 1 shows the GCL enzyme inhibitory activity ( _IC50 value) of the compounds shown in each Example as representative examples of the compounds of the present disclosure.

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

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 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, substrates L-glutamic acid, and L-cysteine 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 final concentration equivalent to 5 nmol/L GCLC to initiate the enzyme reaction. The recombinant human GCLC and recombinant human GCLM were His-tagged and expressed in E. coli and 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.

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 the plate was 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 the respective quantified values 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 value was obtained. In this system, the compound of the present disclosure also showed excellent GCL enzyme inhibitory activity.
[Pharmacological Example 2] In vitro test
(Cell Culture)
Human ovarian cancer cell line TOV21G (hereinafter 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 (hereinafter referred to as 10% FBS-DMEM/Ham's F-12) under conditions of 37°C, 5% _CO2 , and 95% air.
[Pharmacological Example 2-1] In vitro GSH concentration measurement test
(method)
The cells were seeded in a flat-bottom 96-well plate at 2 x ¹⁰³ cells/100 μL/well and then 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 the GSH-Glo ^™ Glutathione Assay (Promega) and the ATP concentration was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). As an alternative to cell number correction, the value obtained by dividing the GSH concentration by the ATP concentration was used. A dose-response curve was created and the _IC50 value was calculated.
(result)
The IC ₅₀ values of the GCL inhibitory activity of each compound produced in BSO (Comparative Example 1), Comparative Example 2, and Examples 1, 1-2, 2, 3, 8, and 8-1 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 an inhibitory activity equivalent to that of BSO, whereas the compound of the present disclosure had an improved GCL inhibitory activity in a cell line compared to BSO. For example, it was confirmed that each compound produced in Examples 1, 1-2, 1-5, 2, 3, 3-2, 3-3, 8, and 8-1 had an improved GCL inhibitory activity of 7, 7, 3, 6, 14, 12, 10, 206, and 106 times, respectively, compared to the activity of BSO in a cell line.
[Pharmacological Example 2-2] In vitro proliferation test
(method)
The cells were seeded in a flat-bottom 96-well plate at 2 x ¹⁰³ cells/100 μL/well and then incubated overnight at 37°C, 5% _CO2 and 95% air. On 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 (registered trademark) Luminescent Cell Viability Assay (Promega). A dose-response curve was created and the _IC50 value was calculated.
(result)
The _IC50 values of cell proliferation inhibition of BSO (Comparative Example 1) and the compounds prepared in Examples 1, 1-2, 2, 3, 8 and 8-1 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 line.

From Pharmacological Example 2-1 and Pharmacological Example 2-2, it was confirmed that the compounds of the present disclosure typified by the compounds described in the above Pharmacological Examples are compounds having 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 under conditions of 37° C., 5% CO ₂ and 95% air.
In vivo xenograft testing
Female CB17/Icr-Prkdc ^scid /CrlCrlj mice aged 7-8 weeks at the time of transplantation were used in the experiment. Cultured cells were mixed with equal amounts of Matrigel to prepare a cell suspension at the desired concentration, and 2.5 x 10 ⁶ cells/0.1 mL/body of cells were transplanted subcutaneously into the right flank of the mouse. For individuals with tumors, 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 )=longest axis of tumor (mm)×(shortest axis of tumor (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)
Mice with an average tumor volume of 140-180 ^mm3 on the day before or on the day of compound administration were used in the experiment, and tumors 24 hours after administration were subjected to concentration measurement. 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 the total GSH concentration using GSH/GSSG-Glo ^™ Assay (Promega). The amount of protein in the supernatant was quantified using Pierce ^™ 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. Grouping was performed 19 days 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 ^mm3 . The 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 the 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%. For the compound prepared in Example 2, GSH in the tumor was dose-dependently reduced, and at the highest dose of 300 mg/kg, it reduced GSH to 20% of the control.

Next, the compound produced in Example 3 was subjected to PD evaluation using the amount of GSH in the tumor after a single administration as an index. Grouping was performed on the 19th day after subcutaneous implantation of TOV21G, and the compound was orally administered once 3 days later. The average tumor volume of each group on the day of administration was 141-177 ^mm3 . The doses of the compound produced in Example 3 were 30, 100, and 300 mg/kg, and the evaluation time point was 24 hours. In addition, in order to confirm the reproducibility and maximum effect of the compound produced 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 produced in Example 3 reduced GSH in the tumor 24 hours after administration (Figure 2). The compound produced in Example 2 was confirmed to be reproducible, and it was found to have dose-responsiveness at 100 mg/kg and 300 mg/kg in the previous test, and it was considered to show maximum effect at 300 mg/kg based on the results of the current test.

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 approximately 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 transplantation model
The in vivo antitumor effects of each compound prepared in Example 2 and Example 3 were evaluated. When the average tumor volume of each group reached 105-108 ^mm3, the animals 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.

The tumor volume of each group is shown in Figure 3. The average tumor volume of each group on Day 23 was 819 mm ³ in the vehicle group, 463 mm ³ in the BSO 750 mg/kg group, 396 mm ³ in the Example 2 300 mg/kg group, 453 mm ³ in the Example 3 30 mg/kg group, and 414 mm ³ in the Example 3 100 mg/kg group. The average tumor growth inhibition rate (TGI _mean ) of the BSO 750 mg/kg group was 44%, while the TGI _mean of the Example 2 300 mg/kg group was 52%, and the TGI _mean of the Example 3 30 mg/kg group and the 100 mg/kg group were 45% and 49%, respectively. 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 approximately 25-fold higher than BSO in terms of dose ratio, respectively.

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 give approximately 10,000 tablets, each containing 10 mg of active ingredient.
(2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid ... 100g
・Carboxymethylcellulose calcium (disintegrant) …… 20g
・Magnesium stearate (lubricant) …… 10g
・Microcrystalline cellulose...870g

Since the disclosed compound has GCL inhibitory activity, pharmaceuticals containing the disclosed compound as an active ingredient are useful as agents for inhibiting the progression, inhibiting recurrence, and/or treating GCL-related diseases such as cancer.

Claims (13)

General formula (I)

(Wherein,
R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group;
^R2 represents (1) -C( ^R3R4 ) ^-R5 or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to ^{9 R6s} ;
^R3 and ^R4 each represent (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom, or (4) a methyl group optionally substituted with 1 to 3 halogen atoms;
^R5 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 by 1 to 3 halogen atoms, and when there are a plurality of R ^6s , the plurality of R ^6s may be the same or different;
^R7 represents a hydrogen atom or a C1-C4 alkyl group;
n represents 0 or 1, or a salt thereof. The compound according to claim 1, wherein R ² is (1) --C(R ³ R ⁴ )--CF ₃ or (2) a C4-C5 cycloalkyl group optionally substituted with 1 to 4 R ⁶ , or a salt thereof. ^R2 is

(wherein the symbols have the same meanings as in claim 1), or

(wherein 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 with 1 to 3 halogen atoms, and when p is 2 or 3, the multiple R ^6a's may be the same or different from each other), or a salt thereof according to claim 1 or 2. The compound or salt thereof according to any one of claims 1 to 3, wherein R ¹ is a hydrogen atom and n is 1. The compound represented by general formula (I) is represented by general formula (II-3)

(Wherein, R ^2a is

(wherein the symbols have the same meanings as in claim 1), or

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. The compound or salt thereof according to any one of claims 1 to 5, wherein R ⁷ is a hydrogen atom, an ethyl group, or an isopropyl group. 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,
The compound according to claim 1, which is a compound selected from the group consisting of (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, or a salt thereof. A pharmaceutical composition containing a compound represented by general formula (I) or a salt thereof according to claim 1. The pharmaceutical composition according to claim 8, which is a GCL inhibitor. The pharmaceutical composition according to claim 8 or 9, which is an agent for inhibiting the progression, inhibiting recurrence and/or treating cancer. A method for inhibiting progression, suppressing recurrence and/or treating cancer, comprising administering an effective amount of a compound represented by general formula (I) or a salt thereof according to claim 1 to a patient in need of such treatment. A compound represented by general formula (I) or a salt thereof according to claim 1, for use in the inhibition of progression, inhibition of recurrence and/or treatment of cancer. Use of a compound represented by general formula (I) or a salt thereof according to claim 1 for the manufacture of an agent for inhibiting progression, inhibiting recurrence and/or treating cancer.

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