Novel thiadiazole compounds and their use as glutaminase-1 inhibitors

Abstract

This invention provides a novel thiadiazole compound having glutaminase-1 inhibitory activity. [Solution] A compound of formula I or a pharmaceutically acceptable salt thereof. TIFF2026095053000008.tif3791 R 1 R includes hydrogen, halogens, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, etc. 2 is hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkoxy, etc.; ring A is an optionally substituted aryl or an optionally substituted heteroaryl; m and n are each integers selected from 1 to 3.

Description

[Technical Field]

[0001] This invention relates to a novel thiadiazole compound having glutaminase-1 inhibitory activity. [Background technology]

[0002] Glutaminase is an enzyme that produces glutamic acid from glutamine and is responsible for the first step in glutamine metabolism. There are two types of glutaminase: glutaminase 1 (GLS1), which is widely found in the kidneys, small intestine, and brain, and glutaminase 2 (GLS2), which is found only in the liver. GLS1 is overexpressed in various cancer cells, and GLS1 inhibitors such as CB-839 are expected to be used as novel anticancer drugs, particularly as treatments for triple-negative breast cancer and hepatocellular carcinoma, which are characterized by protein overexpression.

[0003] In recent years, GLS1 inhibitors have also been reported to selectively remove senescent cells, improving aging phenomena, geriatric syndromes, and lifestyle-related diseases, as well as showing effects in preventing obesity. Facing the problem of an aging population, the number of patients with dementia and metabolic syndrome, as well as cancer, is on the rise. If these diseases can be prevented, it will not only contribute to reducing medical costs but also to the effective use of limited medical resources. The present invention aims to obtain candidate compounds as novel inhibitors of GLS1, an attractive drug discovery target. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Okada, T. et al. Bioorg. Med. Chem. Lett. 2023, 93, 129438 [Overview of the project] [Problems that the invention aims to solve]

[0005] The primary objective of the present invention is to provide a novel thiadiazole compound having glutaminase-1 inhibitory activity. Furthermore, the present invention also aims to provide a pharmaceutical product containing a novel thiadiazole compound having excellent glutaminase-1 inhibitory activity. [Means for solving the problem]

[0006] The inventors have discovered that novel thiadiazole compounds having a specific structure exhibit excellent glutaminase-1 inhibitory activity, and that these may be useful as glutaminase-1 inhibitors.

[0007] In other words, embodiments of the present invention include the following [1] to

[15] . [1] Formula I: [ka] [During the ceremony, R 1 is hydrogen, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl or heteroaryl; Ring A is an optionally substituted aryl or optionally substituted heteroaryl; m and n are integers selected from 1 to 3, respectively. A compound represented by or a pharmaceutically acceptable salt thereof. [2] R 1 C may be substituted with hydrogen, halogen, or other elements. 1-6Alkyl or optionally substituted C 1-6 The compound according to [1] or a pharmaceutically acceptable salt thereof, which is alkenyl. [3] R 2 is optionally substituted C 1-6 The compound according to [1] or a pharmaceutically acceptable salt thereof, which is alkyl or optionally substituted arylalkyl. [4] Ring A is (i) halogen, (ii) cyano, and (iii) hydroxy The compound according to [1] or a pharmaceutically acceptable salt thereof, which is aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from [5] The compound according to [4] or a pharmaceutically acceptable salt thereof, wherein the aryl is phenyl. [6] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1. [7] A medicament comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof. [8] A glutaminase 1 inhibitor comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof. [9] A method for inhibiting glutaminase 1, comprising administering to a subject in need thereof the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[10] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use in inhibiting glutaminase 1.

[11] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a glutaminase 1 inhibitor.

[12] A prophylactic or therapeutic agent for diseases involving glutaminase 1, comprising any of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof.

[13] A method for preventing or treating a disease involving glutaminase 1, comprising administering one of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[14] Any compound [1] to [6] or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diseases involving glutaminase 1.

[15] The use of any of the compounds [1] to [6] or their pharmaceutically acceptable salts in the manufacture of prophylactic or therapeutic agents for diseases involving glutaminase 1. [Effects of the Invention]

[0008] The compounds of the present invention exhibit glutaminase-1 inhibitory activity and can be used as pharmaceuticals to prevent or treat diseases or disorders involving glutaminase-1. [Brief explanation of the drawing]

[0009] [Figure 1] The compounds according to the present invention exhibit GLS1 inhibitory activity. The compounds according to the present invention show concentration-dependent GLS1 inhibitory activity, and in particular, YM-10 and YM-12 showed high inhibitory activity. [Modes for carrying out the invention]

[0010] The following provides detailed definitions of the terms used in this specification. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0011] The abbreviations used herein have the following meanings: The following abbreviations are used in the examples. EtOH: Ethanol THF: Tetrahydrofuran DMF: N,N-dimethylformamide MeCN: Acetonitrile TFA: Trifluoroacetic acid Et3N: Triethylamine LiOH: Lithium hydroxide EDC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole rt: room temperature mL: milliliter mmol: millimoles M: Molar concentration (mol / L) mM: Millimole concentration (mol / L) 1 H-NMR: Proton Nuclear Magnetic Resonance DMSO-d6: Deuterated Dimethyl Sulfoxide

[0012] The definitions of each term used in this specification are described in detail below.

[0013] As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine atoms.

[0014] Examples of the "alkyl" used herein include alkyl groups having one to eight carbon atoms, preferably one to six carbon atoms, in a linear or branched chain. Specifically, examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, isoamyl, -CH(CH2CH3)2, hexyl, isohexyl, -CH2CH2C(CH3)3, -CH2CH(CH2CH3)2, heptyl, isoheptyl, octyl, isooctyl, and the like.

[0015] As used herein, examples of the alkyl moieties of “alkylcarbonyl,” “alkoxy,” “alkoxycarbonyl,” “monoalkylamino,” “dialkylamino,” and “arylalkyl” may be the same as those of “alkyl” described above.

[0016] Examples of “alkoxy” as used herein may include alkoxy having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, in a straight chain or branched chain. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, etc. may be mentioned.

[0017] Examples of “cycloalkyl” as used herein may include saturated hydrocarbon groups having 3 to 10 carbon atoms and being monocyclic to tricyclic. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and bicyclo[3.2.1]octyl, adamantyl (also referred to as tricyclo[3.3.1.1 3,7 decanyl) etc. may be mentioned.

[0018] Examples of “alkenyl” as used herein may include straight-chain or branched-chain alkenyl having 2 to 8 carbon atoms and having 1 or 2 double bonds. Specifically, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, etc. may be mentioned. Preferably, it is alkenyl having 2 to 6 carbon atoms, more preferably alkenyl having 2 to 4 carbon atoms.

[0019] Examples of "aryl" include aromatic hydrocarbon groups that are 1- to 3-cyclic and have 6 to 14 carbon atoms. Specifically, examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Phenyle is particularly preferred.

[0020] The aryl portion of "arylalkyl" can be the same as the "aryl" mentioned above. Specifically, examples of "arylalkyl" include phenylmethyl (benzyl), phenylethyl (phenethyl), phenylpropyl, phenylbutyl, and phenylpentyl.

[0021] Examples of "heteroaryls" include 1-2 cyclic aromatic heterocyclic groups having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms within the ring, and composed of 5 to 10 ring-constituting atoms. Specifically, these include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrrolyl, 4-pyrrolyl), and triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazolyl). (Zol-4-yl), tetrazolyl (e.g., 5-tetrazolyloxazol (e.g., 2-oxazol, 4-oxazol, 5-oxazol)), isoxazol (e.g., 3-isoxazol, 4-isoxazol, 5-isoxazol)), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, i Sothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyridazinyl, 4-pyridazinyl, 5-pyridinyl), pyrazinyl (e.g., 2-pyridazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4- Examples include benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl).More preferably, examples include furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), and the like.

[0022] "Cyano" refers to a group represented by -CN.

[0023] "Hydroxy" refers to a group represented by -OH.

[0024] "Sulfonyl" refers to a group represented by -SO2-.

[0025] "Sulfinyl" refers to a group represented by -SO-.

[0026] "May be substituted" means that the specified group may or may not be substituted, i.e., it may be substituted or unsubstituted. For example, "may be substituted alkyl" means both unsubstituted and substituted alkyl. Examples of substituents that substitute for the specified group include, but are not limited to, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, halogen, cyano, hydroxy, amino, aryl, or heteroaryl as defined above.

[0027] The compounds of the present invention can be produced using known compounds or intermediates readily synthesized from known compounds, for example, by the method described below, the examples described later, or other known methods. In the production of the compounds of the present invention, if the starting materials have substituents that affect the reaction, it is common practice to protect the starting materials with an appropriate protecting group beforehand using a known method before carrying out the reaction. The protecting group can be deprotected after the reaction using a known method.

[0028] The pharmaceutically acceptable salts of the present invention can be produced using known compounds or intermediates readily synthesized from known compounds, for example, by the method described below, the examples described later, or other known methods. In the production of the pharmaceutically acceptable salts of the present invention, if the starting material has substituents that affect the reaction, it is common practice to protect the starting material with an appropriate protecting group beforehand using a known method before carrying out the reaction. The protecting group can be deprotected after the reaction using a known method.

[0029] The compounds according to the present invention can be used as pharmaceuticals as they are, but they can also be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts by known methods. Examples of pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; or salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0030] The compounds according to the present invention may incorporate solvent molecules and become solvates when left in the atmosphere or by recrystallization, and such solvates are also included in the compounds according to the present invention. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0031] The compound according to the present invention has glutaminase 1 inhibitory activity, as shown in the test examples described below.

[0032] Therefore, one embodiment of the present invention provides a glutaminase 1 inhibitor containing a compound according to the present invention.

[0033] Furthermore, one embodiment of the present invention provides a method for inhibiting glutaminase 1, which includes administering the compound according to the present invention to a subject that requires it.

[0034] Furthermore, one embodiment of the present invention provides a compound according to the present invention for use in glutaminase 1 inhibition.

[0035] Furthermore, one embodiment of the present invention provides the use of the compound according to the present invention in the production of a glutaminase 1 inhibitor.

[0036] One embodiment of the present invention provides a preventive or therapeutic agent for a disease involving glutaminase 1, comprising a compound according to the present invention.

[0037] Furthermore, one embodiment of the present invention provides a method for preventing or treating a glutaminase-1-related disease, comprising administering the compound according to the present invention to a subject in need thereof.

[0038] Furthermore, one embodiment of the present invention provides a compound according to the present invention for use in the prevention or treatment of diseases involving glutaminase 1.

[0039] Furthermore, one embodiment of the present invention provides the use of the compound according to the present invention in the manufacture of a preventive or therapeutic agent for a disease involving glutaminase 1.

[0040] As used herein, "subject" means a human or non-human animal that has or is suspected of having a disease involving glutaminase 1. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0041] The compound according to the present invention can be administered to mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys by being used as is or mixed with a pharmaceutically acceptable carrier, etc., to form a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.

[0042] As a carrier, one or more conventionally accepted pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition according to the present invention is preferably administered in dose unit form. The pharmaceutical composition can be administered intratissue, orally, intravenously, topically (transdermally, ophthalmoscopy, intraperitoneally, intrathoracically, etc.), or rectally. The pharmaceutical composition according to the present invention is administered in a dosage form suitable for these administration methods.

[0043] The dosage for pharmaceutical use should preferably be adjusted considering the patient's condition, such as age, weight, type and severity of the disease, the route of administration, the type of compound of the present invention, whether it is a salt or not, and the type of salt.

[0044] The compounds according to the present invention can be produced, for example, in accordance with the examples or known methods described later, from compounds that are known themselves or intermediates that can be easily prepared from known compounds.

[0045] If the solvents, reagents, and raw materials used in the production of the compounds according to the present invention are commercially available, the commercially available products can be used as is. Furthermore, the compounds obtained in each step of the production method described below, and the raw materials used, may form salts, and can be converted to other types of salts or free forms by known methods. Conversely, if the compounds obtained in each step of the production method below, or the raw materials used, are free forms, they can be converted to the desired salt by known methods. Examples of such salts include those similar to the salts used in the compounds according to the present invention described above.

[0046] The compounds according to the present invention can be produced using the following synthesis method.

[0047] 1The 1H NMR spectra were measured using a JEOL JNM-A400 or JEOL JNM-ECX500 (manufactured by JEOL Ltd.). Observed peaks are expressed as chemical shift values ​​δ (ppm) (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, sext=sectet, m=multiplet, dd=doubledoublet). J represents the coupling constant.

[0048] In one embodiment, the compound according to the present invention can be produced according to the synthesis method shown in Scheme 1. Scheme 1: Synthesis of YM-01~YM-09, YM-11 and YM-12 [ka]

[0049] Synthesis of Compound 2 Under an argon gas atmosphere, bromoacetic acid (1.2 equivalents) and potassium hydroxide (2 equivalents) were sequentially added to an ethanol solution of 2-amino-5-mercapto-1,3,4-thiadiazole (1 equivalent) under ice cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the pH of the resulting residue was adjusted to approximately 7 by adding 10% HCl (aq.). The precipitated solid was washed with dichloromethane and water to obtain crude carboxylic acid. The obtained crude carboxylic acid (compound 2) was used in the next reaction without purification.

[0050] Synthesis of Compound 3 Under an argon gas atmosphere, triethylamine (1.5 equivalents), 1-hydroxybenzotriazole monohydrate (1.5 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalents), and benzylamine (1.5 equivalents) were sequentially added to a dichloromethane solution of the obtained crude carboxylic acid (compound 2) (1 equivalent) at room temperature, and the mixture was stirred at room temperature for 20 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the target thiadiazoleamine (compound 3).

[0051] Synthesis of Compound 4 Under an argon gas atmosphere, triethylamine (1.5 equivalents) was added at room temperature to an acetonitrile solution of the obtained thiadiazoleamine (compound 3) (1 equivalent), and then chloroacetyl chloride (1.5 equivalents) was added under ice cooling. The reaction mixture was then stirred at 80°C for 5 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting solid was washed with dichloromethane (5 mL x 3) to obtain the target amide derivative (compound 4).

[0052] Synthesis of YM-01~YM-09, YM-11, and YM-12 Under an argon gas atmosphere, the corresponding benzylamine derivative (1.5 equivalents) and triethylamine (1.5 equivalents) were sequentially added at room temperature to a solution of the obtained amide derivative (compound 4) (1 equivalent) in N,N-dimethylformamide. The reaction mixture was then stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain the target YM derivatives YM-01 to YM-09, YM-11, and YM-12.

[0053] In one embodiment, the compound according to the present invention can be produced according to the synthesis method shown in Scheme 2. Scheme 2: Synthesis method for YM-10 [ka]

[0054] Synthesis of Compound 7 Under an argon gas atmosphere, tert-butyl 4-formylbenzylcarbamate (1.2 equivalents) and potassium hydroxide (2 equivalents) were sequentially added to an ethanol solution of 4-fluoroacetophenone (1 equivalent) under ice cooling, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the pH of the resulting residue was adjusted to approximately 5 by adding 10% HCl (aq.). The aqueous layer was extracted with dichloromethane (5 mL x 3), and the organic layers were combined and dried over sodium sulfate. The solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to obtain the target chalcone derivative.

[0055] Synthesis of compound 8 Under an argon gas atmosphere, trifluoroacetic acid (10 equivalents) was added at room temperature to a dichloromethane solution of the obtained chalcone derivative (1 equivalent), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator to obtain the crude benzylamine derivative. The obtained crude benzylamine derivative was used in the next reaction without purification. Under an argon gas atmosphere, triethylamine (3 equivalents), 1-hydroxybenzotriazole monohydrate (1.5 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalents), and thiadiazole carboxylic acid (1.1 equivalents) were sequentially added at room temperature to a dichloromethane solution of the obtained crude benzylamine derivative (1 equivalent), and the mixture was stirred at room temperature for 22 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the target thiadiazoleamine.

[0056] Synthesis of compound 9 Under an argon gas atmosphere, triethylamine (1.5 equivalents) was added at room temperature to an acetonitrile solution of the obtained thiadiazoleamine (1 equivalent), and then chloroacetyl chloride (1.5 equivalents) was added under ice cooling. The reaction mixture was then stirred at 80°C for 5 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting solid was washed with dichloromethane (5 mL x 3) to obtain the target amide derivative.

[0057] YM-10 synthesis Under an argon gas atmosphere, a solution of the obtained amide derivative (1 equivalent) in N,N-dimethylformamide was sequentially added to benzylamine derivative (1.5 equivalents) and triethylamine (1.5 equivalents) at room temperature. The reaction mixture was then stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain the target YM-10.

[0058] YM-01 to YM-12 manufactured by the above synthesis method 1 The 1H-NMR spectrum is shown below. N-benzyl-2-((5-(2-((4-chlorobenzyl)(methyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-01) 1 H-NMR (400MHz, DMSO-d6)δ 2.23 (3H, s), 3.42 (2H, s), 3.64 (2H, s), 4.02 (2H, s), 4.28 (2H, d, J=6.0Hz) , 7.18-7.23(3H, m), 7.26-7.30(2H, m), 7.37(4H, s), 8.72(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((2-chlorobenzyl)(methyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-02) 1H-NMR (400MHz, DMSO-d6)δ 2.31 (3H, s), 3.51 (2H, s), 3.78 (2H, s), 4.02 (2H, s), 4.29 (2H, d, J=6.0Hz), 7.18-7.35 (5H, m), 7.41 (1H, dd, J=8.0, 1.2Hz), 7.55 (1H, dd, J=8.0, 2.0Hz), 8.72 (1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((3-chlorobenzyl)(methyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-03) 1 H-NMR (400MHz, DMSO-d6)δ 2.23(3H, s), 3.45(2H, s), 3.66(2H, s), 4.02(2H, s), 4.29(2H, d, J=5.6Hz), 7.19-7.37(8H, m), 7.44(1H, s), 8.72(1H, t, J=5.6Hz) N-benzyl-2-((5-(2-((4-chlorobenzyl)(ethyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-04) 1 H-NMR (400MHz, DMSO-d6)δ 0.99 (3H, t, J=7.6Hz), 2.59 (2H, q, J=7.6Hz), 3.46 (2H, s), 3.72 (2H, s), 4.01 (2H, s), 4.29 (2H , d, J=5.6Hz), 7.18-7.22(3H, m), 7.26-7.30(2H, m), 7.34-7.39(4H, m), 8.72(1H, t, J=5.6Hz) N-benzyl-2-((5-(2-(benzyl(4-chlorobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-05) 1 H-NMR (400MHz, DMSO-d6)δ 3.44(2H, s), 3.74(2H, s), 3.75(2H, s), 4.02(2H, s), 4.29(2H, d, J=6.0Hz), 7.19-7.41(14H, m), 8.73(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((4-chlorobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-06) 1 H-NMR (400MHz, DMSO-d6)δ 3.47(2H, s), 3.75(2H, s), 4.01(2H, s), 4.28(2H, d, J=6.0Hz), 7.19-7.30(5H, m), 7.37(4H, s), 8.71(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((4-fluorobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-07) 1 H-NMR (400MHz, DMSO-d6)δ 3.47(2H, s), 3.75(2H, s), 4.00(2H, s), 4.28(2H, d, J=6.0Hz), 7.14(2H, t, J=9.2Hz), 7 .18-7.23(3H, m), 7.26-7.31(2H, m), 7.38(2H, dd, J=8.4, 5.2Hz), 8.71(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((4-bromobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-08) 1 H-NMR (400MHz, DMSO-d6)δ 3.46(2H, s), 3.73(2H, s), 4.01(2H, s), 4.29(2H, d, J=6.0Hz), 7.18-7.2 4(3H, m), 7.26-7.31(4H, m), 7.50(2H, d, J=8.4Hz), 8.71(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((4-chlorobenzyl)(propyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-09) 1H-NMR (400MHz, DMSO-d6)δ 0.79(3H, t, J=7.2Hz), 1.43(2H, sext, J=7.2Hz), 2.50(2H, t, J=7.2Hz), 3.47(2H, s), 3.73(2H, s), 4.02 (2H, s), 4.29(2H, d, J=6.0Hz), 7.18-7.23(3H, m), 7.26-7.30(2H, m), 7.36(4H, s), 8.73(1H, t, J=6.0Hz) (E)-2-((4-chlorobenzyl)(methyl)amino)-N-(5-((2-((4-(3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)benzyl)amino)-2-oxoethyl)thio)-1,3,4-thiadiazole-2-yl)acetamide(YM-10) 1 H-NMR (400MHz, DMSO-d6)δ 2.21(3H, s), 3.42(2H, s), 3.62(2H, s), 4.04(2H, s), 4.34(2H, d, J=6.0Hz), 7.30(2H, d, J=8.0Hz), 7.34(4H, s), 7.39(2H, t, J=9 .2Hz), 7.71(1H, d, J=15.6Hz), 7.81(2H, d, J=8.0Hz), 7.91(1H, d, J=15.6Hz), 8.24(2H, dd, J=9.2, 5.6Hz), 8.72(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-((4-iodobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-11) 1 H-NMR (400MHz, DMSO-d6)δ 3.45(2H, s), 3.71(2H, s), 4.01(2H, s), 4.29(2H, d, J=6.0Hz), 7.15-7.30(7H, m), 7.67(2H, d, J=8.4Hz), 8.72(1H, t, J=6.0Hz) N-benzyl-2-((5-(2-(bis(4-chlorobenzyl)amino)acetamide)-1,3,4-thiadiazole-2-yl)thio)acetamide (YM-12) 1H-NMR (400MHz, DMSO-d6)δ 3.44(2H, s), 3.74(4H, s), 4.02(2H, s), 4.29(2H, d, J=5.6Hz), 7.19-7.30(5H, m), 7.35-7.40(8H, m), 8.73(1H, t, J=5.6Hz) 8.15 (1H, s)

[0059] Tables 1 and 2 show the structural formulas of YM-01 to YM-12 produced by the above synthesis method. [Table 1] [Table 2]

[0060] Test example: Evaluation of Glu production inhibition using mouse recombinant GLS1. The evaluation was basically carried out according to the method of Okada, T. et al. Bioorg. Med. Chem. Lett. 2023, 93, 129438, but some modifications were made to the method due to the use of a new lot of GLS1. 1.25 μL of a candidate GLS1 inhibitor compound (test compound) dissolved in solvent (DMSO) or 1.25 μL of solvent (DMSO) alone (for control) was added to 17.75 μL of reaction mixture (Tris-acetate (50 mM, pH 8.6), KPO4 (150 mM, pH 8.0), EDTA (0.2 mM, pH 8.0)), and then mixed with 1.0 μL of recombinant GLS1 stock solution to a total volume of 20 μL, which was incubated at 37°C for 15 minutes. L-glutamine solution (100 mM) was then added and incubated at 37°C for 30 minutes. The Glu concentration in the reaction solution was calculated by measuring the absorbance at 550 nm using a UV-Vis spectrophotometer (iMark, Bio-Rad) with the L-glutamic acid measurement kit "Yamasa" NEO (manufactured by Yamasa Soy Sauce Co., Ltd.). The results are shown in Figure 1. [Industrial applicability]

[0061] Since the compounds of the present invention exhibit glutaminase-1 inhibitory activity, they can be used in the manufacture of pharmaceuticals for preventing or treating diseases involving glutaminase-1, such as cancer or age-related diseases.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, R １ is hydrogen, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl or heteroaryl; Ring A is an optionally substituted aryl or optionally substituted heteroaryl; m and n are integers selected from 1 to 3. A compound represented by or a pharmaceutically acceptable salt thereof.

2. R １ C may be substituted with hydrogen, halogen, or other elements. １－６ Alkyl or optionally substituted C １－６ The compound according to claim 1, which is an alkenyl, or a pharmaceutically acceptable salt thereof.

3. R ２ C may be substituted. １－６ The compound according to claim 1, which is alkyl or optionally substituted arylalkyl, or a pharmaceutically acceptable salt thereof.

4. Ring A is (i) halogen, (ii) Cyano, and (iii) hydroxy The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is an aryl or heteroaryl which may be substituted with one to three substituents selected from the above.

5. The compound according to claim 4, wherein the aryl is phenyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein m is 1 and n is 1, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical product comprising a compound according to claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. A glutaminase 1 inhibitor comprising a compound according to claims 1 to 6 or a pharmaceutically acceptable salt thereof.

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