WO2023085367A1 - Gcl inhibitor - Google Patents

Abstract

Provided is a compound having a GCL inhibitory activity.　A compound represented by general formula (I) (all symbols in the formula are as defined in the description) or a salt thereof has GCL inhibitory activity, and therefore is useful for inhibiting progression, inhibiting reoccurrence, and/or treatment of GCL-related diseases such as cancer.

Description

GCL inhibitor

The present disclosure relates to compounds having glutamic acid cysteine ligase (hereinafter referred to as "GCL") inhibitory activity or salts thereof, pharmaceutical compositions containing them as active ingredients, and the like. Specifically, the general formula (I):

(In the formula, all symbols have the same meanings as described below.)
or a salt thereof (hereinafter referred to as the compound of the present disclosure) and pharmaceutical compositions containing them as active ingredients.

GCL is composed of a glutamate-cysteine ligase catalytic subunit (hereinafter referred to as "GCLC") and a glutamate-cysteine ligase modification subunit (hereinafter referred to as "GCLM") for glutathione (hereinafter referred to as "GSH") synthesis. is the rate-limiting enzyme of
A relationship between this enzyme and cancer has been reported. For example, it has been reported that a GCLC inhibitor is useful for the treatment of ARID1A-deficient cancer (Patent Document 1), and that knocking out GCLC inhibits acute myeloid leukemia (AML) tumor growth. (Non-Patent Document 1).
L-buthionine sulfoximine (hereinafter referred to as BSO) is known as a GCLC inhibitor. In addition, there are reports on BSO derivatives and low-molecular-weight compounds as GCLC inhibitors (Patent Document 2, Non-Patent Documents 2 to 4).

WO 2020/138385 pamphlet WO 1989/009205 pamphlet

American Journal of Cancer Research, 2911, Vol. 11, No. 6, 2021 (American Journal of Cancer Research, 2911, 11(6), 2021) Bioscience, Biotechnology, and Biochemistry, 1500 pages, Vol. 66, No. 7, 2002 (Bioscience, Biotechnology, and Biochemistry 1500, 66(7), 2002) Bioorganic & Medicinal Chemistry, 1935, Vol. 6, 1998 (Bioorganic & Medicinal Chemistry 1935, 6, 1998) Molecular Pharmacology, pp. 1140, Vol. 71, 2007 (MOLECULAR PHARMACOLOGY 1140, 71, 2007)

An object of the present invention is to provide compounds having inhibitory activity against GCL.

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

That is, the present disclosure provides, in one aspect,
[1] General formula (I):

(wherein R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group, and R ² is (1) —CR ³ R ⁴ —R ⁵ or (2) substituted with 1 to 9 R ⁶ represents a C3-C5 cycloalkyl group, wherein R ³ or R ⁴ is (1) a hydrogen atom, (2) a hydroxyl group, (3) a halogen atom or (4) 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 ) represents a methyl group optionally substituted with 1 to 3 halogen atoms, and when R ⁶ is plural, the plural R ⁶ may be the same or different, and R ⁷ is a hydrogen atom or C1- represents a C4 alkyl group, and n represents 0 or 1.) or a salt thereof,
[2] A pharmaceutical composition containing the compound represented by the general formula (I) or a salt thereof according to [1] above,
[3] Provide an embodiment of the pharmaceutical composition according to [2] above, which is a GCL inhibitor.

Since the compound of the present disclosure has an inhibitory activity against GCL, it can be used as an active ingredient for suppressing progression, suppressing recurrence and/or treating diseases related to GCL (GCL-related diseases) such as cancer.

24 shows tumor GSH levels 24 hours after administration of BSO and the compound prepared in Example 2. FIG. 24 shows tumor GSH levels 24 hours after administration of BSO and each of the compounds prepared in Examples 2 and 3. FIG. 3 shows changes in tumor volume in each group after administration of BSO and each compound prepared in Examples 2 and 3. FIG. The drug concentration in plasma after administration of BSO and each compound prepared in Example 2, Example 3, Example 3-3, Example 4 and Example 5, respectively, is shown.

The present disclosure will be described in detail below.

In the present disclosure, halogen atoms include fluorine, chlorine, bromine and iodine atoms and the like. A fluorine or chlorine atom is preferred, and a fluorine atom is more preferred.
In the present disclosure, a methyl group optionally substituted with 1 to 3 halogen atoms is, for example, a methyl group optionally substituted with 1, 2 or 3 halogen atoms, specifically includes a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group and a trifluoromethyl group.

In this disclosure, C1-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 this disclosure, C4-C5 cycloalkyl groups include cyclobutyl and cyclopentyl groups.
etc.

In the present disclosure, R ¹ is preferably a hydrogen atom.
In the present 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) —CR ³ R ⁴ —R ⁵ or (2) substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R ⁶ (C3-C5 cycloalkyl group is preferably C3-C4 cycloalkyl group or C4-C5 cycloalkyl group, more preferably cyclobutyl group).
In the present disclosure, R ³ is preferably a hydrogen atom, a halogen atom or a hydroxyl group, more preferably a hydrogen atom or a hydroxyl group, still 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, more preferably a hydrogen atom, a methyl group or a trifluoromethyl group.
In the present disclosure, ^R6 is preferably a hydroxyl group, a halogen atom, a methyl group or a trifluoromethyl group, more preferably a hydroxyl group or a halogen atom.

In the present disclosure, one preferred embodiment for R ² is

(In the formula, the wavy line indicates the bonding position with the adjacent group (the bonding position with CH ₂ (CHR ¹ ) _n ), and the other symbols have the same meanings as above.).
In the present disclosure, one preferred embodiment for R ² is

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

In the present disclosure, one preferred embodiment for R ² is

(Wherein, m−1 represents 1 or 2, and other symbols have the same meanings as above.), or

(In the formula, m-2 represents 1 or 2, and other symbols have the same meanings as above.).
In the present disclosure, one preferred embodiment for R ² is

(wherein all symbols have the same meanings as above).

In the present disclosure, R ^6a is preferably a halogen atom, a methyl group or a trifluoromethyl group, more preferably a halogen atom.
In the present disclosure, m is preferably 2.
In the present disclosure, m−1 is preferably 2.
In the present disclosure, m−2 is preferably 1.
In the present disclosure, p is preferably 0 to 2, more preferably 0 or 1, still more preferably 0.
In the present disclosure, ^R7 is preferably a hydrogen atom, an ethyl group or an isopropyl group, more preferably a hydrogen atom.

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

(wherein all symbols have the same meanings as above).

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

(wherein all symbols have the same meanings as above).

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

(wherein all symbols have the same meanings as above).

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

(wherein all symbols have the same meanings as above).

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).

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

(Wherein, R ^2a is

(In the formula, the symbols have the same meanings as above.), or

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

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

In the present disclosure, as another aspect of the compound represented by general formula (I), the example compounds or salts thereof described in Examples below are most preferred.

The compound of the present disclosure has GCL inhibitory activity. In the present disclosure, GCL inhibitory activity is GCLC inhibitory activity in one embodiment. A compound of the present disclosure, in one embodiment, has GCL inhibitory activity equal to or greater than that of BSO. In one embodiment, the compounds of the present disclosure have stronger intracellular GCL inhibitory activity than BSO. In one embodiment, the compounds of the present disclosure are about 2-fold or more, about 3-fold or more, about 4-fold or more, about 5-fold or more, or about 10-fold or more more potent in inhibiting GCL intracellularly than BSO. The intracellular GCL inhibitory action can be confirmed using a general measurement method, for example, it can be measured by the method described in Pharmacological Example 2 below.

The compound of the present disclosure, in one embodiment, has excellent pharmacokinetics. Each parameter related to kinetics (AUC, CLtotal, T1/2 and/or BA, etc.) can be confirmed using a general measurement method, for example, it can be measured by the method described in the pharmacokinetic examples below. can be done.

The compound of the present disclosure, in one embodiment, has a stronger in vivo action than BSO and exhibits efficacy from a lower concentration than BSO. The in vivo action (efficacy, etc.) can be confirmed, for example, using a general measuring method, and can be measured, for example, by the method described in Pharmacological Example 3 below.

In the present disclosure, all isomers are included unless otherwise indicated. For example, alkyl groups, alkoxy groups, alkylene groups, and the like include straight-chain and branched-chain ones. Furthermore, isomers (E, Z, cis, trans) at double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , isomers (R, S, enantiomers, diastereomers) due to the presence of a sulfur atom (asymmetric) of sulfoximine, optically active isomers (D, L, d, l), chromatograph Separation of polar forms (more polar forms, less polar forms), equilibrium compounds, rotamers, mixtures thereof in any proportion, racemic mixtures are all included in this disclosure. The present disclosure also includes all tautomeric isomers.

Among the compounds represented by general formula (I), when R7 represents a hydrogen atom, the compounds of the present invention also include those represented by ions represented by the following general formula (II-4).

In the present disclosure, unless otherwise specified, the symbol

represents binding beyond the plane of the paper (i.e. α-configuration),

indicates that it is bound to the front side of the paper (that is, β-configuration),

represents any mixture of α-configuration and β-configuration.

[salt]
A compound represented by general formula (I) or the like is converted into a salt by a known method.
The salt is preferably a pharmaceutically acceptable salt.
Preferably, the salt is water-soluble.
Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts or amine salts.

Acid addition salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate or acetates, lactates, tartrates, benzoates. , citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and gluconate. be done.

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

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

Examples of ammonium salts include tetramethylammonium salts.

Amine salts include, for example, 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 and the like.

In addition, the compounds of the present disclosure can be converted into N-oxides by any method. The N-oxide represents a compound obtained by oxidizing the nitrogen atom of the compound represented by general formula (I).

Compounds represented by general formula (I) and salts thereof may exist in unsolvated form, or may exist in solvated form with pharmaceutically acceptable solvents such as water and ethanol. good. The solvate is preferably a hydrate. A compound represented by general formula (I) or the like and a salt thereof can be converted into a solvate.

A compound represented by general formula (I) or the like can form a co-crystal with an appropriate co-crystal former. Co-crystals are preferably pharmaceutically acceptable, formed with a pharmaceutically acceptable co-crystal former. Co-crystals are typically defined as crystals in which two or more different molecules are formed through intermolecular interactions other than ionic bonding. Co-crystals may also be complexes of neutral molecules and salts. 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 compounds of the present disclosure are compounds represented by general formula (I) and the like, salts thereof, N-oxide forms thereof, solvates thereof (e.g., hydrates), or cocrystals thereof, or N-oxide forms of salts of compounds represented by general formula (I), etc., solvates thereof (eg, hydrates), or co-crystals thereof are included.

[Prodrug]
A prodrug of a compound represented by general formula (I) or the like refers to a compound that is converted into a compound represented by general formula (I) or the like by a reaction with an enzyme, gastric acid, or the like in vivo. Examples of prodrugs of compounds represented by general formula (I) and the like include, for example, when the compound represented by general formula (I) and the like has an amino group, the amino group is acylated, alkylated, or phosphorylated. (For example, the amino group of the compound represented by general formula (I) etc. is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated , tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); Acylated, alkylated, phosphorylated, and borated compounds (for example, hydroxyl groups of compounds represented by general formula (I) are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, and alanylated). , dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by general formula (I) has a carboxy group, the carboxy group is esterified or amidated (e.g., general formula ( The carboxy group of the compound represented by I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified. , phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterification, methylamidated compounds etc.). These compounds can be produced by methods known per se. In addition, prodrugs of compounds represented by general formula (I etc.) may be either hydrates or non-hydrates. In addition, prodrugs of compounds represented by general formula (I) and the like are generally used under physiological conditions, as described in Hirokawa Shoten 1990, "Drug Development", Vol. It may be converted into a compound represented by formula (I).

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

[Method for producing the compound of the present disclosure]
The compounds of the present disclosure can be prepared by known methods, for example, the methods shown below, methods based on these, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018). It can be produced by appropriately improving the methods described above or the methods shown in the examples and using them in combination. A salt may be used as the starting material. The order in which each reaction is performed can be changed as appropriate depending on the protecting groups introduced and the reaction conditions.

In addition, compounds having an amino group, a carboxyl group, or a hydroxyl group may, if necessary, have protective groups commonly used for these groups, such as T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, using a compound protected with a protecting group, after an appropriate reaction step, can be produced by performing a known deprotection reaction. can.

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

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

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

A 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 silyl group,
(5) a deprotection reaction using a metal;
(6) deprotection reaction using a metal complex, and the like.

Specifically, these methods are:
(1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter, THF), dioxane, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.) or carbonates (e.g., sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof, or mixtures thereof, It is carried out at 0-40°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, trifluoro the presence of 2,2,2-trifluoroethanol in acetic acid, methanesulfonic acid, p-tosylic acid, etc.) or inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g., hydrogen bromide/acetic acid, etc.) at 0-100° C. with or without presence.
(3) Deprotection reaction by hydrogenolysis can be carried out, for example, in solvents (e.g., ether-based (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (e.g., methanol, ethanol, etc.), benzene-based (e.g., , benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (hereinafter, DMF), etc.), water, ethyl acetate , acetic acid or a mixed solvent of two or more thereof), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under a hydrogen atmosphere under normal pressure or under pressure. Alternatively, it is carried out at 0 to 200° C. in the presence of ammonium formate.
(4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (eg, THF, acetonitrile, etc.) at 0 to 40°C. Also, for example, organic acids (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.) or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.), or mixtures thereof (eg, hydrogen bromide/acetic acid, etc.) It is carried out at -10 to 100°C.
(5) Deprotection reaction using a metal, for example, in an acidic solvent (e.g., acetic acid, pH 4.2-7.2 buffer solution or a mixture of a solution thereof and an organic solvent such as THF), powder zinc It is carried out at 0-40° C. in the presence, with sonication 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 mixed solvent thereof, a trap reagent (e.g., hydrogen tributyltin chloride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (e.g., sodium 2-ethylhexanoate, 2- Potassium ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), metal complexes (e.g., tetrakistriphenylphosphine palladium (0), bis(triphenylphosphine dichloride), ) palladium (II), palladium (II) acetate, tris(triphenylphosphine) rhodium (I) chloride, etc.) at 0-40°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 other symbols have the same meanings as above.)

In reaction scheme 1, reaction 1-1 is an S-alkylation reaction. S-alkylation reactions are known, for example alkali metal hydroxides (sodium hydroxide, hydroxide potassium, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof, or mixtures thereof, in the presence of 0 to It is carried out by reacting at 100°C.

In reaction scheme 1, reaction 1-2 is an oxidation reaction from sulfide to sulfoximine. For example, in the presence of iodobenzene diacetate and ammonium carbamate in an organic solvent (methanol (MeOH)) at 0° C. to room temperature.
In reaction scheme 1, reaction 1-3 is a deprotection reaction, which can be carried out in the same manner as described above.
In reaction scheme 1, reaction 1-4 is a deprotection reaction, which can be carried out in the same manner as described above.

In each reaction herein, the compounds represented by general formula 1a and general formula 1b used as starting materials are known, or known methods such as Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018) or the like, or by using a combination of methods partially modified from known methods.

Among the compounds used in the present invention, optically active compounds are produced by using optically active starting materials or reagents, or by optically resolving racemic production intermediates and then leading to compounds of the present disclosure. Alternatively, it can be produced by optically resolving a racemic compound of the present disclosure.

This optical resolution is known. For example, after forming a salt or complex with another optically active compound and recrystallizing, the target compound is isolated or directly separated using a chiral column or the like. and methods to do so.

In each reaction herein, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath or microwaves, as is apparent to those skilled in the art.

In each reaction in this specification, a solid-supported reagent supported by a high-molecular polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

In each reaction herein, the reaction product can be purified by usual purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by a method such as scavenger resin or column chromatography, washing, or recrystallization. Purification may be performed for each reaction or may be performed after completion of some reactions.

[toxicity]
Due to the low toxicity of the compounds of the present disclosure, they can be safely used as pharmaceuticals.

[Application to pharmaceuticals]
Since the compounds of the present disclosure have inhibitory activity against GCL, they can be formulated as effective agents for suppressing progression, suppressing recurrence, or treating diseases associated with GCL (GCL-associated diseases), such as cancer.

Cancers for which the compounds of the present disclosure are intended for inhibition of progression, inhibition of recurrence and/or treatment include any solid tumors and blood cancers. , malignant melanoma in the skin, oral mucosal epithelium, or in the orbit, etc.), non-small cell lung cancer (e.g., squamous non-small cell lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary gland cancer and tongue cancer), renal cell carcinoma (e.g. clear cell renal cell carcinoma), breast cancer, ovarian cancer (e.g. serous ovarian cancer and ovarian cancer) clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (e.g., cervical and endometrial cancer), anal cancer (e.g., anal canal cancer), colon cancer (e.g., MSI-H and/or dMMR-positive colon cancer) , rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer, ureteral cancer, renal pelvic cancer and urethral cancer), Prostate cancer, fallopian tube cancer, primary peritoneal cancer, malignant pleural mesothelioma, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, skin cancer (e.g. uveal malignant melanoma and Merkel cell carcinoma), testicular cancer (germ cell tumor) , vaginal cancer, vulvar cancer, penile cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spine tumor, neuroblastoma, medulloblastoma, ocular retinoblastoma, neuroendocrine tumor, Brain tumors (eg, gliomas (eg, glioblastoma and gliosarcoma) and meningioma), squamous cell carcinoma, and the like.

Among solid cancers, sarcomas of bone and soft tissue (e.g., Ewing's sarcoma, childhood rhabdomyosarcoma, uterine corpus leiomyosarcoma, chondrosarcoma, lung sarcoma, osteosarcoma, congenital fibrosarcoma) and Kaposi's sarcoma sarcoma and the like.

In addition, hematologic cancers include, for example, multiple myeloma, malignant lymphoma (e.g., non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's lymphoma (e.g., precursor B-cell lymphoblastic lymphoma, precursor B-cell acute lymphoblast) chronic B-lymphocytic leukemia (small lymphocytic lymphoma or progenitor cell leukemia), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, nodal marginal zone B-cell lymphoma, extranodal marginal Zone B-cell lymphoma (MALT lymphoma), primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, hairy cell leukemia/variant type, follicular lymphoma, childhood follicular lymphoma, diffuse large B-cell lymphoma lymphoma, diffuse large B-cell lymphoma/unspecified type, splenic diffuse red pulp small B-cell lymphoma, lymphoplasmacytic lymphoma, primary mediastinal large B-cell lymphoma, primary exudative lymphoma , Burkitt's lymphoma, mantle cell lymphoma, monoclonal B-cell lymphocytosis, splenic B-cell lymphoma/leukemia, unclassifiable, monoclonal gammaglobulinemia of unknown significance, IgM type, mu heavy chain disease, lambda Heavy chain disease, alpha heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, monoclonal immunoglobulin deposition disease, large B-cell lymphoma with IRF4 rearrangement, primary central follicular cutaneous lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, primary central nervous system diffuse large B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type, EBV Positive diffuse large B-cell lymphoma/non-specific type, EBV-positive mucocutaneous ulcer, chronic inflammation-associated diffuse large B-cell lymphoma, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, ALK-positive large Cellular B-cell lymphoma, plasmablastic lymphoma, primary coelomic fluid lymphoma, HHV8-positive diffuse large B-cell lymphoma nonspecific, Burkitt-like lymphoma with 11q aberration, MYC and both BCL2 and BCL6 High-grade B-cell lymphoma with one-sided rearrangement, high-grade B-cell lymphoma/non-specific and B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma/unclassifiable type) , T/NK-cell non-Hodgkin's lymphoma (e.g. precursor T-cell lymphoblastic lymphoma, chronic T-lymphocytic leukemia, T-type large granular lymphocytic leukemia, large granular NK-cell leukemia, aggressive NK-cell Leukemia, peripheral T-cell lymphoma, peripheral T-cell lymphoma/unspecified, unclassifiable peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell (CD30-positive) lymphoma, angiocentric lymphoma , intestinal T-cell lymphoma, enteropathic T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, Sézary syndrome, Hodgkin-like/Hodgkin-associated anaplastic large cell lymphoma , extranodal NK/T-cell lymphoma, adult T-cell lymphoma, T-cell prolymphocytic leukemia, chronic NK-cell lymphoproliferative disorder, pediatric systemic EBV-positive T-cell lymphoma, vaccinated bullous-like lymphoproliferative disorder , extranodal NK/T-cell lymphoma/nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, gastrointestinal indolent T-cell lymphoproliferative disorder, hepatosplenic T-cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8-positive rapidly progressive epidermotropic cytotoxic T-cell lymphoma , primary cutaneous CD8-positive T-cell lymphoma, primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disease, follicular T-cell lymphoma, nodal peripheral T-cell lymphoma with follicular helper T-cell phenotype, large undifferentiated Cellular lymphoma/ALK-positive, anaplastic large-cell lymphoma/ALK-negative, and breast implant-associated anaplastic large cell lymphoma)) and Hodgkin lymphoma (e.g., classical Hodgkin lymphoma (e.g., nodular sclerosing, mixed cell, lymphocytic abundant and lymphopenic) or nodular lymphocyte-predominant Hodgkin's lymphoma)), leukemia (e.g., acute myelogenous leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia (lymphoblastic lymphoma), chronic lymphocytic leukemia (small lymphocytic lymphoma), myelodysplastic syndrome and chronic myelogenous leukemia), primary central nervous system malignant lymphoma and myeloproliferative syndrome.

Furthermore, cancers targeted for inhibition of progression, inhibition of recurrence, and/or treatment by the compounds of the present disclosure include pediatric cancers and cancers of unknown primary origin.

Cancers targeted for the inhibition of progression, inhibition of recurrence and/or treatment by the compounds of the present disclosure include any solid tumors and hematological cancers. sensitive cancer).

As used herein, ARID1A deficiency means ARID1A gene deficiency or ARID1A protein deficiency caused by ARID1A gene mutation. An ARID1A-deficient cancer refers to a cancer that has 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.

GCL-sensitive cancers include, for example, acute myelogenous leukemia and B-cell lymphoma.

As used herein, the term “cancer treatment” includes, for example, (a) reducing the proliferation of cancer cells, (b) reducing symptoms caused by cancer, and improving the quality of life of cancer patients. , (c) to reduce the dose of other anti-cancer agents or cancer therapeutic adjuvants already administered, and/or (d) to prolong the survival of cancer patients. In addition, "inhibition of progression of cancer" means delaying progression of cancer, stabilizing symptoms associated with cancer, and reversing progression of symptoms. "Recurrence suppression" means prophylactic suppression of cancer recurrence in patients whose cancer lesions have completely or substantially disappeared or been eliminated by cancer treatment or cancer surgical resection.

Furthermore, the compounds of the present disclosure are useful for (a) cancer patients whose therapeutic effects with other anticancer agents are insufficient or insufficient, or cancers that have been exacerbated after treatment with other anticancer agents, (b) curative or unresectable, metastatic, recurrent, and refractory cancers. (c) cancer patients with TPS or CPS ≥50%, ≥25%, ≥10%, ≥5% or ≥1%; (d) MSI-H or (e) BRAF V600E mutation-positive malignant melanoma or non-small cell lung cancer; (f) EGFR gene mutation-positive or ALK fusion gene-positive cancer; or (g) TMB It may be prescribed to patients with cancer who have a high incidence of

On the other hand, the compounds of the present disclosure can be used in (a) cancer patients who have not been treated with other anticancer agents, (b) TPS or CPS of less than 50%, less than 25%, less than 10%, less than 5% or less than 1% (c) cancer patients without MSI-H and/or dMMR or with MSI-L, (d) patients with melanoma or non-small cell lung cancer who are BRAF V600 wild type, ( It may be more desirable for e) patients with EGFR mutation-negative and/or ALK fusion-negative non-small cell lung cancer, or (f) patients with TMB-infrequent cancers.

It can also be prescribed as postoperative adjuvant therapy to prevent recurrence or metastasis after surgical resection of cancer or neoadjuvant therapy performed before surgical resection.

Here, the "other anticancer agents" include the anticancer agents described in the item "combination or combination drug" below, that is, alkylating agents, platinum agents, antimetabolites (e.g., antifolates, pyridine metabolism inhibitors, drugs and purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogues, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular targeted drugs and drugs exemplified as cancer immunotherapeutic drugs. In addition, "the therapeutic effect of other anticancer drugs is insufficient or not sufficient" means, for example, that RECIST, which evaluates the tumor shrinkage effect, shows "stable (SD)" or "progressive (PD)" even after treatment with existing anticancer drugs. There is a case where it is determined that

In order to use the compound of the present disclosure for the purpose of suppressing progression, suppressing recurrence and/or treatment of the above diseases, the substance, which is an active ingredient, is usually combined with a pharmaceutically acceptable carrier such as various additives or solvents. After formulation, they are administered systemically or locally, orally or parenterally. Here, a pharmaceutically acceptable carrier means a substance other than an active ingredient, which is generally used in pharmaceutical formulations. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, pharmaceutically acceptable carriers can be used for the purpose of enhancing the usefulness of active ingredients and formulations, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances described in Yakuji Nippo 2000, "Pharmaceutical Excipient Encyclopedia" (edited by Japan Pharmaceutical Excipients Association) may be appropriately selected according to the purpose.

Dosage forms used for administration include, for example, oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jelly, etc.), oral preparations (e.g., oral tablets, Oral spray, oral semi-solid, mouthwash, etc.), injection preparations (e.g. injections), dialysis preparations (e.g. dialysis preparations), inhalation preparations (e.g. inhalants), 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 semi-solid formulations, intestinal injections, etc.), vaginal formulations (e.g., vaginal tablets, vaginal suppositories, etc.), and skin formulations (e.g., external solid formulations, external liquid formulations, sprays, ointments, creams, gels, patches, etc.) and the like.

[Formulation for oral administration]
Formulations for oral administration include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies and the like. Formulations for oral administration include rapid-disintegrating preparations in which the release of the active ingredient from the preparation is not particularly adjusted, and formulations in which the release is adjusted according to the purpose by a unique formulation design and manufacturing method, such as enteric-coated formulations. There are formulations and modified release formulations such as sustained release formulations. Enteric-coated preparations are designed to release active ingredients mainly in the small intestine, rather than in the stomach, in order to prevent the active ingredients from decomposing in the stomach or to reduce the irritation of the active ingredients to the stomach. Generally, it can be produced by coating with an acid-insoluble enteric base. Sustained-release preparations refer to preparations in which the release rate, release time, and release site of the active ingredient are adjusted for the purpose of reducing the number of administrations or reducing side effects. can be produced by using Among preparations for oral administration, capsules, granules, tablets, etc. are coated with appropriate coating agents such as sugars, sugar alcohols, and high-molecular compounds for the purpose of facilitating administration or preventing decomposition of active ingredients. It can also be coated.

(1) Tablets Tablets are solid preparations with a certain shape that are orally administered. In addition, intraoral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets and the like are included. When producing uncoated tablets, the following methods (a), (b), or (c) are usually used:
(a) Add excipients such as excipients, binders, and disintegrants to the active ingredient, mix and homogenize, granulate by an appropriate method using water or a solution containing a binder, and then add a lubricant. etc. are added and mixed, and compression molding is performed;
(b) Add additives such as excipients, binders, disintegrants, etc. to the active ingredient and mix them to homogeneity, and directly compress and mold them, or add the active ingredient and lubricant to granules previously prepared with additives. Add a lubricant or the like, mix and homogenize, and then compress and mold;
(c) Add excipients, binders, and other additives to the active ingredient, mix and homogenize, pour the kneaded product moistened with a solvent into a certain mold, and then dry it by an appropriate method. ;
is used. A film-coated tablet can usually be produced by thinly coating an uncoated tablet with an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating an uncoated tablet with a coating agent containing sugars or sugar alcohols. A multilayer tablet can be produced by stacking powdery or granular materials having different compositions in layers by an appropriate method and then compression-molding the layers. Dry-coated tablets can be produced by covering an inner core tablet with an outer layer having a different composition. Tablets can also be made into enteric-coated tablets or sustained-release tablets using known appropriate techniques. Rapidly disintegrating orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets with unique functions imparted by appropriate selection of excipients, and should be manufactured according to the aforementioned tablet manufacturing method. can be done. The oral rapidly disintegrating tablet is a tablet that dissolves or disintegrates rapidly in the oral cavity and can be taken; the chewable tablet is a tablet that is chewed and taken; the effervescent tablet is a tablet that rapidly foams in water Tablets that dissolve or disperse; Dispersible tablets refer to tablets that are dispersed in water before administration; Dissolving tablets refer to tablets that are dissolved in water before administration. Effervescent tablets can be produced by using suitable acidic substances, carbonates, hydrogen carbonates and the like as excipients.

(2) Capsules Capsules are preparations filled in capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules are made by mixing active ingredients with excipients and other additives to make them homogeneous, or by making them into granules or moldings by an appropriate method, and filling them into capsules as they are or by lightly molding them. It can be manufactured by Soft capsules are manufactured by encapsulating active ingredients with additives in a suitable capsule base such as gelatin to which glycerin, D-sorbitol, etc. have been added to increase plasticity into a certain shape. can do. Capsules can be made into enteric-coated capsules or sustained-release capsules using known appropriate techniques, and colorants, preservatives, and the like can be added to the capsule base.

(3) Granules Granules are granulated formulations, and generally include effervescent granules and the like, in addition to those generally called granules. When producing granules, the following methods (a), (b), or (c) are usually used:
(a) Add excipients, binders, disintegrants, or other additives to the powdered active ingredient, mix and homogenize, and then granulate by a suitable method;
(b) Add additives such as excipients to the active ingredient prepared in advance into granules and mix to homogenize;
(c) Add additives such as excipients to the active ingredient previously made into granules, mix them, and make granules by an appropriate method;
is used. The granules can be coated, if necessary, and can also be made into enteric-coated granules or sustained-release granules using a known appropriate technique. Effervescent granules can be produced by using suitable acidic substances, carbonates, hydrogen carbonates and the like as additives. The effervescent granules refer to granules that dissolve or disperse in water while rapidly foaming. Granules can also be made into fine granules by adjusting the particle size.

(4) Powders Powders are powdery formulations, and can usually be produced by adding excipients or other additives to active ingredients and mixing them to homogenize them.

(5) Oral liquid preparations Oral liquid preparations are liquid or fluid viscous gel preparations, and in addition to what is generally called oral liquid preparations, there are elixirs, suspensions, emulsions, limonade preparations, and the like. included. Oral liquid preparations can usually be produced by adding additives and purified water to the active ingredient, mixing them to dissolve homogeneously, or emulsifying or suspending them, and filtering if necessary. Elixirs are clear liquid oral preparations containing sweetened and fragrant ethanol, usually containing ethanol, purified water, flavoring agents, and sucrose, other sugars, or It can be produced by adding a sweetening agent, dissolving it, and making a clear liquid by filtration or other methods. Suspension refers to an oral solution in which the active ingredient is finely and homogeneously suspended. Usually, a suspending agent or other additives and purified water or oil are added to the solid active ingredient and suspended by an appropriate method. , can be manufactured by homogenizing the whole. Emulsions refer to oral liquid preparations in which an active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to a liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. . A limonade agent is a clear liquid oral liquid preparation with a sweet and sour taste.

(6) Syrups Syrups are viscous liquid or solid preparations containing sugars or sweeteners, and include syrup preparations and the like. Syrups are usually prepared by adding an active ingredient to a solution of sucrose, other sugars, or a sweetener, or a simple syrup, dissolving, mixing, suspending, or emulsifying the mixture, if necessary, boiling the mixture, and then heating it. It can be produced by filtration. A syrup formulation refers to a granular or powder formulation that becomes a syrup when water is added, and is sometimes referred to as a dry syrup. Syrup formulations can be produced according to the above-mentioned granules or powder production techniques, usually using saccharides or sweeteners as additives.

(7) Oral Jelly Oral jelly is a non-fluid, molded gel formulation. Generally, an active ingredient is mixed with additives and a polymer gel base, and gelled by an appropriate method. It can be manufactured by molding into a certain shape.

[Oral formulation]
(1) Oral tablets Oral tablets are solid preparations of a certain shape that are applied to the oral cavity, and include lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, and the like. Oral tablets can be generally produced according to the aforementioned tablet production method. A lozenge is an oral tablet that is gradually dissolved or disintegrated in the oral cavity and applied topically to the oral cavity, pharynx, etc.; Buccal tablet is an oral tablet that dissolves the active ingredient gradually between the molars and cheeks and is absorbed from the oral mucosa; tablets for oral use; chewing gums refer to oral tablets that release active ingredients upon chewing.

(2) Oral sprays Oral sprays are formulations in which active ingredients are sprayed in the form of mist, powder, foam, or paste. After turbidity and, if necessary, filtering, the container is filled with a liquefied or compressed gas, or a solution or suspension is prepared using the active ingredient and additives, which is filled into a container and pumped for spraying. can be manufactured by installing

(3) Oral semi-solid preparation Oral semi-solid preparation is a formulation applied to the oral mucosa, and includes creams, gels, ointments and the like. Oral semi-solid preparations are usually prepared by emulsifying active ingredients together with additives with purified water and oily ingredients such as petroleum jelly, or by mixing active ingredients and additives with polymer gel or oil as a base to homogenize them. It can be manufactured by The cream refers to a semi-solid formulation emulsified in oil-in-water or water-in-oil, and a lipophilic formulation emulsified in water-in-oil is sometimes called an oily cream. Creams are usually composed of petrolatum, higher alcohols, etc. as they are, or by adding additives such as emulsifiers to form an oil phase, and purified water as it is or by adding additives such as emulsifiers to form an aqueous phase. It can be produced by adding an active ingredient to each of the phases of (1), heating each, and emulsifying by mixing the oil phase and the water phase together until the whole becomes homogeneous. Gels refer to gel formulations, including aqueous gels, oily gels, and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink. An oily gel can be produced by adding and mixing an active ingredient with a liquid oily base such as glycols and higher alcohols and other additives. An ointment refers to a semi-solid formulation in which an active ingredient is dissolved or dispersed in a base, and includes oleaginous ointments, water-soluble ointments, and the like. A oleaginous ointment is usually prepared by heating and melting an oleaginous base such as fats, waxes, and hydrocarbons such as paraffin, adding an active ingredient, and mixing to dissolve or disperse, until the whole is homogeneous. It can be produced by mixing and kneading until it becomes A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole is homogeneous.

(4) Mouthwash Mouthwash is a liquid preparation that is applied locally to the oral cavity, pharynx, etc., and includes solid preparations that are dissolved before use. A gargle can usually be produced by adding a solvent and an additive to an active ingredient, mixing them, dissolving them homogeneously, and filtering if necessary. In the case of a solid preparation to be dissolved before use, it can be usually manufactured according to the manufacturing method for tablets, granules, etc. described above.

[Injection formulation]
(1) Injectables Injectables are solutions, suspensions, emulsions, or solids that are used by dissolving or suspending before use. In addition to what is generally called an injection, it also includes freeze-dried injections, powdered injections, pre-filled syringes, cartridges, infusions, implanted injections, and long-acting injections. be When manufacturing injections, the following (a) or (b) method is usually used:
(a) For injection, the active ingredient as it is, or the active ingredient with additives dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc., is homogenized. of the container, sealed and sterilized;
(b) Dissolve, suspend, or emulsify the active ingredient as it is, or the active ingredient with additives in water for injection, other aqueous solvents, or non-aqueous solvents, etc., and filter aseptically. or aseptically prepared and homogenized into containers for injection and sealed;
is used. Freeze-dried injections are usually prepared by dissolving the active ingredient as it is, or by dissolving the active ingredient and additives such as excipients in water for injection, filtering the mixture aseptically, filling it in a container for injection, and then freeze-drying it. It can be produced by freeze-drying in a dedicated container and then filling it directly into a container. Powder injections can be produced by adding sterilized excipients to powders obtained by crystallization after aseptic filtration, and filling the mixture into containers for injections. A pre-filled syringe can be generally manufactured by preparing a solution, suspension, or emulsion of the active ingredient as it is or by using the active ingredient and an additive, and filling the syringe. Cartridge formulation refers to an injection that uses a cartridge filled with a drug solution in a dedicated syringe. Cartridges filled with a drug solution usually contain the active ingredient as it is or a solution using an active ingredient and additives. It can be manufactured by preparing a suspension or emulsion and filling it into cartridges. An infusion means an injection of 100 mL or more that is administered intravenously. An implantable injection refers to a solid or gel injection applied subcutaneously or intramuscularly using an implantable device or by surgery for the purpose of releasing an active ingredient over a long period of time. Implantable injections can usually be produced by using biodegradable polymer compounds and making them into pellets, microspheres, or gels. Long-acting injections refer to injections applied intramuscularly, etc., for the purpose of releasing active ingredients over a long period of time. It can be produced by making a suspension of microspheres using.

[Preparation for dialysis]
(1) Dialysis agent A dialysis agent is a liquid preparation used for peritoneal dialysis or hemodialysis or a solid preparation that dissolves before use, and includes peritoneal dialysis agents and hemodialysis agents. A peritoneal dialysis agent is a sterile dialysis agent used for peritoneal dialysis, and is usually an active ingredient with additives dissolved in a solvent to make a fixed volume, or an active ingredient with additives. into a container, sealed, and sterilized as necessary. In the case of a solid formulation that dissolves before use, it can be generally produced according to the production method for tablets, granules, and the like. A hemodialysis agent is a dialysis agent used in hemodialysis. Generally, the active ingredient is added with additives and dissolved in a solvent to make a fixed volume, or the active ingredient and additives are placed in a container. It can be produced by filling the In the case of a solid formulation that dissolves before use, it can be generally produced according to the production method for tablets, granules, and the like.

[Formulation for inhalation]
(1) Inhalant An inhalant is a formulation for inhaling an active ingredient as an aerosol and applying it to the bronchi or lungs, and includes powder inhalants, liquid inhalants, inhalable aerosols, and the like. A powder inhaler refers to a formulation to be inhaled as a solid particle aerosol prepared so that the inhalation amount is constant. Usually, the active ingredient is made into fine particles and mixed with additives such as lactose as necessary. It can be produced by homogenizing by An inhalation solution refers to a liquid inhalation that is applied by a nebulizer or the like. Generally, an active ingredient is added with a solvent, an appropriate tonicity agent, a pH adjuster, etc., mixed to homogenously dissolved or suspended, and if necessary It can be produced by filtering accordingly. An inhalation aerosol is a metered dose inhaler that sprays a fixed amount of an active ingredient together with a propellant filled in a container. Inhalation aerosol formulations are usually prepared by adding a solvent and appropriate dispersant, stabilizer, etc. to the active ingredient to form a solution or suspension, which is then filled together with a liquid propellant into a pressure-resistant container and fitted with a metering valve. It can be manufactured by

[Ophthalmic formulation]
(1) Eye drops Eye drops are liquid or solid sterile preparations that are dissolved or suspended before use and applied to ocular tissues such as the conjunctival sac. Eye drops can be usually produced by adding additives to an active ingredient and dissolving or suspending it in a solvent or the like to make a fixed volume, or by filling a container with an active ingredient and additives. .

(2) Ophthalmic ointment Ophthalmic ointment is a semi-solid, sterile preparation applied to eye tissue such as the conjunctival sac, and is usually homogenized by mixing a base such as petrolatum and a solution or fine powder of the active ingredient. , can be produced by filling a container.

[Otological formulation]
(1) Ear drops Ear drops are liquid, semi-solid, or solid preparations that are dissolved or suspended before use and are administered to the outer or middle ear. Ear drops are usually manufactured by adding additives to an active ingredient and dissolving or suspending it in a solvent or the like to make a fixed volume, or by filling a container with an active ingredient and additives. can.

[Nasal preparations]
(1) Nasal drops Nasal drops are formulations administered to the nasal cavity or nasal mucosa, and include nasal powders, nasal drops and the like. Nasal powders refer to finely powdered nasal drops that are administered to the nasal cavity, and are usually produced by making the active ingredient into moderately fine particles and, if necessary, mixing them with additives to homogenize them. can be done. Nasal solution refers to a liquid nasal solution administered to the nasal cavity, or a solid nasal solution that is dissolved or suspended before use. can be produced by filtering according to Tonicity agents, pH adjusters and the like can be used as additives for nasal drops.

[Rectal formulation]
(1) Suppositories Suppositories are semi-solid preparations of fixed shape that release active ingredients by melting at body temperature or by slowly dissolving or dispersing in water for application in the rectum. Suppositories are usually prepared by adding additives such as dispersants and emulsifiers to the active ingredient and mixing them uniformly. It can be manufactured by filling a certain amount of the material and solidifying/molding it. As a base for suppositories, an oleaginous base or a hydrophilic base is usually used.

(2) Rectal semi-solid formulations Rectal semi-solid formulations are formulations applied around or in the anus, and include rectal creams, rectal gels, rectal ointments and the like. Semi-solid preparations for rectal use are usually made by emulsifying the active ingredient together with additives with purified water and an oily component such as vaseline, or by mixing the active ingredient and additives with a polymer gel or oil as a base to homogenize it. It can be manufactured by Rectal creams are usually composed of petroleum jelly, higher alcohol, etc. as they are or additives such as emulsifiers are added to form an oil phase, and purified water as such or to which additives such as emulsifiers are added to form an aqueous phase. It can be produced by adding the active ingredient to either phase, heating each, and emulsifying by combining the oil phase and the water phase and stirring until the whole is homogeneous. A gel for rectal use refers to a gel preparation, and includes aqueous gels, oily gels, and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink. An oily gel can be produced by adding and mixing an active ingredient with a liquid oily base such as glycols and higher alcohols and other additives. A rectal ointment refers to a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base, and includes oil-based ointment, water-soluble ointment, and the like. A oleaginous ointment is usually prepared by heating and melting an oleaginous base such as fats, waxes, and hydrocarbons such as paraffin, adding an active ingredient, and mixing to dissolve or disperse, until the whole is homogeneous. It can be manufactured by mixing and kneading until it becomes. A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole is homogeneous.

(3) Enemas Enemas are liquid or viscous gel formulations that are applied through the anus. Usually, purified water or an appropriate aqueous solvent is used to dissolve or suspend the active ingredient in a solvent or the like. It can be produced by filling a container with a fixed volume. Dispersants, stabilizers, pH adjusters and the like can be used as additives for enema preparations.

[Vaginal formulation]
(1) Vaginal tablet A vaginal tablet is a solid preparation of a certain shape that is applied to the vagina and releases an active ingredient by gradually dissolving or dispersing in water. can do.

(2) Vaginal suppositories Vaginal suppositories are semi-solid preparations of fixed shape that are applied to the vagina and release the active ingredient by melting at body temperature or by slowly dissolving or dispersing in water. , usually according to the manufacturing method of the aforementioned rectal suppositories and the like.

[Skin preparation]
(1) Solid Formulations for External Use Solid forms for external use are solid preparations that are applied or sprayed on the skin including the scalp or nails, and include powders for external use. Powders for external use refer to solid powders for external use, and can usually be produced by adding additives such as excipients to the active ingredient, mixing them homogeneously, and then powdering them.

(2) Liquid preparation for external use Liquid preparation for external use is a liquid preparation applied to the skin including the scalp or nails, and includes liniments, lotions, and the like. A liquid preparation for external use can usually be produced by adding a solvent, an additive, etc. to an active ingredient, dissolving, emulsifying, or suspending the mixture, and filtering if necessary. A liniment is a liquid or mud-like solution for external use that is rubbed into the skin. A lotion is a liquid preparation for external use in which an active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid. It can be manufactured by homogenizing the whole as a liquid.

(3) Spray A spray is a formulation in which an active ingredient is sprayed onto the skin in the form of mist, powder, foam, paste, or the like, and includes external aerosols, pump sprays, and the like. Sprays can generally be produced by preparing a solution or suspension of the active ingredient, filtering if necessary, and filling a container. An external aerosol agent is a spray agent in which an active ingredient is sprayed together with a liquefied gas or compressed gas filled in a container. External aerosol preparations can generally be produced by preparing a solution or suspension of an active ingredient, filling a pressure-resistant container with a liquid propellant, and attaching a continuous injection valve. Additives such as a dispersant and a stabilizer can be added to the external aerosol formulation, if necessary. A pump spray agent refers to a spray agent that sprays an active ingredient in a container by means of a pump. Pump sprays can usually be produced by dissolving or suspending active ingredients and additives and attaching a pump to a filled container.

(4) Ointments Ointments are semi-solid preparations in which an active ingredient is dissolved or dispersed in a base to be applied to the skin, and include oleaginous ointments, water-soluble ointments, and the like. A oleaginous ointment is usually prepared by heating and melting an oleaginous base such as oils, waxes, and hydrocarbons such as paraffin, adding an active ingredient, and mixing to dissolve or disperse the ingredients until the whole is homogenous. It can be produced by mixing and kneading until it becomes A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole is homogeneous.

(5) Creams Creams are oil-in-water or water-in-oil emulsified semi-solid formulations applied to the skin. Water-in-oil emulsified lipophilic formulations are also called oily creams. Sometimes. Creams usually contain petrolatum, higher alcohols, etc. as they are or additives such as emulsifiers are added to form an oil phase, and purified water as such or additives such as emulsifiers are added to form an aqueous phase. It can be produced by adding an active ingredient to the phase of , heating each, and emulsifying by mixing the oil phase and the water phase together until the whole becomes homogeneous.

(6) Gels Gels are gel preparations applied to the skin, and include aqueous gels, oily gels, and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink. An oily gel can be produced by adding and mixing an active ingredient with a liquid oily base such as glycols and higher alcohols and other additives.

(7) Patches Patches are preparations that are applied to the skin, and include tapes, poultices, and the like. Adhesive patches are usually produced by mixing a high-molecular compound or a mixture thereof as a base, mixing an active ingredient with the base, homogenizing the mixture, spreading it on a support or a liner (release body), and molding it. can. In addition, a release control membrane can be used to prepare a transdermal preparation. Additives such as pressure-sensitive adhesives and absorption promoters can also be used in the patch, if necessary. A tape refers to a patch that uses a base that contains almost no water, and includes plaster, plasters, and the like. Tape agents are generally based on water-insoluble natural or synthetic high-molecular compounds such as resins, plastics, rubbers, etc., and the active ingredients are used as they are, or additives are added to the active ingredients, and the whole is homogenized and spread on a cloth. It can be produced by spreading or by spreading or enclosing in a plastic film or the like and molding. It can also be produced by encapsulating and molding a mixture comprising an active ingredient and a base or other additives in a release body composed of a modified release membrane, a support and a liner (release body). A poultice is a patch that uses a water-containing base. Generally, the active ingredient is mixed with purified water, glycerin, or another liquid substance to homogenize the whole, or a water-soluble polymer or highly absorbent patch is used. It can be produced by mixing a natural or synthetic polymer compound such as a molecule with purified water and kneading, adding an active ingredient, homogenizing the whole, spreading it on a cloth or the like and molding it.

[Combination or combination drug]
The presently disclosed compound or a pharmaceutical composition containing the presently disclosed compound as an active ingredient (hereinafter abbreviated as "the presently disclosed compound, etc.") is used for (a) suppressing cancer progression, suppressing recurrence, and/or enhancing therapeutic effects; (b) for reducing the dosage of other drugs that are prescribed in combination, (c) for reducing the side effects of other drugs that are prescribed in combination, and/or (d) in combination It may also be formulated in combination with one or more other drugs to enhance the immune-enhancing effects of other drugs administered, ie, as an adjuvant. In the present disclosure, the dosage form when prescribed in combination with other drugs (e.g., other anticancer drugs) may be in the form of a combination drug in which both components are combined in one formulation, or as separate formulations. may be in the dosage form of By using them in combination, it is possible to complement the preventive, suppress symptom progression, suppress recurrence and/or therapeutic effects of other drugs, or to maintain or reduce the dose or frequency of administration. When the compounds of the present disclosure, etc. and other agents are prescribed separately, they may be co-administered for a certain period of time, and then the compounds of the present disclosure, etc. alone or the other agents alone may be administered. In addition, the compound of the present disclosure, etc. may be administered first, and then another drug may be administered after that administration, or the other drug may be administered first, and the compound of the present disclosure, etc. may be administered later, and In the administration, there may be a period during which both drugs are administered simultaneously. Moreover, the administration method of each drug may be the same or different. Depending on the nature of the drug, it may also be provided as a kit of formulations containing the compounds of the present disclosure and formulations containing other drugs. Here, the dose of the other drug can be appropriately selected based on the clinically used dose. In addition, other drugs may be administered in combination of any two or more 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.

Anticancer agents that can be used in combination with the compounds of the present invention in cancer therapy include, for example, alkylating agents (e.g., Dacarbazine, Nimustine, Temozolomide, Fotemustine, Dendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil and Procarbazine), Platinum agents (e.g. Cisplatin, Carboplatin, Nedaplatin and Oxaliplatin), antimetabolites (e.g. antifolates (e.g. Pemetrexed, Leucovorin and Methotrexate), pyridine metabolism inhibitors (e.g. TS-1®) , 5-fluorouracil, UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine and Capecitabine, etc.), purine metabolism inhibitors (e.g., Fludarabine, Cladribine, Nelarabine, etc.), ribonucleotide reductase inhibitors, nucleotide analogues (e.g., Gemcitabine, etc.), Topoisomerase inhibitors (e.g. Irinotecan, Nogitecan and Etoposide), microtubule polymerization inhibitors (e.g. Vinblastine, Vincristine, Vindesine, Vinorelbine, Eribulin etc.), microtubule depolymerization inhibitors (e.g. Docetaxel and Paclitaxel), antitumor antibiotics (e.g., Bleomycin, Mitomycin C, Doxorubicin, Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin and Epirubicin, etc.), cytokine preparations (e.g., IFN-α2a, IFN-α2b, pegylated IFN -α2b, native IFN-β and Interleukin-2, etc.), anti-hormonal drugs (e.g. Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole and Exemestane, etc.), molecular targeted drugs, cancer immunotherapeutic drugs and other antibody drugs etc.

Here, molecular target drugs include, for example, ALK inhibitors (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib and Lorlatinib), BCR-ABL inhibitors (e.g., Imatinib and Dasatinib), EGFR inhibitors (e.g., Erlotinib, EGF816 , Afatinib, Osimertinib mesylate, Gefitinib and Rociletinib), B-RAF inhibitors (e.g. Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and Zanubrutinib), VEGFR inhibitors (e.g. Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib), FGFR inhibitors (e.g. AZD4547, Vofatmab, Roblitinib and Pemigatinib), c-MET inhibitors (e.g. Savolitinib, merestinib, Capmatinib, INC280 and Glesatinib), AXL inhibitors (e.g. ONO-7475 and Bemcentinib), MEK inhibitors (e.g. Cobimetinib, Binimetinib, Selumetinib and Trametinib), CDK inhibitors (e.g. Dinaciclib, Abemaciclib, Palbociclib and trilaciclib), BTK inhibitors (e.g. Ibrutinib and Acalabrutinib), PI3K-delta/gamma Inhibitors (e.g. Umbralisib, Parsaclisib and IPI-549), JAK-1/2 inhibitors (e.g. Itacitinib and Ruxolitinib), ERK inhibitors (e.g. SCH 900353), TGFbR1 inhibitors (e.g. Galunisertib), Cancer cells stemness kinase inhibitors (e.g. Amcasertib), FAK inhibitors (e.g. Defactinib), SYK/FLT3 dual inhibitors (e.g. Mivavotinib), ATR inhibitors (e.g. Ceralasertib), WEE1 kinase inhibitors (e.g. Adavosertib), multityrosine kinase inhibitors (e.g. Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib and Midostaurin), mTOR inhibitors (e.g. Temsirolimus, Everolimus, Vistusertib, Irinotecan), HDAC inhibitors (e.g. Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat, Valproate), PARP inhibitors (e.g. Niraparib, Olaparib, Veliparib, Rucaparib, Beigene-290), aromatase inhibitors (e.g. Exemestane, Letrozole), EZH2 inhibitors (e.g. tazemetostat), Galectin-3 inhibitors (e.g. Belapectin), STAT3 inhibitors (e.g. Napabucasin), DNMT inhibitors (e.g. Azacitidine), BCL-2 inhibitors (e.g. Navitoclax and Venetoclax, etc.), SMO inhibitors (e.g. Vismodegib ), HSP90 inhibitors (e.g. XL888), γ-tubulin specific inhibitors (e.g. Glaziovianin A, Plinabulin), HIF2α inhibitors (e.g. PT2385), glutaminase inhibitors (e.g. Telaglenastat), E3 ligase inhibitors (e.g. Avadomide), NRF2 activators (e.g. Omaveloxolone), Arginase inhibitors (e.g. CB-1158), Cell cycle inhibitors (e.g. Trabectedin), Ephrin B4 inhibitors (e.g. sEphB4-HAS), IAPs Antagonists (e.g., Birinapant), anti-HER1 antibodies (e.g., Cetuximab, Cetuximab sarotalocan, Panitumumab, Necitumumab, Nimotuzumab, Depatuxizumab, Depatuxizumab mafodotin, Futuximab, Laprituximab, Laprituximab emtansine, Matuzumab, Modotuximab, Petosemtamab, Tomuzot uximab, Losatuxizumab, Losatuxizumab vedotin, Serclutamab, Serclutamab talirine, Imgatuzumab, Futuximab and Zalutumumab), anti-HER2 antibodies (e.g. Pertuzumab, Margetuximab, Disitamab, Disitamab vedotin, Gancotamab, Timigutuzumab, Zanidatamab, Zenocutuzumab, Trastuzumab, Trastuzumab beta, Trastuzumab deruxtecan, Trastuzumab astuzumab duocarmazine, trastuzumab emtansine, R48 and ZW33), anti-HER3 antibodies (e.g. Duligotuzumab, Elgemtumab, Istiratumab, Lumretuzumab, Zenocutuzumab, Patritumab, Patritumab deruxtecan and Seribantumab), anti-CD40 antibodies (e.g. Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Ravagalimab, Selicrelumab, T eneliximab, ABBV-428 and APX005M), anti-CD70 antibodies (e.g. Cusatuzumab, Vorsetuzumab, Vorsetuzumab mafodotin and ARGX-110), anti-VEGF antibodies (e.g. Bevacizumab, Bevacizumab beta, Ranibizumab, Abicipar pegol, Aflibercept, Brolucizumab, Conbercept, Dilimab , Faricimab, Navicixizumab, Varisacumab and IMC-1C11), anti-VEGFR1 antibodies (e.g. Icrucumab), anti-VEGFR2 antibodies (e.g. Ramucirumab, Alacizumab, Alacizumab pegol, Olinvacimab, Pegdinetanib and AMG596), anti-CD20 antibodies (e.g. Rituximab, Blontuvetmab , Epitumomab, Ibritumomab tiuxetan, Ocaratuzumab, Ocrelizumab, Technetium ( ^99mTc ) nofetumomab merpentan, Tositumomab, Veltuzumab, Ofatumumab, Ublituximab, Obinutuzumab and Nofetumomab), anti-CD30 antibodies (e.g. Brentuximab Vedotin and Iratumumab), anti-CD38 Antibodies (e.g. Daratumumab , Isatuximab, Mezagitamab, AT13/5 and MOR202), anti-TNFRSF10B antibodies (e.g. Benfutamab, Conatumumab, Drozitumab, Lexatumumab, Tigatuzumab, Eftozanermin alfa and DS-8273a), anti-TNFRSF10A antibodies (e.g. Mapatumumab), anti-MUC1 antibodies (e.g. , Cantuzumab, Cantuzumab ravtansine, Clivatuzumab, Clivatuzumab tetraxetan, Yttrium ( ⁹⁰ Y) clivatuzumab tetraxetan, Epitumomab, Epitumomab cituxetan, Sontuzumab, Gatipotuzumab, Nacolomab, Nacolomab tafenatox, 7F11C7, BrE-3, CMB-40 1, CTM01 and HMFG1), anti-MUC5AC antibodies (e.g. Ensituximab), anti-MUC16 antibodies (e.g. Oregovomab, Abagovomab, Igovomab and Sofituzumab vedotin), anti-DLL4 antibodies (e.g. Demcizumab, Dilpacimab, Navicixizumab and Enoticumab), anti-fucosyl GM1 antibodies (e.g. BMS-986012), anti-gpNMB antibody (e.g. Glembatumumab vedotin), anti-Mesothelin antibody (e.g. Amatuximab, Anetumab ravtansine, Anetumab corixetan, RG7784 and BMS-986148), anti-MMP9 antibody (e.g. Andecaliximab), anti-GD2 antibody (e.g. Dinutuximab, Dinutuximab beta , Lorukafusp alfa, Naxitamab, 14G2a, MORAb-028, Surek, TRBs07 and ME361), anti-MET antibodies (e.g. Emibetuzumab, Onartuzumab, Telisotuzumab and Telisotuzumab vedotin), anti-FOLR1 antibodies (e.g. Farletuzumab, Mirvetuximab and Mirvetuximab soravtansine), anti CD79b antibodies (e.g. Iladatuzumab, Iladatuzumab vedotin and Polatuzumab vedotin), anti-DLL3 antibodies (e.g. Rovalpituzumab and Rovalpituzumab Tesirine), anti-CD51 antibodies (e.g. Abituzumab, Etaracizumab and Intetumumab), anti-EPCAM antibodies (e.g. Adecatumumab, Catumaxomab, Edrecolomab, Oportuzumab monatox, Citatuzumab bogatox and Tucotuzumab celmoleukin), anti-CEACAM5 antibodies (e.g. Altumomab, Arcitumomab, Cergutuzumab amunaleukin, Labetuzumab, Labetuzumab govitecan, 90Y-cT84.66, AMG211, BW431/26, CE25/B7, COL-1 and T8 4. 66 M5A), anti-CEACAM6 antibodies (e.g. Tinurilimab), anti-FGFR2 antibodies (e.g. Aprutumab, Aprutumab ixadotin and Bemarituzumab), anti-CD44 antibodies (e.g. bivatuzumab mertansine), anti-PSMA antibodies (e.g. Indium ( ¹¹¹ In) capromab pendetide , 177 Lu-J591 and ES414), anti-Endoglin antibodies (e.g. Carotuximab), anti-IGF1R antibodies (e.g. Cixutumumab, Figitumumab, Ganitumab, Dalotuzumab, teprotumumab and Robatumumab), anti-TNFSF11 antibodies (e.g. Denosumab), anti-GUCY2C (e.g. , Indusatumab vedotin), anti-SLC39A6 antibodies (e.g., Ladiratuzumab vedotin), anti-SLC34A2 antibodies (e.g., Lifastuzumab vedotin), anti-NCAM1 antibodies (e.g., Lorvotuzumab mertansine and N901), anti-ganglioside GD3 antibodies (e.g., Ecromeximab and Mitumomab), anti AMHR2 antibodies (e.g. Murlentamab), anti-CD37 antibodies (e.g. Lilotomab, Lutetium (177lu) lilotomab satetraxetan, Naratuximab, Naratuximab emtansine and Otlertuzumab), anti-IL1RAP antibodies (e.g. Nidanilimab), anti-PDGFR2 antibodies (e.g. Olaratumab and Tovetumab) , anti-CD200 antibodies (e.g. Samalizumab), anti-TAG-72 antibodies (e.g. Anatumomab mafenatox, Minretumomab, Indium ( ¹¹¹ In) satumomab pendetide, CC49, HCC49 and M4), anti-SLITRK6 antibodies (e.g. Sirtratumab vedotin), anti-DPEP3 antibodies (e.g. Tamrintamab pamozirine), anti-CD19 antibodies (e.g. Axicabtagene ciloleucel, Coltuximab ravtansine, Denintuzumab mafodotin, Inebilizumab, Loncastuximab, Loncastuximab tesirine, Obexelimab, Tafasitamab, Taplitumomab paptox, Taplitumomab paptox and huAnti-B4) NOTCH2/3 antibody (e.g., Tarextumab), anti-tenascin C antibody (e.g., Tenatumomab), anti-AXL antibody (e.g., Enapotamab, Enapotamab vedotin and Tilvestamab), anti-STEAP1 antibody (e.g., Vandortuzumab vedotin), anti-CTAA16 antibody (e.g., technetium ( ^99mTc ) votumumab), CLDN18 antibody (e.g. Zolbetuximab), anti-GM3 antibody (e.g. Racotumomab, FCGR1 and H22), anti-PSCA antibody (e.g. MK-4721), anti-FN extra domain B antibody (e.g. AS1409), anti-HAVCR1 Antibodies (e.g. CDX-014), anti-TNFRSF4 antibodies (e.g. MEDI6383), anti-HER1-MET bispecific antibody (Amivantamab), anti-EPCAM-CD3 bispecific antibody (Solitomab and Catumaxomab), anti-Ang2-VEGF Bispecific antibody (Vanucizumab), anti-HER2-CD3 bispecific antibody (Ertumaxomab), anti-HER3-IGF1R bispecific antibody (Istiratumab), anti-PMSA-CD3 bispecific antibody (Pasotuxizumab), anti-HER1 - LGR5 bispecific antibody (Petosemtamab), anti-SSTR2-CD3 bispecific antibody (Tidutamab), anti-CD30-CD16A bispecific antibody (e.g. AFM13), anti-CEA-CD3 bispecific antibody (e.g. , Cibisatamab and RO6958688), anti-CD3-CD19 bispecific antibody (Duvortuxizumab and Blinatumomab), IL3RA-CD3 bispecific antibody (Flotetuzumab and Vibecotamab), anti-GPRC5D-CD3 bispecific antibody (Talquetamab), anti-CD20 -CD3 bispecific antibody (Plamotamab, Odronextamab, Mosunetuzumab, Glofitamab, Epcoritamab and REGN1979), anti-TNFRSF17-CD3 bispecific antibody (Teclistamab), anti-CLEC12A-CD3 bispecific antibody (Tepoditamab), anti-HER2- HER3 bispecific antibodies (Zenocutuzumab), anti-FAP antibody/IL-2 fusion proteins (eg RO6874281), anti-CEA antibody/IL-2 fusion proteins (eg Cergutuzumab amunaleukin), and the like.
Cancer immunotherapeutics include, for example, anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab , Sasanlimab, Cetrelimab, Zimberelimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-36 1, JY034, HX008, ISU106 and CX-188), anti-PD-L1 antibodies (e.g. Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 and JS003, etc.), PD-1 antagonists (e.g., AUNP-12, BMS-M1 to BMS-M10 compounds (WO2014/ 151634, WO2016/039749, WO2016/057624, WO2016/077518, WO2016/100285, WO2016/100608, WO2016/126646, WO2016/149351, WO2017/151830 and WO2017/1766 08), BMS-1, BMS-2, BMS- 3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001 and BMS-1166 (WO2015/034820, WO2015/160641, WO2017/066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.), compounds of Incyte-1 to Incyte-6 (see WO2017/070089, WO2017/087777, WO2017/106634, WO2017/112730, WO2017/192961 and WO2017/205464) , CAMC-1 to CAMC-4 (see WO2017/202273, WO2017/202274, WO2017/202275 and WO2017/202276), RG_1 (see WO2017/118762) and DPPA-1 (Angew. Chem. Int. Ed. 2015, 54 , 11760-11764), etc.), PD-L1/VISTA antagonists (e.g. CA-170), PD-L1/TIM3 antagonists (e.g. CA-327), anti-PD-L2 antibodies, PD-L1 fusion proteins , PD-L2 fusion proteins (such as AMP-224), anti-CTLA-4 antibodies (such as Ipilimumab, Zalifrelimab, Nurulimab and Tremelimumab), anti-LAG-3 antibodies (such as Relatlimab, Ieramilimab, Fianlimab, Encelimab and Mavezelimab). etc.), anti-TIM3 antibodies (e.g. MBG453 and Cobolimab), anti-KIR antibodies (e.g. Lirilumab, IPH2101, LY3321367 and MK-4280), anti-BTLA antibodies, anti-TIGIT antibodies (e.g. Tiragolumab, Etigilimab, Vibostolimab and BMS -986207, etc.), anti-VISTA antibodies (e.g., Onvatilimab, etc.), anti-CD137 antibodies (e.g., Urelumab and Utomilumab, etc.), anti-CSF-1R antibodies/CSF-1R inhibitors (e.g., Cabiralizumab, Emactuzumab, LY3022855, Axatilimab, MCS -110, IMC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382, etc.), anti-OX40 antibodies (e.g., MEDI6469, Ivuxolimab, MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178 and MOXR0916, etc.), OX40L antibody (Oxelumab and Tavolimab), anti-HVEM antibody, anti-CD27 antibody (e.g., Varlilumab, etc.), anti-GITR antibody/GITR fusion protein (e.g., Efaprinermin alfa, Efgivanermin alfa, MK-4166, INCAGN01876, GWN323 and TRX-518, etc.), anti-CD28 antibody , anti-CCR4 antibodies (e.g., Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, Mirzotamab, Mirzotamab clezutoclax and Omburtamab, etc.), anti-ICOS agonist antibodies (e.g., Vopratelimab and GSK3359609, etc.), anti-CD4 antibodies (e.g., Zanolimumab and IT1208, etc.), anti-DEC-205 antibody/NY-ESO-1 fusion protein (CDX-1401), anti-SLAMF7 antibody (e.g., Azintuxizumab, Azintuxizumab vedotin and Elotuzumab, etc.), anti-CD73 antibody (e.g., Oleclumab and BMS-986179 etc.), PEGylated IL-2 (Bempegaldesleukin), IDO inhibitors (e.g. Epacadostat, Indoximod and Linrodostat etc.), TLR agonists (e.g. Motolimod, CMP-001, G100, Tilsotolimod, SD-101 and MEDI9197 etc.), adenosine A2A receptor antagonists (e.g., Preladenant, AZD4635, Taminadenant, Ciforadenant, etc.), anti-NKG2A antibodies (e.g., Monalizumab, etc.), anti-CSF-1 antibodies (e.g., PD0360324, etc.), immune enhancers (e.g., PV-10, etc.) ), IL-15 super agonists (e.g., ALT-803, etc.), soluble LAG3 (e.g., Eftilagimod alpha, etc.), anti-CD47 antibodies/CD47 antagonists (e.g., ALX148, etc.) and IL-12 antagonists (e.g., M9241, etc. ) and the like. Nivolumab can be produced according to the method described in WO2006/121168, Pembrolizumab can be produced according to the method described in WO2008/156712, and BMS-936559 can be manufactured according to the method described in WO2007/005874. Ipilimumab can be produced according to the method described in WO2001/014424.
Furthermore, other antibody drugs include, for example, anti-IL-1β antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).

[Prescription]
In order to use the compound of the present disclosure, etc. or a combination drug of the compound of the present disclosure and other drugs for the above purposes, they are generally 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 administered orally once or several times a day in the range of 1 ng to 2,000 mg per adult. or administered parenterally in the range of 0.1 ng to 200 mg per adult once to several times a day, or intravenously continuously administered in the range of 30 minutes to 24 hours a day be done. Of course, as mentioned above, since the dose varies depending on various conditions, there are cases where a dose smaller than the above dose is sufficient, and there are cases where administration beyond the above range is necessary.

The compounds of the present disclosure are administered to mammals (preferably humans, more preferably human patients) in pharmaceutically effective amounts.

Unless defined otherwise, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art belonging to the field of the invention.

In addition, the contents of all patent documents and non-patent documents or references explicitly cited in this specification can be cited here as part of this specification.

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

(In the formula,
R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group,
R ² represents (1) —CR 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; may be the same or different,
R ⁷ represents a hydrogen atom or a C1-C4 alkyl group,
n represents 0 or 1; ) or a salt thereof,
[2] R ² is (1) —CR ³ R ⁴ —CF ₃ or (2) a C3-C5 cycloalkyl group optionally substituted with 1 to 4 R ⁶ (preferably 1 to 4 (preferably 1 to 3, more preferably 1 or 2) R ⁶ optionally substituted cyclobutyl groups), the compound or a salt thereof according to [1],
[3] The compound or salt thereof according to [1] or [2] above, wherein R ³ is a hydrogen atom, a halogen atom or a hydroxyl group (more preferably, a hydrogen atom or a hydroxyl group);
[4] The compound 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), or the salt,
[5] ^R2 is

(Wherein, the symbols have the same meanings 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), and R ^6a is (1) a hydroxyl group, (2) a halogen atom or (3) represents a methyl group optionally substituted with 1 to 3 halogen atoms, and when p is 2 or 3, the plurality of R ^6a may be the same or different), the above [1] or [2] the compound or a salt thereof,
[6] ^R2 is

(wherein the symbols have the same meanings as in [1] above), the compound or salt thereof according to [5] above,
[7] 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) A compound or a salt thereof according to
[8] ^R2 is

(wherein the symbols have the same meanings as in [5] above), the compound or salt thereof according to [5] above,
[9] The compound or salt thereof according to [5] or [8] above, 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 [1] to [10], wherein n is 1;
[12] The compound or salt thereof according to any one of [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 [5] above), and the other symbols have the same meanings as in [1] above. ), the compound or salt thereof according to [1] above, which is a compound represented by
[14] The compound or salt thereof according to [13] above, 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 [13] above, 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 [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 the general formula (I) is
(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) (S)-2-amino-4-((R)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butylsulfonimidoyl)butanoic acid,
(19) ethyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate,
(20) isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate,
(21) ethyl (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate, and (22) isopropyl (2S)-2-amino -4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate, the compound or a salt thereof according to [1] above, which is a compound selected from the group consisting of;
[18] A pharmaceutical composition containing the compound represented by the general formula (I) described in [1] or a salt thereof,
[19] The pharmaceutical composition according to [18] above, which is a GCL inhibitor;
[20] The pharmaceutical composition according to [18] or [19] above, which is an agent for suppressing progression, suppressing recurrence and/or treating GCL-related diseases (e.g., cancer);
[21] An effective amount of the compound represented by the general formula (I) or a salt thereof according to [1] above is administered to a patient in need of suppression of progression, suppression of recurrence and/or treatment of a GCL-related disease (e.g., cancer). A method for suppressing progression, suppressing recurrence and/or treating a GCL-related disease (e.g., cancer), characterized by administering
[22] A compound represented by general formula (I) or a salt thereof according to [1], which is used for suppressing progression, suppressing recurrence, and/or treating GCL-related diseases (e.g., cancer), and
[23] Use of the compound represented by the general formula (I) or a salt thereof according to [1] above for producing an agent for suppressing progression, suppressing recurrence and/or treating GCL-related diseases (eg, cancer).
This disclosure, in one aspect, provides the following embodiments, but the scope of the invention is not limited thereto. Various changes or modifications are possible for those skilled in the art based on the description of this disclosure, and these changes or modifications are also included in the present invention.

[Synthesis example]
Solvents in parentheses shown in chromatographic separation and TLC indicate elution solvents or developing solvents used, and ratios represent volume ratios.
Solvents in parentheses shown in NMR indicate solvents used for measurement.

The compound names used herein generally use ACD/Name (registered trademark), a computer program that performs naming according to IUPAC rules, or use ChemDraw Professional (version 18.0, manufactured by PerkinElmer). used or named according to the IUPAC nomenclature.

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 (mobile phase (A): describing the ratio of mobile phase (B)): [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 (mobile phase (A): describe the ratio of mobile phase (B)): [ 0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:50; [1.21 min] 5:95; [1.6 min] 5:95; UV (PDA), ELSD, MS.
HPLC retention times indicate retention times under condition A for synthetic intermediates and under condition B for compounds of the present disclosure.

SFC fractionation was performed under any of the following conditions.
Condition C; column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250×20 mm ID); 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: UV220 nm.
Condition D; column: Daicel CHIRALPAK IC (particle size: 5 μm; column length: 250×20 mm ID); 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: 250×20 mm ID); 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: UV220 nm.

Reference Example 1: Methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[(4,4,4-trifluorobutyl)thio]butanoate methyl (2S )-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (750 mg) in DMF (10 mL) solution of potassium carbonate (415 mg) ) and 4,4,4-trifluorobutyl methanesulfonate (CAS: 164523-19-7) (806 mg) were added and stirred at 60° C. for 2 hours under nitrogen atmosphere. The reaction 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain the title compound (1.08 g) having the following physical data.
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] Iodobenzene diacetate (2.03 g) and ammonium carbamate (351 mg) were added to a methanol (10 mL) solution of the compound (1.08 g) produced in Butanoate Reference Example 1, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate 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 resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (820 mg) having the following physical data.
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]butane An aqueous solution (3 mL) of lithium hydroxide monohydrate (176 mg) was added to a solution of the compound (820 mg) prepared in Acid Reference Example 2 in THF (6 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (764 mg) having the following physical data.
HPLC retention time (min): 0.845

Example 1: (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid

A 5N hydrochloric acid aqueous solution (5 mL) was added to the compound (764 mg) produced in Reference Example 3, and the mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added to the reaction solution, and the solution was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, it was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (473 mg) having the following physical data.
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
Using the corresponding methanesulfonate instead of 4,4,4-trifluorobutyl methanesulfonate, the following procedure was carried out in the same manner as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1. A compound of the present disclosure having physical properties was obtained.

Example 1-1: (2S)-2-amino-4-[S-(2-cyclopentylethyl)sulfonimidoyl]butanoic acid

A compound of the present disclosure (23 mg) having the following physical properties was obtained.
HPLC retention time (min): 0.683;
MS (ESI, Pos.): 263 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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

A compound of the present disclosure (75 mg) having the following physical properties was obtained.
HPLC retention time (min): 0.567;
MS (ESI, Pos.): 249 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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

A 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

A 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) ⁺ ;
¹ H-NMR (D ₂ O): 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 2-(3,3-difluorocyclobutyl)ethanol (CAS: 1056467-54-9) (200 mg) in dichloromethane (2 mL) Diisopropylethylamine (0.38 mL) and mesylic anhydride (281 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 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 to obtain the title compound (314 mg) having the following physical data.
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

By using the compound produced in Reference Example 4 instead of 4,4,4-trifluorobutyl methanesulfonate and performing the same operations as Reference Example 1 → Reference Example 2 → Reference Example 3 → Example 1, A compound of the present disclosure (61 mg) having the following physical properties was obtained.
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

A compound of the present disclosure (25 mg) having the following physical properties was obtained.
HPLC retention time (min): 0.714;
MS (ESI, Pos.): 265 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 A solution of 1-(2-hydroxyethyl)cyclobutanol (CAS: 83237-27-8) (200 mg) in dichloromethane (2 mL) was added under ice cooling. Diisopropylethylamine (0.4 mL) and mesylic anhydride (329 mg) were added and stirred at room temperature for 2 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 to obtain the title compound (335 mg) having the following physical data.
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 methyl ( 2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (200 mg) in DMF (4 mL) was added potassium carbonate ( 166 mg) and the compound (202 mg) produced in Reference Example 5 were added, and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction 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 data.
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 Iodobenzene diacetate (132 mg) and ammonium carbamate (653 mg) were added to a solution of the compound (235 mg) prepared in Reference Example 6 in methanol (5 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate 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 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 data.
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) An aqueous solution (0.5 mL) of lithium hydroxide monohydrate (20 mg) was added to a solution of the compound (90 mg) prepared in Butanoic Acid Reference Example 7 in THF (1 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (62 mg) having the following physical data.
HPLC retention time (min): 0.773

Example 2: (2S)-2-amino-4-{S-[2-(1-hydroxycyclobutyl)ethyl]sulfonimidoyl}butanoic acid

A 5N hydrochloric acid aqueous 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, which was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, it was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (12 mg) having the following physical data.
MS (ESI, Pos.): 265 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 ethyl 4,4,4-trifluoro-3-hydroxybutanoate Imidazole (439 mg) and tert-butyldimethylchlorosilane (632 mg) were added to a solution of (CAS: 372-30-5) (600 mg) in DMF (2 mL), and the mixture was stirred overnight at room temperature. The reaction 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 to obtain the title compound having the following physical data.
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 In a THF (10 mL) solution of the residue obtained in Reference Example 9, Lithium borohydride (140 mg) and methanol (0.52 mL) were added under ice-cooling, and the mixture was stirred overnight at room temperature. 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 data.
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 Dichloromethane ( 2 mL) of the compound (200 mg) prepared in Reference Example 10 Diisopropylethylamine (0.2 mL) and mesylic anhydride (162 mg) were added to the solution under ice-cooling, and the mixture was stirred at room temperature for 2 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 to obtain the title compound (260 mg) having the following physical data.
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 methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637 -98-0) (180 mg) in DMF (8 mL), potassium carbonate (100 mg) and the compound prepared in Reference Example 11 (267 mg) were added, and the mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere. The reaction 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 data.
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) prepared in Reference Example 12 in methanol (5 mL) was added iodobenzene diacetate (690 mg) and ammonium carbamate (140 mg). ) was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate 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 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 data.
TLC: Rf 0.5 (hexane:ethyl acetate=1:1)

Reference Example 14: (2S)-4-[S-(3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4,4,4-trifluorobutyl)sulfonimidoyl]-2- ({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoic acid A solution of the compound (270 mg) prepared in Reference Example 13 in THF (2 mL) was mixed with an aqueous solution of lithium hydroxide monohydrate (44 mg) ( 1 mL) was added at 0° C. and 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 data.
HPLC retention time (min): 1.114

Example 3: (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoic acid

A 5N hydrochloric acid aqueous solution (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, which was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, it was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (47 mg) having the following physical data.
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

Using the corresponding methanesulfonate instead of the compound produced in Reference Example 11, by performing the same operation as Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3, this product having the following physical property values The disclosed compound (95 mg) was obtained.
HPLC retention time (min): 0.596;
MS (ESI, Pos.): 267 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (CAS: 338-03- A borane-THF complex (0.92 M, 3.9 mL) was added to a THF (2 mL) solution of 4) (200 mg) under ice-cooling, and the mixture was stirred overnight at room temperature. Methanol was added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure. Paratoluenesulfonyl chloride (266 mg) was added to a solution of the obtained residue in pyridine (2 mL), 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 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 data.
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

Using the compound prepared in Reference Example 15 instead of the compound prepared in Reference Example 11, the following physical properties were obtained by performing the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3. A compound of the present disclosure (62 mg) having
HPLC retention time (min): 0.329;
MS (ESI, Pos.): 307 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 4,4,4-trifluoro-3-(trifluoromethyl)-1, Paratoluenesulfonyl chloride (149 mg) was added to a solution of 3-butanediol (CAS: 21379-33-9) (139 mg) in pyridine (2 mL), and the mixture was stirred overnight at room temperature. 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 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 data.
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

Using the compound prepared in Reference Example 16 instead of the compound prepared in Reference Example 11, the following physical properties were obtained by performing the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3. A compound of the present disclosure (66 mg) having
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

Using the corresponding iodide (CAS: 40723-80-6) instead of the compound produced in Reference Example 11, by performing the same operations as in Reference Example 12 → Reference Example 13 → Reference Example 14 → Example 3, A compound of the present disclosure (110 mg) having the following physical properties was obtained.
HPLC retention time (min): 0.637;
MS (ESI, Pos.): 313 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 (3R)-4,4,4-trifluoro-3-hydroxybutanoic acid (CAS: 108211-36-5 ) (1 g) in DMF (10 mL) was added with potassium carbonate (1.75 g) and benzyl bromide (826 mL) and stirred at room temperature for 3 hours. The reaction was diluted with water and extracted with ethyl acetate: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 data.

Reference Example 18: Benzyl (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butanoate To a DMF (8 mL) solution of the residue (1.57 g) obtained in Reference Example 17 was added imidazole ( 861 mg) and TESCl (1.37 mL) were added and stirred overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate: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 data.
TLC: Rf 0.8 (hexane:ethyl acetate=5:1)

Reference Example 19: (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]-1-butanol In a THF (20 mL) solution of the compound (2.3 g) obtained in Reference Example 18, Lithium borohydride (276 mg) and methanol (1.0 mL) were added under ice-cooling, and the mixture was stirred overnight at room temperature. 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 give the title compound (1.32 g) having the following physical data.
TLC: Rf 0.6 (hexane:ethyl acetate=5:1)

Reference Example 20: (3R)-4,4,4-trifluoro-3-[(triethylsilyl)oxy]butyl methanesulfonate A solution of the compound (1.32 g) prepared in Reference Example 19 in dichloromethane (10 mL) was added with ice. Diisopropylethylamine (1.3 mL) and mesylic anhydride (1 g) were added under cooling, and the mixture was stirred at room temperature for 2 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 to obtain the title compound (1.7 g) having the following physical data.
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 methyl (2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) Potassium carbonate (554 mg) and the compound (1.62 g) prepared in Reference Example 20 were added to a solution of (1 g) in DMF (15 mL), and the mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was diluted with water and extracted with ethyl acetate: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 data.
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) prepared in Reference Example 21 in methanol (19 mL) was added iodobenzene diacetate (2.6 g) and ammonium carbamate (450 mg). was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate 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 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 data.
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) prepared in Reference Example 22 in dichloromethane (10 mL). , and stirred at room temperature for 2 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 resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3). The title compound (680 mg) having the following physical property values was obtained by fractionating the obtained compound by SFC (condition E).
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)butylsulfone Imidoyl)butanoate Palladium on carbon (68 mg) was added to a methanol (8 mL) solution of the compound (680 mg) prepared in Reference Example 23, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. 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 data.
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 Reference Example An aqueous solution (1 mL) of lithium hydroxide monohydrate (78 mg) was added to a THF (2 mL) solution of the compound (540 mg) prepared in 24 at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by diol silica gel column chromatography (dichloromethane:methanol=85:15) to obtain the title compound (360 mg) having the following physical data.
HPLC retention time (min): 0.792

Example 4: (S)-2-amino-4-((R,3R)-4,4,4-trifluoro-3-hydroxybutylsulfonimidoyl)butanoic acid

A 5N hydrochloric acid aqueous solution (3 mL) was added to the compound (360 mg) produced in Reference Example 25, and the mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the solution was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, it was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (236 mg) having the following physical data.
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 (3R)-4,4,4-trifluoro-3-hydroxybutanoic acid alternative , using (3S)-4,4,4-trifluoro-3-hydroxybutanoic acid (CAS: 128899-79-6), Reference Example 17 → Reference Example 18 → Reference Example 19 → the same as Reference Example 20 to obtain the title compound (1.78 g) having the following physical property values.
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 are carried out. Thus, the title compound (185 mg) having the following physical data was obtained.
MS (ESI, Pos.): 293 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): 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 methyl ( 2S)-4-mercapto-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)butanoate (CAS: 690637-98-0) (6.3 g) in DMF (100 mL) was Potassium (3.5 g) and 1-(2-bromoethyl)cyclobutanol (CAS: 1909309-61-0) (5 g) were added and stirred at 60° C. for 2 hours under nitrogen atmosphere. The reaction 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4) to obtain the title compound (8.7 g) having the following physical data.
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 Reference Example Diisopropylethylamine (10 mL), acetic anhydride (4.3 mL) and 4-dimethylaminopyridine (CAS: 1122-58-3) (610 mg) were added to a solution of the compound prepared in 27 (8.7 g) in dichloromethane (150 mL). and stirred overnight at room temperature. A saturated aqueous sodium hydrogencarbonate 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 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 data.
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 Iodobenzene diacetate (16.2 g) and ammonium carbamate (2.8 g) were added to a solution of the compound (9.35 g) prepared in Reference Example 28 in methanol (100 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate 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 resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (8.35 g) having the following physical data.
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 To a dichloromethane (4 mL) solution of the compound (500 mg) prepared in Reference Example 29, pyridine (1 mL) and benzyl chloroformate (0.25 mL) were added, and the mixture was stirred at room temperature for 2 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 resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3). The obtained compound was fractionated by SFC (condition D) to obtain the title compound (250 mg) having the following physical data.
HPLC retention time (min): 1.208

Reference Example 31: Methyl (S)-4-((R)-2-(1-acetoxycyclobutyl)ethylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate Compound prepared in Reference Example 30 Palladium on carbon (25 mg) was added to a solution of (250 mg) in methanol (4 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Ethyl acetate (4 mL) was added to the reaction mixture, and the mixture was filtered through Celite (trade name) to obtain the title compound (180 mg) having the following physical data.
HPLC retention time (min): 0.967

Reference Example 32: (S)-2-((tert-butoxycarbonyl)amino)-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid Compound prepared in Reference Example 31 An aqueous solution (1 mL) of lithium hydroxide monohydrate (54 mg) was added to a solution of (180 mg) in THF (2 mL) 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 data.
HPLC retention time (min): 0.837

Example 6: (S)-2-amino-4-((R)-2-(1-hydroxycyclobutyl)ethylsulfonimidoyl)butanoic acid

A 5N hydrochloric acid aqueous solution (2 mL) was added to the compound (156 mg) produced in Reference Example 32, and the mixture was stirred at room temperature for 2 hours. Water (2 mL) was added to the reaction solution, which was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of water, it was eluted with an 8% aqueous ammonia solution. The fractions reacting with ninhydrin were collected and concentrated to give the compound of the present disclosure (60 mg) having the following physical data.
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 methyl (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate ( 215 mg) in dichloromethane (10 mL), pyridine (1 mL) and benzyl chloroformate (0.17 mL) were added at 0° C., and the mixture was stirred overnight at room temperature. 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 title compound (87 mg) having the following physical property values was obtained by fractionating the obtained compound by SFC (condition C).
MS (ESI, Pos.): 547 (M+Na) ^<+> .

Reference Example 34: Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoate The compound prepared in Reference Example 33 ( 79 mg) in methanol (4 mL) was added with palladium carbon (35 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Ethyl acetate (4 mL) was added to the reaction solution, filtered through celite, and concentrated to obtain the title compound (60 mg) having the following physical property values.
MS (ESI, Pos.): 391 (M+H) ⁺ .

Reference Example 35: Methyl (S)-2-amino-4-((S)-4,4,4-trifluorobutylsulfonimidoyl)butanoate Methanol (1 mL) solution of the compound (60 mg) prepared in Reference Example 34 4N Hydrochloric acid/ethyl acetate solution (1 mL) was added to and stirred at room temperature for 3 hours. After concentrating the reaction solution, it was supported on an ion exchange resin (trade name: DOWEX (H ⁺ form)). After washing with a sufficient amount of methanol, it was eluted with a 2N ammonia/methanol solution. The fractions reacting with ninhydrin were collected and concentrated to give the title compound (39 mg) having the following physical data.
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. A 1N sodium hydroxide aqueous 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 (NH ₄ ⁺ form)) and eluted with a sufficient amount of water. The ninhydrin-reactive fractions were collected and concentrated to give the compound of the present disclosure (33 mg) having the following physical data.
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 Reference Example 1 An aqueous solution (0.5 mL) of lithium hydroxide monohydrate (16 mg) was added to a THF (1 mL) solution of the compound prepared in (70 mg) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (67 mg) having the following physical data.
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 Reference Example 36 ethanol (0.057 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (CAS: 25952-53-8) (56 mg) and 4 -Dimethylaminopyridine (CAS: 1122-58-3) (5 mg) was added and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogencarbonate 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 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 data.
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] Iodobenzene diacetate (123 mg) and ammonium carbamate (24 mg) were added to a solution of the compound (57 mg) prepared in Butanoate Reference Example 37 in methanol (3 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate 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 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 data.
HPLC retention time (min): 1.05

Example 8: (S)-2-amino-4-((R)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butylsulfonimidoyl)butanoic acid

Using the compound prepared in Reference Example 16 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 are performed. Thus, the title compound (1.3 g) having the following physical properties was obtained.
MS (ESI, Pos.): 361 (M+H) ⁺ ;
¹ H-NMR (D ₂ O): δ 2.28 - 2.35, 2.44 - 2.46, 3.27-3.49, 3.80-3.83.

Example 9: 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) produced in Reference Example 38, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by amino silica gel column chromatography (ethyl acetate:methanol=2:1) to obtain the compound of the present disclosure (45 mg) having the following physical data.
MS (ESI, Pos.): 305 (M+H) ⁺ ;
¹ H-NMR (CDCl ₃ ): 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 9-1: Isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate

A compound of the present disclosure (43 mg) having the following physical properties was obtained by performing the same operations as in Reference Example 37→Reference Example 38→Example 8 using 2-propanol instead of ethanol.
MS (ESI, Pos.): 319 (M+H) ⁺ ;
¹ H-NMR (CDCl ₃ ): 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.

Example 10: Ethyl (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate

Thionyl chloride (0.05 mL) was added to an ethanol (1 mL) solution of the compound (100 mg) prepared in Example 3 under ice-cooling, and the mixture was stirred at 60°C overnight. The reaction solution was concentrated, and the obtained residue was purified by amino silica gel column chromatography (ethyl acetate:methanol=2:1) to obtain the compound of the present disclosure (106 mg) having the following physical property values.
MS (ESI, Pos.): 321 (M+H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 1.29, 2.01 - 2.09, 2.16 - 2.28, 3.22 - 3.34, 3.58 - 3.62, 4.09 - 4.13, 4.21.

Example 10-1: Isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate

Thionyl chloride (0.05 mL) was added to a solution of the compound (100 mg) prepared in Example 3 in 2-propanol (1 mL) under ice cooling, and the mixture was stirred at 60° C. overnight. The reaction solution was concentrated, and the resulting residue was purified by amino silica gel column chromatography (ethyl acetate:methanol=2:1) to obtain the compound of the present disclosure (76 mg) having the following physical data.
MS (ESI, Pos.): 335 (M+H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 1.28, 2.01 - 2.05, 2.19 - 2.24, 3.24 - 3.32, 3.55 - 3.59, 4.08 - 4.15, 5.04.

[Pharmacological Example]
In the following pharmacological examples, as comparative examples, BSO (Toronto Research Chemicals) (CAS number: 83730-53-4) and compound number Ic described in Non-Patent Document 2 ((2S)-2-amino-4-[ (2R,S)-2-carboxybutyl-(R,S)-sulfonimidoyl]butanoic acid ((2S)-2-Amino-4-[(2R,S)-2-carboxybutyl-(R,S) -sulfonimidoyl]butanoic acid)) was used as Comparative Example 1 and Comparative Example 2, respectively.

[Pharmacological Example 1] Evaluation of GCL enzyme inhibitory activity (GCL-compound pre-incubation enzyme inhibitory activity evaluation system (substrate start))
Recombinant human GCLC and recombinant human GCLM were mixed at a molar ratio of 1:2 using an assay buffer containing 200 mmol/L Tris-HCl (pH 8.0), 20 mmol/L MgCl ₂ , 150 mmol/L KCl, 0.1% BSA. A human GCL enzyme solution was obtained by mixing at a concentration ratio and standing at 37° C. for 60 minutes to form a complex. Next, ATP at a final concentration of 0.2 mmol/L and each compound at a final concentration of 0.001, 0.003, 0.01, and 0.03 were added to a human GCL enzyme complex solution corresponding to a final concentration of 5 nmol/L GCLC. , 0.1, 0.3, 1, 3, 10 or 30 μmol/L. This human GCL enzyme complex-ATP-compound mixed solution was preincubated at room temperature for 60 minutes. Furthermore, the substrates L-glutamic acid (Nacalai tesque) and L-cysteine (L-cysteine, Nacalai tesque) were added to final concentrations of 1.2 and 0.2 mmol/L, respectively. , initiated the enzymatic reaction. Recombinant human GCLC and recombinant human GCLM, each with a His tag, were used after being expressed in E. coli and then purified with a nickel column and an anion exchange column. The enzymatic reaction was performed at room temperature using a 384-well polypropylene microplate, and the wells to which no enzyme was added were used as a blank group.

One hour after initiation of the enzymatic reaction, a 1% formic acid aqueous solution containing 20 μmol/L of ophthalmic acid was added as an internal standard substance to stop the enzymatic reaction. The upper part of the enzyme reaction plate was sealed with aluminum, and after centrifugation at 560 g for 5 minutes at room temperature, γ-glutamylcysteine (γ-glutamylcysteine), which is an enzyme reaction product, and ophthalmic acid, an internal standard, were analyzed using a Rapid Fire-Mass Spectrometry system. quantified. Taking the ratio of each quantitative value, the average value of the blank group is 100% inhibition, the average value of the compound-free group is 0% inhibition, the γ-glutamylcysteine production inhibition rate at each compound concentration is calculated, IC ₅₀ value asked for

The disclosed compounds 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 improved the binding affinity to E. coli GCLC by about 500 times (Ki value ratio) than BSO, but in this assay system , had an inhibitory activity equivalent to that of BSO.

In addition, the GCL enzyme inhibitory activity can also be evaluated by the following method.

(GCL enzyme inhibitory activity evaluation system (enzyme start))
Using an assay buffer containing 200 mmol/L Tris-HCl (pH 8.0), 20 mmol/L MgCl2, 150 mmol/L KCl, 0.1% BSA, recombinant human GCLC and recombinant human GCLM were mixed 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 final concentrations of 0.001 and 0.003. , 0.01, 0.03, 0.1, 0.3, 1, 3, 10 or 30 μmol/L. Subsequently, the human GCL-enzyme complex prepared in advance as described above was added to a concentration corresponding to a final concentration of 5 nmol/L GCLC to initiate the enzymatic reaction. Recombinant human GCLC and recombinant human GCLM each have a His tag, and were purified using a nickel column and an anion exchange column after being expressed in E. coli. The enzymatic reaction was performed at room temperature using a 384-well polypropylene microplate, and the wells to which no enzyme was added were used as a blank group.
One hour after initiation of the enzymatic reaction, a 1% formic acid aqueous solution containing 20 μmol/L of ophthalmic acid was added as an internal standard to terminate the enzymatic reaction. The upper part of the enzyme reaction plate was sealed with aluminum, centrifuged at 560 g for 5 minutes at room temperature, and then γ-glutamylcysteine as an enzyme reaction product and ophthalmic acid as an internal standard were quantified using a Rapid Fire-Mass Spectrometry system. Taking the ratio of each quantitative value, the average value of the blank group is 100% inhibition, the average value of the compound-free group is 0% inhibition, the γ-glutamylcysteine production inhibition rate at each compound concentration is calculated, IC ₅₀ value asked for Also in this system, the compounds of the present disclosure exhibited 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. Cells are DMEM/Ham's F-12 containing 2 mmol/L L-glutamine, 10% (vol%) FBS, 1% (vol%) Penicillin-Streptomycin-Amphotericin B Suspension (hereinafter referred to as 10% FBS-DMEM/Ham 's F-12) and cultured under conditions of 37° C., 5% CO ₂ and 95% Air.

[Pharmacological Example 2-1] In vitro GSH concentration measurement test (method)
Cells were seeded in flat-bottom 96-well plates at 2×10 ³ cells/100 μL/well and then incubated overnight at 37° C., 5% CO ₂ and 95% Air. On the day after cell seeding, each compound was added to the cultured cells, and after culturing for 24 hours under conditions of 37° C., 5% CO ₂ and 95% Air, the GSH concentration was measured using the GSH-Glo ^™ Glutathione Assay (Promega), and the ATP concentration was measured. It was measured by CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega). A numerical value obtained by dividing the GSH concentration by the ATP concentration was used as a substitute for cell number correction. Dose-response curves were generated and _IC50 values were calculated.

(result)
BSO (Comparative Example 1), Comparative Example 2, and Example 1, Example 1-2, Example 2, Example 3, Example 3-3, Example 4, Example 5, Example 6, Example The IC ₅₀ values of the GCL inhibitory activity of each compound prepared in Example 9-1, Example 10 and Example 10-1 are 1.5, 1.3, 0.2, 0.2, respectively. 0.3, 0.1, 0.2, 0.03, 0.03, 0.06, 0.007, 0.01, 0.02 and 0.02 μmol/L. While Comparative Example 2 had an inhibitory activity equivalent to that of BSO, the compound of the present disclosure had an improved GCL inhibitory activity in cell lines compared to BSO. For example, Example 1, Example 1-2, Example 1-5, Example 2, Example 3, Example 3-2, Example 3-3, Example 4, Example 5, Example 6, Each of the compounds produced in Example 9, Example 9-1, Example 10 and Example 10-1 had a GCL inhibitory activity of 7, 7, 3, 6-, 14-, 12-, 10-, 50-, 50-, 25-, 206-, 106-, 75- and 75-fold improvements were observed.

[Pharmacological Example 2-2] In vitro proliferation test (method)
Cells were seeded in flat-bottom 96-well plates at 2×10 ³ cells/100 μL/well and then incubated overnight at 37° C., 5% CO ₂ and 95% Air. On the day after the cell seeding, each compound was added to the cultured cells, and after culturing for 48 hours under conditions of 37°C, 5% CO ₂ , 95% Air, the ATP concentration was measured by CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega). measured by Dose-response curves were generated and _IC50 values were calculated.

(result)
BSO (Comparative Example 1) and Example 1, Example 1-2, Example 2, Example 3, Example 3-3, Example 4, Example 5, Example 6, Example 9, Example 9 -1, the IC ₅₀ values for cell growth inhibition of each compound prepared in Example 10 and Example 10-1 are 4.8, 0.5, 0.6, 0.5, 0.2, 0, respectively. .5, 0.06, 0.04, 0.4, 0.02, 0.03, 0.04 and 0.05 μmol/L, and the growth inhibitory activity against the activity of BSO in the cell line. , were found to be 11, 9, 11, 27, 9, 80, 120, 13, 292, 166, 133 and 94 times better, respectively.
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, have improved activity in cell lines compared to BSO. rice field.

[Pharmacological Example 3] In vivo test (cell culture)
Human ovarian cancer cell line TOV21G cells were purchased from ATCC. The same cells were cultured using 10% FBS-DMEM/Ham's F-12 under conditions of 37° C., 5% CO ₂ and 95% Air.

(In vivo xenograft test)
Female CB17/Icr-Prkdc ^scid /CrlCrlj mice aged 7-8 weeks at transplantation were used for the experiments. A cell suspension was prepared by mixing equal amounts of cultured cells and matrigel to a target concentration, and 2.5×10 ⁶ cells/0.1 mL/body of the cells were subcutaneously transplanted to the right flank of the mouse. For individuals in which tumors were observed, the major and minor diameters of the tumors were measured with an electronic caliper, and the tumor volume was calculated according to the following formula.
Tumor volume (mm ³ ) = long diameter of tumor (mm) × (short diameter of tumor (mm)) ² × 0.5
The compound was dissolved in water for injection and orally administered once a day using a probe.

(In vivo GSH concentration measurement test)
Individuals with an average tumor volume of 140 to 180 mm ³ 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 volume of 5% 5-Sulfosalic acid was added, and the tumor was crushed with a homogenizer under ice-cooling. The supernatant after centrifugation was used to measure total GSH concentration using the GSH/GSSG-Glo ^™ Assay (Promega). The amount of protein in the supernatant was quantified using the Pierce ^™ BCA Protein Assay Kit and used for correction.

[Pharmacological Example 3-1] Pharmacokinetic (PD) Evaluation in a TOV21G Cell Subcutaneous Implantation Model PD evaluation was performed using the amount of GSH in the tumor after a single administration as an index. On the 19th day after the subcutaneous implantation of TOV21G cells, the mice were divided into groups, and on the following day, BSO (Comparative Example 1) and the compound prepared in Example 2 were orally administered in a single dose. The average tumor volume in each group at the time of grouping was 141-158 mm ³ . 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 single administration (Fig. 1). BSO reduced tumor GSH in a dose-dependent manner, up to 21% at the highest dose of 750 mg/kg. The compound prepared in Example 2 dose-dependently reduced GSH in the tumor, with the highest dose of 300 mg/kg reducing it to 20% of control.

Next, the compound prepared in Example 3 was evaluated for PD using the amount of GSH in the tumor after single administration as an index. Grouping was performed 19 days after subcutaneous implantation of TOV21G, and a single dose of the same compound was orally administered 3 days later. The average tumor volume in each group on the day of administration was 141-177 mm ³ . Doses of the compound prepared in Example 3 were 30, 100 and 300 mg/kg, and the time point was 24 hours. In order to confirm the reproducibility and maximal effect of the compound prepared in Example 2, 300 mg/kg and 750 mg/kg doses of the same compound were also evaluated 24 hours after administration. As a result, it was confirmed that the compound prepared in Example 3 reduced tumor GSH 24 hours after administration (Fig. 2). Regarding the compound produced in Example 2, reproducibility was confirmed, and from the results of the previous test, there was a dose response at 100 mg/kg and 300 mg/kg, and from the results of this test, the maximum effect was shown at 300 mg/kg. it was thought.

From the above, 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. It was confirmed that each of the prepared compounds had about 3-fold and about 7.5-fold improvement in in vivo activity relative to BSO, respectively, on a dose ratio basis.

[Pharmacological Example 3-2] Evaluation of Antitumor Effect in TOV21G Cell Subcutaneous Implantation Model The in vivo antitumor effect of each compound produced in Examples 2 and 3 was evaluated. When the average tumor volume in each group reached 105 to 108 mm ³ , 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 dose of the compound prepared in Example 3 was 30 and 100 mg/kg. The final evaluation date for this test was Day 23.

Figure 3 shows the tumor volume of each group. 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 Example 2 300 mg/kg group, and 453 mm ³ in Example 3 30 mg/kg group. Example 3 414 mm ³ in the 100 mg/kg group. The mean tumor growth inhibition rate (TGI _mean ) of the BSO 750 mg/kg group was 44%, whereas the TGI _mean of Example 2 300 mg/kg group was 52%, Example 3 30 mg/kg group and 100 mg/kg. The group TGI _mean was 45% and 49%, respectively. From the above, 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. It was confirmed that each of the prepared compounds had about 3-fold and about 25-fold improvement in in vivo activity over BSO in dose ratios, 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.

[Pharmacokinetic Example]
The pharmacokinetics of each compound produced in Example 2, Example 3, Example 3-3, Example 4, and Example 5 were evaluated. A solution of 1 mg/kg of each compound dissolved in purified water was orally administered to rats, and plasma concentrations were measured after 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours (Fig. 4). ).
As shown in Table 2, each compound was confirmed to have improved kinetic properties in terms of T1/2, AUC or BA compared to BSO. The drug concentration in plasma was calculated using the following apparatus and conditions.

[Formulation example]
Formulation example 1
Each of the following ingredients is mixed by a conventional method and then tableted to obtain about 10,000 tablets each containing 10 mg of the 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 ... 870 g

Formulation example 2
After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into 5 mL ampules and lyophilized by a conventional method to obtain 10,000 ampoules containing 20 mg of the active ingredient per ampoule. be able to.
・(2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoic acid 200 g
・Mannitol 20g
・Distilled water 50L

Since the compounds of the present disclosure have GCL inhibitory activity, pharmaceuticals containing the compounds of the present disclosure as active ingredients are useful as agents for suppressing progression, suppressing recurrence, and/or treating GCL-related diseases such as cancer.

Claims (13)

general formula (I)

(In the formula,
R ¹ represents a hydrogen atom, a methyl group or a hydroxyl group,
R ² represents (1) —CR 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; may be the same or different,
R ⁷ represents a hydrogen atom or a C1-C4 alkyl group,
n represents 0 or 1; ) or a salt thereof. _The compound according ^{to claim} 1 ^{or its} salt. ^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 is (1) a hydroxyl group, (2) a halogen atom or (3) 1 to 3 halogen atoms represents a methyl group optionally substituted with, and when p is 2 or 3, the plurality of R ^6a may be the same or different), or a salt thereof according to claim 1 or 2. The compound or its salt 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

(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 according to claim 1, which is a compound represented by ^6. The compound or its salt according to any one of claims 1 to 5, wherein R7 is a hydrogen atom, an ethyl group or an isopropyl group. The compound represented by the general formula (I) is
(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) (S)-2-amino-4-((R)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butylsulfonimidoyl)butanoic acid,
(19) ethyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate,
(20) isopropyl (2S)-2-amino-4-[S-(4,4,4-trifluorobutyl)sulfonimidoyl]butanoate,
(21) ethyl (2S)-2-amino-4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate, and (22) isopropyl (2S)-2-amino -4-[S-(4,4,4-trifluoro-3-hydroxybutyl)sulfonimidoyl]butanoate, or a salt thereof according to claim 1, which is a compound selected from the group consisting of: A pharmaceutical composition containing the compound represented by the general formula (I) according to claim 1 or a salt thereof. The pharmaceutical composition according to claim 8, which is a GCL inhibitor. The pharmaceutical composition according to claim 8 or 9, which is a cancer progression suppression, recurrence suppression and/or therapeutic agent. Cancer progression characterized by administering an effective amount of the compound represented by the general formula (I) according to claim 1 or a salt thereof to a patient in need of cancer progression suppression, recurrence suppression and/or treatment. Suppression, prevention of recurrence and/or therapeutic methods. The compound represented by the general formula (I) according to claim 1 or a salt thereof, which is used for suppressing progression, suppressing recurrence and/or treatment of cancer. Use of the compound represented by the general formula (I) according to claim 1 or a salt thereof for the production of a cancer progression suppression, recurrence suppression and/or therapeutic agent.

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