Novel pyridazine compounds and their use as serine racemase inhibitors

Abstract

This provides a novel pyridazine compound having serine racemase inhibitory activity. [Solution] A compound of formula I or a pharmaceutically acceptable salt thereof. TIFF2026095065000013.tif3172

Description

[Technical Field]

[0001] This invention relates to a novel pyridazine compound having serine racemase inhibitory activity. [Background technology]

[0002] D-serine, present in the mammalian brain, is synthesized from L-serine by the racemizing enzyme serine racemase (SRR). In the brain, D-serine functions as an agonist of the NMDA receptor, one of the glutamate receptors responsible for excitatory neurotransmission. That is, the NMDA receptor is activated when both glutamate and D-serine bind to it, and is involved in higher brain functions such as memory and learning by allowing Na+ and Ca2+ to pass into the cell. On the other hand, excessive activation of the NMDA receptor causes neuronal cell death. For example, in Alzheimer's disease patients, excessive accumulation of amyloid-beta peptide increases the expression levels of glutamate and D-serine, resulting in NMDA receptor-mediated neuronal cell death. Since the brain D-serine content decreases to 10% of normal in SRR gene knockout mice, it is inferred that SRR is the main player in D-serine production. Therefore, SRR inhibitors are considered to have the potential to become new treatments for Alzheimer's disease.

[0003] However, the SRR inhibitors currently reported are malonic acid (IC) 50 The available SRR inhibitors are limited to those with a value of 0.77 mM (mutant-type SRR) or dipeptides, which have low specificity and are undesirable as pharmaceuticals. Therefore, there is a need for the development of more practical novel SRR inhibitors. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] H. Mori, et al. Bioorg. Med. Chem. 2017, 25, 107-115 [Non-Patent Document 2] H. Mori, et al. Bioorg. Med. Chem. 2017, 25, 3736-3745 [Non-Patent Document 3] H. Mori, et al. Bioorg. Med. Chem. Lett. 2018, 28, 441-445 [Summary of the Invention] [Problems to be Solved by the Invention]

[0005] The main object of the present invention is to provide a novel pyridazine compound having serine racemase inhibitory activity. Another object of the present invention is also to provide a medicament containing a novel pyridazine compound having excellent serine racemase inhibitory activity. [Means for Solving the Problems]

[0006] The present inventors have discovered that novel pyridazine compounds having a specific structure exhibit excellent serine racemase inhibitory activity and may be useful as serine racemase inhibitors.

[0007] That is, embodiments of the present invention can include the following [1] to

[15] . [1] Formula I: [Chemical Formula] [In the formula, R 1 is hydrogen, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl; R 2is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 3 is hydrogen, halogen, -CO2R 4 hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl; R 4 is hydrogen or optionally substituted alkyl; X is O, S, SO or SO2; n is an integer selected from 1 to 3〕 a compound represented by or a pharmaceutically acceptable salt thereof. [2] R 1 is hydrogen, halogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl or optionally substituted amino, the compound according to [1] or a pharmaceutically acceptable salt thereof. [3] R 2 is hydrogen or optionally substituted C 1-6 alkyl, the compound according to [1] or a pharmaceutically acceptable salt thereof. [4] R 3 is -CO2R 4 hydroxy or optionally substituted amino, the compound according to [1] or a pharmaceutically acceptable salt thereof. [5] R 4 is hydrogen or C 1-6 alkyl, the compound according to [1] or a pharmaceutically acceptable salt thereof. [6] The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted amino is selected from amino, monoalkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, mono(alkylsulfonyl)amino, di(alkylsulfonyl)amino, and arylsulfonylamino. [7] A pharmaceutical product comprising any of the compounds listed in [1] to [6] or a pharmaceutically acceptable salt thereof. [8] A serine racemase inhibitor comprising any of the compounds described in [1] to [6] or a pharmaceutically acceptable salt thereof. [9] A method for inhibiting serine racemase, comprising administering one of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

[10] Any of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof for use in serine racemase inhibition.

[11] Use of any of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of serine racemase inhibitors.

[12] A prophylactic or therapeutic agent for serine racemase-related diseases comprising any of the compounds [1] to [6] or a pharmaceutically acceptable salt thereof.

[13] A method for preventing or treating a serine racemase-related disease, 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 serine racemase.

[15] Any compound [1] to [6] or a pharmaceutically acceptable salt thereof, in the manufacture of a prophylactic or therapeutic agent for a disease involving serine racemase. [Effects of the Invention]

[0008] Because the compounds of the present invention exhibit serine racemase inhibitory activity, they can be used as pharmaceuticals to prevent or treat diseases or disorders involving serine racemase. [Brief explanation of the drawing]

[0009] [Figure 1] The results of the serine racemase inhibitory activity test of the compound of the present invention are shown. [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 Et3N: Triethylamine LiOH: Lithium hydroxide EDC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(II) PdCl2(dppf): Bis(diphenylphosphin)ferrocenepalladium(II) rt: room temperature mL: milliliter mmol: millimoles M: Molar concentration (mol / L) mM: Millimole concentration (mol / L) 1 H-NMR: Proton Nuclear Magnetic Resonance CDCl3: Deuterated chloroform DMSO-d6: Deuterated Dimethyl Sulfoxide Acetone-d6: Heavy acetone

[0012] As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine atoms.

[0013] 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.

[0014] The alkyl portion of "alkylcarbonyl," "alkoxy," "alkoxycarbonyl," "monoalkylamino," "dialkylamino," "mono(alkylsulfonyl)," and "di(alkylsulfonyl)" amino used herein can be the same as the "alkyl" mentioned above.

[0015] Examples of "alkoxy" as used herein include linear or branched alkoxys having one to eight carbon atoms, preferably one to six carbon atoms. Specifically, examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the like.

[0016] As used herein, "cycloalkyl" can refer to, for example, saturated hydrocarbon groups having 3 to 10 carbon atoms and being 1-3 cyclic. Specifically, these include 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, and adamantyl (tricyclo[3.3.1.1 3,7 Examples include (also known as decanil).

[0017] Examples of "alkenyls" as used herein include linear or branched alkenyls with 2 to 8 carbon atoms and one or two double bonds. Specifically, examples include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, and 1-methyl-4-pentenyl. Preferably, alkenyls have 2 to 6 carbon atoms, and more preferably, alkenyls have 2 to 4 carbon atoms.

[0018] Examples of "aryl" as used herein include 1- to 3-cyclic aromatic hydrocarbon groups having 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.

[0019] As used herein, "heteroaryl" refers to monocyclic or bicyclic 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.

[0020] "Cyano" refers to a group represented by -CN.

[0021] "Hydroxy" refers to a group represented by -OH.

[0022] "Sulfonyl" refers to a group represented by -SO2-.

[0023] "Sulfinyl" refers to a group represented by -SO-.

[0024] "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, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, halogen, cyano, hydroxy, amino, aryl, or heteroaryl as defined above.

[0025] 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.

[0026] 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.

[0027] The compounds according to the present invention can be used as pharmaceuticals as is, 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.

[0028] 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.

[0029] The compounds according to the present invention have serine racemase inhibitory activity, as shown in the test examples described below.

[0030] Therefore, one embodiment of the present invention provides a serine racemase inhibitor containing a compound according to the present invention.

[0031] Furthermore, one embodiment of the present invention provides a method for inhibiting serine racemase, which includes administering the compound according to the present invention to a subject that requires it.

[0032] Furthermore, one embodiment of the present invention provides a compound according to the present invention for use in serine racemase inhibition.

[0033] Furthermore, one embodiment of the present invention provides the use of the compound according to the present invention in the production of a serine racemase inhibitor.

[0034] Furthermore, in one embodiment of the present invention, a preventive or therapeutic agent for serine racemase-related diseases is provided, comprising a compound according to the present invention.

[0035] Furthermore, one embodiment of the present invention provides a method for preventing or treating a serine racemase-related disease, comprising administering the compound according to the present invention to a subject in need thereof.

[0036] Furthermore, in one embodiment of the present invention, a compound according to the present invention is provided for use in the prevention or treatment of diseases involving serine racemase.

[0037] 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 serine racemase.

[0038] As used herein, "subject" means a human or non-human animal that has or is suspected of having a disease involving serine racemase. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0039] 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%.

[0040] As a carrier, one or more conventionally used solid, semi-solid, or liquid diluents, fillers, and other formulation aids that are pharmaceutically acceptable 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The compounds according to the present invention can be produced using the following synthesis method.

[0045] 1 The 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.

[0046] 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 method for YS-01 to YS-10 [ka]

[0047] Synthesis of Compound 2 Under an argon gas atmosphere, 1.00 mmol of 3,6-dichloropyridazine was mixed with 5 mL of toluene and 1 mL of water. At room temperature, 1.20 mmol of 4-chlorophenylboronic acid, 0 mmol of tetrakis(triphenylphosphine)palladium, and 2.00 mmol of cesium carbonate were added sequentially, and the reaction solution was stirred under reflux for 18 hours. After cooling, the reaction solution was extracted with ethyl acetate (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the target coupling compound (compound 2).

[0048] Synthesis of Compound 3 Under an argon gas atmosphere, 1.00 mmol of compound 2 was dissolved in 5 mL of ethanol, to which 1.50 mmol of thiourea was added at room temperature. The reaction solution was then heated under reflux and stirred for 20 hours. After cooling, water was added dropwise, the resulting solid was filtered, and dried to obtain the target thiolpyridazine derivative (compound 3).

[0049] Synthesis of Compound 4 Under an argon gas atmosphere, 1.00 mmol of compound 3 (obtained) was dissolved in 1,4-dioxane. At room temperature, 1.20 mmol of ethyl bromo and 1.20 mmol of triethylamine were added sequentially, and the reaction solution was stirred at 40°C for 18 hours. After cooling, water was added, and the reaction solution was extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to obtain the target ester (compound 4).

[0050] YS-03, YS-04, and YS-10 combination Under an argon gas atmosphere, lithium hydroxide monohydrate (2.00 mmol) was added to a mixed solution of tetrahydrofuran (4 mL) and water (1 mL) containing the ester (1.00 mmol) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. After acidifying the reaction solution with 10% aqueous HCl, it was extracted with ethyl acetate (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator to obtain the crude carboxylic acid derivative. To a solution of the obtained crude carboxylic acid derivative in dichloromethane (5 mL), aniline derivative (1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 mmol), 1-hydroxybenzotriazole monohydrate (1.10 mmol), and triethylamine (2.20 mmol) were added sequentially at room temperature, and the reaction solution was stirred at room temperature for 2 hours. After adding water to the reaction solution, it was extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 5:1 to 1:1) to obtain the target YS derivatives YS-03, YS-04, and YS-10.

[0051] YS-01 and YS-02 combination Under an argon gas atmosphere, 1.50 mmol of acylating agent and 1.50 mmol of triethylamine were sequentially added to a 5 mL solution of YS-03 (1.00 mmol) in dichloromethane at room temperature, and the reaction solution was stirred at room temperature for 16 hours. After adding water to the reaction solution, it was extracted with 3 x 5 mL of dichloromethane. After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 2:1 to 1:1) to obtain the target YS derivatives YS-01 and YS-02.

[0052] YS-05 synthesis Under an argon gas atmosphere, bromomethane (1.50 mmol) and potassium carbonate (1.50 mmol) were sequentially added to a solution of YS-03 (1.00 mmol) in N,N-dimethylformamide (3 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. After adding water to the reaction solution, it was extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 1:1) to obtain the target YS derivative YS-05.

[0053] YS-06~YS-09 combination Under an argon gas atmosphere, methyl chloroformate, methanesulfonyl chloride or benzenesulfonyl chloride (1.50 mmol), and triethylamine (1.50 mmol) were sequentially added to a 5 mL solution of YS-03 (1.00 mmol) in dichloromethane at room temperature. The reaction solution was then stirred at room temperature for 12 hours. After adding water to the reaction solution, it was extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 5:1 to 1:1) to obtain the target YS derivatives YS-06 to YS-09.

[0054] 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 YS-11~YS-18, YS-21, YS-22, YS-25, and YS-26 [ka]

[0055] Synthesis of Compound 6 Under an argon gas atmosphere, a mixed solution of 3,6-dichloropyridazine (1.00 mmol) in toluene or 1,4-dioxane (5 mL) and water (1 mL) was sequentially added at room temperature to the corresponding phenylboronic acid (1.20 mmol), tetrakis(triphenylphosphine)palladium (0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.02 mmol), cesium carbonate or potassium carbonate (2.00 mmol). The reaction solution was then heated under reflux and stirred for 18 hours. After cooling, the reaction solution was extracted with ethyl acetate (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 7:1 to 1:1) to obtain the target coupling compound (compound 6).

[0056] Synthesis of Compound 7 An aniline derivative (compound 7) was obtained according to the method for the synthesis of compounds 3, 4 and YS-03 in Scheme 1.

[0057] Synthesis of YS-11~YS-18, YS-21, YS-22, YS-25 and YS-26 Under an argon gas atmosphere, acetyl chloride (1.50 mmol) and triethylamine (1.50 mmol) were sequentially added to a solution of the obtained aniline derivative (compound 7) (1.00 mmol) in dichloromethane (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 16 hours. After adding water to the reaction solution, it was extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 2:1 to 1:1) to obtain the target compounds YS-11 to YS-18, YS-21, YS-22, YS-25, and YS-26.

[0058] In one embodiment, the compound according to the present invention can be produced according to the synthesis method shown in Scheme 3. [ka]

[0059] YS-19 and YS-20 were synthesized according to the methods shown for the synthesis of compounds 3, 4, and YS-03 in Scheme 1.

[0060] YS-23 and YS-24 combination Under an argon gas atmosphere, a mixed solution of YS-01 (1.00 mmol) with 1,4-dioxane (5 mL) and water (1 mL) was mixed with oxone monosulfate chloride (1.00 mmol for YS-24, or 3.00 mmol for YS-23) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was then extracted with dichloromethane (5 mL x 3). After drying with sodium sulfate, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:acetone = 1:1) to obtain the target YS-23 and YS-24.

[0061] YS-01 to YS-26 manufactured by the above synthesis method 1 The 1H-NMR spectrum is shown below. N-(4-acetamidophenyl)-2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)acetamide(YS-01) 1 H-NMR (400MHz, Acetone-d6)δ 2.00(3H, s), 4.27(2H, s), 7.49(4H, s), 7.59(2H, d, J=8.4Hz), 7.84(1H, d, J=9.2Hz), 8.12(1H, d, J=9.2Hz), 8.16(2H, d, J=8.4Hz) N-(4-(2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)acetamide)phenyl)butylamide (YS-02) 1 H-NMR (400MHz, DMSO-d6)δ 0.89 (3H, t, J=7.2Hz), 1.58 (2H, sext, J=7.2Hz), 2.24 (2H, t, J=7.2Hz), 4.27 (2H, s), 7.50 (4H , s), 7.59(2H, d, J=8.4Hz), 7.84(1H, d, J=9.2Hz), 8.12(1H, d, J=9.2Hz), 8.13(2H, d, J=8.4Hz) N-(4-aminophenyl)-2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)acetamide(YS-03) 1 H-NMR (400MHz, Acetone-d6)δ 4.18(2H, s), 6.59(2H, d, J=8.4Hz), 7.31(2H, d, J=8.8Hz), 7.58(2H, d, J=8 .4Hz), 7.76(1H, d, J=9.2Hz), 8.06(1H, d, J=9.2Hz), 8.18(2H, d, J=8.8Hz) 2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)-N-(4-hydroxyphenyl)acetamide (YS-04) 1H-NMR (400MHz, DMSO-d6)δ 4.23(2H, s), 6.68(2H, d, J=8.8Hz), 7.35(2H, d, J=8.8Hz), 7.59(2H, d, J=8 .8Hz), 7.83(1H, d, J=9.2Hz), 8.11(1H, d, J=9.2Hz), 8.13(2H, d, J=8.8Hz) 2-((6-(4-chlorophenyl)pyridazine-3-yl)thio)-N-(4-(methylamino)phenyl)acetamide (YS-05) 1 H-NMR (400MHz, Acetone-d6)δ 2.72(3H, s), 4.19(2H, s), 6.52(2H, d, J=8.8Hz), 7.37(2H, d, J=8.8Hz), 7.56(2H , d, J=8.8Hz), 7.75(1H, d, J=9.2Hz), 8.04(1H, d, J=9.2Hz), 8.16(2H, d, J=8.8Hz) Methyl (4-(2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)acetamide)phenyl)carbamate (YS-06) 1 H-NMR (400MHz, DMSO-d6)δ 3.63(3H, s), 4.26(2H, s), 7.36(2H, d, J=8.8Hz), 7.48(2H, d, J=8.8Hz), 7.59(2H , d, J=8.8Hz), 7.83(1H, d, J=9.2Hz), 8.08(1H, d, J=9.2Hz), 8.12(2H, d, J=8.8Hz) 2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)-N-(4-(methylsulfonamide)phenyl)acetamide (YS-07) 1 H-NMR (400MHz, DMSO-d6)δ 3.49(3H, s), 4.32(2H, s), 7.15(2H, d, J=8.8Hz), 7.54(2H, d, J=8.8Hz), 7.59(2H, d, J=8.8Hz), 7.83(1H, d, J=9.2Hz), 8.09-8.14(3H, m) 2-((6-(4-chlorophenyl)pyridazin-3-yl)thio)-N-(4-(N-(methylsulfonyl)methylsulfonamide)phenyl)acetamide (YS-08) 1 H-NMR (400MHz, DMSO-d6)δ 3.49(6H, s), 4.32(2H, s), 7.44(2H, d, J=8.8Hz), 7.59(2H, d, J=8.8Hz), 7.67(2H , d, J=8.8Hz), 7.85(1H, d, J=9.2Hz), 8.12(1H, d, J=9.2Hz), 8.13(2H, d, J=8.8Hz) 2-((6-(4-chlorophenyl)pyridazine-3-yl)thio)-N-(4-(phenylsulfonamide)phenyl)acetamide (YS-09) 1 H-NMR (400MHz, Acetone-d6)δ 4.28(2H, s), 6.97(1H, d, J=8.8Hz), 7.58(2H, d, J=8.4Hz), 7.65-7.70(5H, m), 7.79( 2H, d, J=8.4Hz), 7.89(2H, d, J=8.4Hz), 8.09(1H, d, J=8.8Hz), 8.18(2H, d, J=8.4Hz) 4-(2-((6-(4-chlorophenyl)pyridazine-3-yl)thio)acetamide)benzoic acid (YS-10) 1 H-NMR (400MHz, CDCl3)δ 4.39(2H, s), 6.75(2H, d, J=8.8Hz), 7.41-7.54(4H, m), 8.08(2H, d, J=8.8Hz), 8.09(2H, d, J=8.8Hz) N-(4-acetamidophenyl)-2-((6-(p-toluyl)pyridazine-3-yl)thio)acetamide(YS-11) 1H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 2.36(3H, s), 4.26(2H, s), 7.33(2H, d, J=8.0Hz), 7.50(4H, s), 7.79(1H, d, J=9.2Hz), 7.99(2H, d, J=8.0Hz), 8.06(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thio)acetamide(YS-12) 1 H-NMR (400MHz, DMSO-d6) δ 2.00(3H, s), 4.29(2H, s), 7.49(4H, s), 7.99(3H, d, J=9.2Hz), 8.20(1H, d, J=9.2Hz), 8.32(2H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-fluorophenyl)pyridazin-3-yl)thio)acetamide(YS-13) 1 H-NMR (400MHz, Acetone-d6)δ 2.19(3H, s), 4.27(2H, s), 7.20(2H, d, J=8.8Hz), 7.31(2H, d, J=8.8Hz), 7.74(2H, d, J=8.8Hz), 7.77(1H, d, J=9.2Hz), 8.06(1H, d, J=9.2Hz), 8.21(2H, dd, J=8.8, 5.6Hz) N-(4-acetamidophenyl)-2-((6-(4-ethylphenyl)pyridazin-3-yl)thio)acetamide(YS-14) 1 H-NMR (400MHz, DMSO-d6)δ 1.21 (3H, t, J=7.2Hz), 2.00 (3H, s), 2.67 (2H, q, J=7.2Hz), 4.26 (2H, s), 7.36 (2H, d, J=8 .6Hz), 7.49(4H, s), 7.79(1H, d, J=9.2Hz), 8.01(2H, d, J=8.6Hz), 8.06(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-(dimethylamino)phenyl)pyridazin-3-yl)thio)acetamide(YS-15) 1 H-NMR (400MHz, DMSO-d6)δ 2.15(3H, s), 2.97(6H, s), 4.27(2H, s), 6.80(2H, d, J=9.2Hz), 7.20(2H, d, J=8.4Hz), 7. 66(2H, d, J=8.4Hz), 7.68(1H, d, J=9.2Hz), 7.96(2H, d, J=9.2Hz), 7.96(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-cyanophenyl)pyridazine-3-yl)thio)acetamide(YS-16) 1 H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 4.29(2H, s), 7.49(4H, s), 7.90(1H, d, J=9.2Hz), 8.00(2H, d, J=8.4Hz), 8.21(1H, d, J=9.2Hz), 8.30(2H, d, J=8.4Hz) N-(4-acetamidophenyl)-2-((6-(4-(difluoromethyl)phenyl)pyridazin-3-yl)thio)acetamide(YS-17) 1 H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 4.28(2H, s), 7.11(1H, t, J=16.0Hz), 7.49(4H, s), 7.72(2H, d, J =8.4Hz), 7.87(1H, d, J=8.4Hz), 8.15(1H, d, J=8.4Hz), 8.24(2H, d, J=8.4Hz) N-(4-acetamidophenyl)-2-((6-(4-bromophenyl)pyridazine-3-yl)thio)acetamide(YS-18) 1H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 4.26(2H, s), 7.49(4H, s), 7.73(2H, d, J=8.4Hz), 7.83(1H, d, J=9.2Hz), 8.06(2H, d, J=8.4Hz), 8.11(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-3-((6-(4-chlorophenyl)pyridazine-3-yl)thio)propenamide(YS-19) 1 H-NMR (400MHz, DMSO-d6)δ 2.00 (3H, s), 2.82 (2H, t, J=6.4Hz), 3.56 (2H, t, J=6.4Hz), 7.47 (4H, s), 7.61 (2H , d, J=8.8Hz), 7.75(1H, d, J=8.8Hz), 8.10(1H, d, J=8.8Hz), 8.15(2H, d, J=8.8Hz) N-(4-acetamidophenyl)-4-((6-(4-chlorophenyl)pyridazin-3-yl)thio)butanamide(YS-20) 1 H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 2.02(2H, quin, J=6.8Hz), 2.50(2H, t, J=6.8Hz), 3.35(2H, t, J=6.8Hz), 7.47(4H , s), 7.60(2H, d, J=8.8Hz), 7.75(1H, d, J=9.2Hz), 8.08(1H, d, J=9.2Hz), 8.14(2H, d, J=8.8Hz) N-(4-acetamidophenyl)-2-((6-(4-cyclohexylphenyl)pyridazine-3-yl)thio)acetamide(YS-21) 1H-NMR (400MHz, Acetone-d6)δ 0.84-0.88(1H, m), 1.26-1.31(4H, m), 1.87-1.89(4H, m), 2.08(3H, s), 2.19-2.20(2H, m), 4.21(2H, s), 7.40(2H, d, J=8.8Hz), 7.55(4H, s), 7.73(1H, d, J=9.2Hz), 8.01(1H, d, J=9.2Hz), 8.07(2H, d, J=8.8Hz) N-(4-acetamidophenyl)-2-((6-(4-iodophenyl)pyridazin-3-yl)thio)acetamide(YS-22) 1 H-NMR (400MHz, Acetone-d6)δ 2.08(3H, s), 4.24(2H, s), 7.56(4H, s), 7.78(1H, d, J=9.2Hz), 7.93(2H, d, J=8.8Hz), 7.96(2H, d, J=8.8Hz), 8.06(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-chlorophenyl)pyridazin-3-yl)sulfonyl)acetamide(YS-23) 1 H-NMR (400MHz, DMSO-d6)δ 1.99(3H, s), 4.84(2H, s), 7.37(2H, d, J=9.2Hz), 7.48(2H, d, J=9.2Hz), 7.70(2H , d, J=8.8Hz), 8.29(2H, d, J=8.8Hz), 8.36(1H, d, J=9.2Hz), 8.61(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-(4-chlorophenyl)pyridazin-3-yl)sulfinyl)acetamide(YS-24) 1H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 4.10(1H, d, J=13.2Hz), 4.37(1H, d, J=13.2Hz), 7.44(2H, d, J=9.2Hz), 7.50(2H, d, J= 9.2Hz), 7.68(2H, d, J=8.8Hz), 8.21(1H, d, J=9.2Hz), 8.25(2H, d, J=8.8Hz), 8.58(1H, d, J=9.2Hz) N-(4-acetamidophenyl)-2-((6-phenylpyridazine-3-yl)thio)acetamide(YS-25) 1 H-NMR (400MHz, DMSO-d6)δ 2.00(3H, s), 4.27(2H, s), 7.49-7.55(7H, m), 7.82(1H, d, J=9.2Hz), 8.09(1H, d, J=9.2Hz), 8.09(2H, d, J=6.4Hz) N-(4-acetamidophenyl)-2-((6-(3-chlorophenyl)pyridazin-3-yl)thio)acetamide(YS-26) 1 H-NMR (400MHz, DMSO-d6)δ 1.99(3H, s), 4.27(2H, s), 7.48(4H, s), 7.55-7.58(2H, m), 7.85(1H, d, J=9.2Hz), 8.07(1H, d, J=6.8, 2.0Hz), 8.15(1H, d, J=9.2Hz), 8.15(1H, s)

[0062] Tables 1 to 3 show the structural formulas of YS-01 to YS-26 produced by the above synthesis method. [Table 1] [Table 2] [Table 3]

[0063] In vitro evaluation using wild-type serine racemase (wild-type SRR). The reaction substrates, 20 mM L-serine, various synthesized YS derivatives dissolved in DMSO, and wild-type SRR were mixed and reacted at 37°C for 30 minutes. The resulting D-serine was then specifically converted to pyruvate using Dsd1, and further reacted with 0.05% dinitrophenol / HCl to obtain the corresponding hydrazone. The inhibitory activity of the obtained hydrazones on D-serine formation was evaluated using a standard evaluation method that measures the absorbance at 515 nm (Takahara, S. et al. Bioorg. Med. Chem. Lett. 2018, 28, 441). The results are shown in Figure 1. [Industrial applicability]

[0064] Since the compounds of the present invention exhibit serine racemase inhibitory activity, they can be used in the manufacture of pharmaceuticals for treating or preventing diseases involving serine racemase, such as Alzheimer's disease.

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 heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ It is hydrogen, halogen, -CO ２ R ４ , hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ４ is hydrogen or an optionally substituted alkyl group; X is O, S, SO or SO ２ And; n is an integer selected from 1 to 3. A compound represented by or a pharmaceutically acceptable salt thereof, However, the structure is as follows: 【Chemistry 2】 Compounds or their pharmaceutically acceptable salts, excluding the compounds represented by [the specified formula / code].

2. R １ is hydrogen, halogen, cyano, optionally substituted C １－６ alkyl, optionally substituted C ３－６ cycloalkyl or optionally substituted amino, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ C may be hydrogen or substituted. １－６ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

4. R ３ ga-CO ２ R ４ A compound according to claim 1, wherein the compound is a hydroxyl or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

5. R ４ is hydrogen or C １－６ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted amino is selected from amino, monoalkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, mono(alkylsulfonyl)amino, di(alkylsulfonyl)amino, and arylsulfonylamino.

7. Formula I: 【Transformation 3】 [During the ceremony, R １ is hydrogen, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ It is hydrogen, halogen, -CO ２ R ４ , hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ４ is hydrogen or an optionally substituted alkyl group; X is O, S, SO or SO ２ And; n is an integer selected from 1 to 3. A pharmaceutical product comprising a compound represented by or a pharmaceutically acceptable salt thereof.

8. Formula I: 【Chemistry 4】 [During the ceremony, R １ is hydrogen, halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ It is hydrogen, halogen, -CO ２ R ４ , hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl; R ４ is hydrogen or an optionally substituted alkyl group; X is O, S, SO or SO ２ And; n is an integer selected from 1 to 3. A serine racemase inhibitor comprising a compound represented by or a pharmaceutically acceptable salt thereof.

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