Novel oxopyridazinyl-phenyl-carbazonyldinitrile compounds and their uses

Abstract

The present invention relates to a novel oxopyridazinyl-phenyl-carbazonyldinitrile compound and its use.

Description

Technical Field

[0001] The present invention relates to novel oxopyridazinyl-phenyl-carbonohydrazonoyl dicyanide compounds and their uses. Background Art

[0002] Tau protein is a microtubule-associated protein (MAP) mainly expressed in the axons of nerve cells, with a molecular weight of 50,000 to 70,000, which is used to stabilize microtubules and exhibits molecular diversity through phosphorylation. In humans, tau protein forms six subtypes by inserting 29 or 58 amino acid residues at the N-terminus and selectively splicing 3 or 4 repeat structures (called microtubule-binding domains) of mRNA at the C-terminus.

[0003] In healthy nerves, tau protein stabilizes microtubules by promoting axonal growth and neuronal polarization. When pathological hyperphosphorylation occurs, tau protein dissociates from microtubules, generating insoluble aggregates. In addition, a structural scaffold for inducing tau protein aggregation has been proposed, and evidence has been provided that insoluble filaments are formed from 10 soluble monomers, and these filaments bind into a high-dimensional structure called neurofibrillary tangles (NFT). Full-length human tau protein includes a microtubule-binding domain consisting of four repeat conserved sequences. Among these repeat sequences, positively charged residues play an important role in binding to highly negatively charged microtubules (20 to 30 electrons per αβ-tubulin dimer). The binding affinity of tau to microtubules is also actively regulated by phosphorylation of tau protein, which causes dynamic rearrangement of the microtubule network. When tau protein is abnormally hyperphosphorylated, the balance of this dynamic rearrangement is disrupted, and the affinity for microtubules rapidly decreases.

[0004] Hyperphosphorylation and / or aggregation of tau protein lead to abnormal aggregation of these tau proteins in nerve cells, which is considered to be the cause of various neurodegenerative diseases and the like. Tau protein aggregates mainly exist in the cell bodies and dendrites of nerve cells, and these tau protein aggregates are called neurofibrillary tangles (NFT) and neuropil threads. Examination of the microstructure of neurofibrillary tangles (NFT) shows that its microstructure consists of paired helical filaments (PHF), in which tau protein is tangled like a thin thread and aggregated and hyperphosphorylated, which is different from normal tau protein. Abnormal tau protein aggregation also occurs in tauopathies. In this case, although it is not exactly known what role tau protein aggregation plays in the progression of tauopathies, this tau protein aggregation phenomenon seems to be similar to the aggregation phenomenon commonly seen in general neurodegenerative diseases.

[0005] Thus, although it is known that hyperphosphorylation and / or aggregation of tau protein lead to various neurodegenerative diseases, including Alzheimer's disease and tauopathies, the specific mechanisms by which these abnormal tau species cause changes in signaling pathways and trigger neurotoxicity have not been confirmed, and there are no effective therapeutic methods or therapeutic agents available for treating these diseases. Summary of the Invention

[0006] Technical Problem

[0007] The inventors have made extensive efforts to develop novel small molecule compounds that can inhibit tau protein aggregation and / or hyperphosphorylation. As a result, the inventors have discovered a series of novel oxopyridazinyl-phenyl-carbazonyldinitrile compounds that can effectively inhibit tau protein aggregation at effective concentrations without exhibiting cytotoxicity, thus completing the present invention.

[0008] Technical Solution

[0009] An object of the present invention is to provide a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Formula 1]

[0011]

[0012] In the above formula 1,

[0013] is or

[0014] R1 is hydrogen or halogen;

[0015] R2 is hydrogen or C 1-6 alkyl; and

[0016] R3 is C 1-6 alkyl, C 1-6 alkoxy-C 0-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or C 1-6 alkoxy-C 6-10 aryl.

[0017] Another object of the present invention is to provide a method for preparing the above compound.

[0018] Another object of the present invention is to provide a composition for inhibiting tau protein aggregation, which contains the above compound as an active ingredient.

[0019] Another object of the present invention is to provide a composition for inhibiting the hyperphosphorylation of tau protein, which comprises the above compound as an active ingredient.

[0020] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises the above compound as an active ingredient.

[0021] Another object of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which method comprises administering the above pharmaceutical composition to a subject in need thereof.

[0022] Beneficial effects

[0023] The novel oxopyridazinyl-phenyl-carbazonyldinitrile compound of the present invention can effectively inhibit tau protein aggregation and / or hyperphosphorylation, and thus can be effectively used for preventing or treating diseases caused thereby, such as Alzheimer's disease and various tauopathies. Detailed embodiments

[0024] The first aspect of the present invention is to provide a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0025] [Formula 1]

[0026]

[0027] In the above formula 1,

[0028] is or

[0029] R1 is hydrogen or halogen;

[0030] R2 is hydrogen or C 1-6 alkyl; and

[0031] R3 is C 1-6 alkyl, C 1-6 alkoxy-C 0-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or C 1-6 alkoxy-C 6-10 aryl.

[0032] Specifically, in the compounds of the present invention,

[0033] R1 is hydrogen, chlorine or fluorine;

[0034] R2 is hydrogen or methyl; and

[0035] R3 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, 2,2,2-trifluoroethyl, methoxyphenyl or methoxyethyl, but the present invention is not limited thereto.

[0036] For example, the compounds of the present invention can be represented by the following Formula 2 or Formula 3:

[0037] [Formula 2]

[0038]

[0039] [Formula 3]

[0040]

[0041] In the above Formula 2 or 3, the substituents are as defined above.

[0042] More specifically, the compounds can be:

[0043] 1. (4-(1-Isopropyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0044] 2. (4-(1-Isopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0045] 3. (4-(1-Ethyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0046] 4. (4-(4-Methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0047] 5. (4-(1-(2-Methoxyethyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0048] 6. (4-(1-Cyclopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0049] 7. (4-(1-(4-Methoxyphenyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0050] 8. (4-(1-Methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0051] 9. (4-(1-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile,

[0052] 10. (4-(1-(Difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile,

[0053] 11. (4-(1,4-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile,

[0054] 12. (4-(1-Isopropyl-4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile,

[0055] 13. (3-Chloro-4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, or

[0056] 14. (4-(1,4-Dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-fluorophenyl)carbazonyldinitrile.

[0057] In addition, these compounds may be compounds represented by the chemical formulas shown in Table 1 below.

[0058] Table 1

[0059]

[0060] Meanwhile, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As salts, acid addition salts formed from pharmaceutically acceptable free acids are useful. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of the compound represented by Formula 1 that is relatively non-toxic and harmless to the patient and the side effects caused by the salt do not impair the beneficial effects of the compound.

[0061] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of an excess of acid and precipitating the solution with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. An aqueous solution of the same molar amount of the compound and acid or alcohol (such as ethylene glycol monoethyl ether) is heated, and subsequently the mixture can be evaporated and dried, or the precipitated salt can be filtered by suction.

[0062] In this case, organic or inorganic acids can be used as the free acid. Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids. Methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used as organic acids. However, the present invention is not limited thereto.

[0063] In addition, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts are obtained by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salts, and then evaporating and drying the filtrate. In this case, preparing sodium salts, potassium salts, or calcium salts as metal salts is suitable for pharmaceutical use, but the present invention is not limited thereto. In addition, the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (such as silver nitrate).

[0064] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of Formulas 1 to 3. For example, pharmaceutically acceptable salts may include sodium salts, calcium salts, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups may include hydrobromide salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, acetate salts, succinate salts, citrate salts, tartrate salts, lactate salts, mandelate salts, mesylate salts, and tosylate salts. These pharmaceutically acceptable salts can be prepared using methods for preparing salts known in the art.

[0065] As salts of the compounds of Formulas 1 to 3 of the present invention, any salt can be used without limitation as a pharmaceutically acceptable salt as long as it exhibits pharmacological activity equivalent to that of the compound of Formula 1. For example, it inhibits tau protein aggregation and / or hyperphosphorylation.

[0066] In addition, the compounds represented by Formulas 1 to 3 according to the present invention include, but are not limited to, their pharmaceutically acceptable salts, solvates, such as possible hydrates that can be prepared therefrom, and all possible stereoisomers. Solvates and stereoisomers of the compounds represented by Formulas 1 to 3 can be prepared from the compounds represented by Formulas 1 to 3 using any method known in the art.

[0067] In addition, the compounds represented by Formulas 1 to 3 according to the present invention can be prepared in crystalline or amorphous form, and if prepared in crystalline form, they can be optionally hydrated or solvated. In the present invention, stoichiometric hydrates of the compounds represented by Formulas 1 to 3, as well as compounds containing different amounts of water, are provided. Solvates of the compounds represented by Formulas 1 to 3 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0068] The second aspect of the present invention provides a method for preparing the compound of Formula 1.

[0069] For example, the compounds of the present invention can be prepared by a method including the following steps: reacting a compound represented by Formula 4 containing a reactive amino group at one end thereof with sodium nitrite and malononitrile in the presence of an acid to form an imine bond:

[0070] [Formula 4]

[0071]

[0072] In Formula 4 above, R1 to R3 are as defined above.

[0073] Specifically, the method can be carried out through a series of steps, including:

[0074] In the first step, the compound of Formula 4 and sodium nitrite are dissolved in a C 1-4 lower alcohol solvent, and an aqueous solution of an acid is added thereto at a temperature of -5°C to 5°C to form a diazonium salt.

[0075] In the second step, malononitrile is added to the reaction solution containing the diazonium salt obtained in the first step, and the reaction is carried out at a temperature of 15°C to 40°C, and

[0076] in the third step, an aqueous solution of a base is added to the reaction solution of the second step for neutralization. However, the present invention is not limited thereto.

[0077] Specifically, the compound of Formula 4 for preparing the compound of the present invention may be a compound represented by Formula 4-a or 4-b below:

[0078] [Formula 4-a]

[0079]

[0080] [Formula 4-b]

[0081]

[0082] More specifically, the compound represented by Formula 4-a can be prepared through a series of steps, including the following steps: a-1) reacting 4-(4-acetamidophenyl)-4-oxo-(unsubstituted or R2-substituted)-butyric acid with hydrazine, a-2) reacting the N-(6-oxo-(unsubstituted or R2-substituted)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide obtained in the previous step with an acid, and a-3) optionally, when R3 is a substituent other than hydrogen, reacting the 6-(4-aminophenyl-(unsubstituted or R2-substituted)-4,5-dihydropyridazin-3(2H)-one obtained in the previous step with R3X (where X is a halogen) under basic conditions, or

[0083] Step a-1') reacting 4-(4-aminophenyl)-4-oxo-(unsubstituted or R2-substituted)-butyric acid with unsubstituted or R3-substituted hydrazine, but not limited thereto.

[0084] For example, as the compound represented by Formula 4-a, a commercially available compound purchased can be used, or the reactants or intermediates of each step can be synthesized individually or in combination through reactions well-known in the art, but not limited thereto.

[0085] In addition, if necessary, after each reaction, the process of further separating and / or purifying the product can be carried out using various methods well-known in the art.

[0086] For example, the reaction of step a-1) can use C 1-4 lower alcohols, such as ethanol or propanol as the solvent, and is carried out at a temperature of 70 °C to 130 °C for 1 hour to 12 hours, but not limited thereto.

[0087] In addition, the reaction of step a-2) can be carried out in an aqueous solution phase containing water in the solvent at a temperature of 90 °C to 130 °C for 30 minutes to 6 hours, and can further include a neutralization step by adding a base, but not limited thereto.

[0088] In addition, the reaction of step a-3) can be carried out using NaH or K2CO3 as the base, and an organic solvent such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP) as the solvent, but not limited thereto. For example, the reaction can be carried out at a low temperature of about 0 °C with stirring for 5 hours to 24 hours, but not limited thereto.

[0089] Meanwhile, the reaction of step a-1’) can use C 1-4 lower alcohols such as propanol as the organic solvent, and is carried out in a microwave at a temperature of 80 °C to 120 °C with stirring for 30 minutes to 6 hours, but not limited thereto.

[0090] More specifically, the above compound represented by Formula 4-b can be prepared through a series of steps, including the following steps:

[0091] b-1) Reacting by dissolving 3,6-dihalo (unsubstituted or R2-substituted) pyridazine in an acid, and solidifying by adding a base thereto,

[0092] b-2) Optionally, when R3 is a substituent other than hydrogen, under basic conditions, reacting the 6-halo-(unsubstituted or R2-substituted) pyridazin-3(2H)-one prepared in the previous step with R3X (where X is a halogen),

[0093] b-3) Reacting the 6-halo-2-(unsubstituted or R3-substituted)-(unsubstituted or R2-substituted) pyridazin-3(2H)-one obtained in the previous step with 4-amino or nitro-(unsubstituted or R1-substituted phenyl) boronic acid pinacol ester in the presence of a Pd(PPh3)2 catalyst, and

[0094] b-4) Optionally, when reacting with 4-nitro-(unsubstituted or R1-substituted phenyl)boronic acid pinacol ester in step b-3), the compound obtained in the previous step having a nitro substituent at one end is reacted in a hydrogen atmosphere in the presence of a Pd / C catalyst to reduce the nitro group to an amino group. However, the present invention is not limited thereto.

[0095] For example, as the compound represented by formula 4-b, a commercially available compound can be used, or the reactants or intermediates of each step can be synthesized individually or in combination by reactions well known in the art, but not limited thereto.

[0096] Furthermore, if necessary, after each reaction, the process of separating and / or purifying the product can be further carried out using various methods well known in the art.

[0097] For example, the reaction in step b-1) can be carried out in an acid solution at a temperature of 100 °C to 115 °C with stirring for 6 hours to 24 hours, and then an aqueous solution of a base is added thereto and the mixture is stirred at room temperature, but not limited thereto. In this case, the acid can be acetic acid or hydrochloric acid, but not limited thereto. Meanwhile, the base can be sodium bicarbonate, potassium acetate or sodium hydroxide, but not limited thereto, and the type of base is not particularly limited as long as the base is neutralized to obtain a neutral product.

[0098] Furthermore, the reaction in step b-2) can be carried out using potassium carbonate as a base at room temperature in an organic solvent, for example, in a solution dissolved in DMF, with stirring for 30 minutes to 10 hours, but not limited thereto.

[0099] Furthermore, the above reaction in step b-3) can be carried out using an organic solvent (e.g., 1,4-dioxane), in the presence of an aqueous potassium phosphate solution, by heating to 130 °C to 180 °C in a microwave with stirring for 10 minutes to 5 hours, but not limited thereto. For example, the reaction can be carried out at a low temperature of about 0 °C with stirring for 5 hours to 24 hours, but not limited thereto.

[0100] Furthermore, the reaction in step b-4) can be carried out in an organic solvent, for example, in a 1,4-dioxane solution, but not limited thereto.

[0101] The third aspect of the present invention is to provide a composition for inhibiting tau protein aggregation, which comprises the compound of the present invention as an active ingredient.

[0102] The fourth aspect of the present invention is to provide a composition for inhibiting tau protein hyperphosphorylation, which comprises the compound of the present invention as an active ingredient.

[0103] The fifth aspect of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises a compound of the present invention as an active ingredient.

[0104] In a specific embodiment of the present invention, a total of 14 compounds numbered 1 to 14 and represented by Formula 1 were newly synthesized, and their effects of inhibiting tau protein aggregation and hyperphosphorylation were confirmed. In addition, in order to confirm the possibility of being used as a pharmaceutical composition, it was confirmed that these compounds are not toxic to cells.

[0105] As used herein, the term "prevention" refers to any act of inhibiting or delaying the occurrence, spread and recurrence of diseases induced by tau protein aggregation or hyperphosphorylation by administering the pharmaceutical composition of the present invention, and the term "treatment" refers to any act of improving or beneficially changing the symptoms of diseases by administering the pharmaceutical composition of the present invention.

[0106] As described above, since the compound of the present invention not only inhibits tau protein aggregation or hyperphosphorylation, but also is not toxic to cells, the pharmaceutical composition containing the compound as an active ingredient can be used for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation. The diseases caused by tau protein aggregation or hyperphosphorylation to which the pharmaceutical composition of the present invention can be applied can be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, craniocerebral trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma or tauopathy. Non-limiting examples of tauopathy can include: chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argentophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinson's syndrome associated with chromosome 17, Lytico-bodig disease (Guam-type Parkinson's syndrome-dementia complex), ganglioglioma, gangliocytoma, meningioangiomatosis, post-encephalitic Parkinson's syndrome, subacute sclerosing panencephalitis, lead poisoning encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis and traumatic brain injury.

[0107] For example, the composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into various forms and used according to general methods for each purpose of use, such as oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injectable drugs in sterile injection solutions, and can be administered orally or can be administered by various routes, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Examples of suitable carriers, excipients or diluents contained in the composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate and mineral oil. The composition of the present invention may further include fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, etc.

[0108] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are formulated by mixing one or more excipients such as starch, calcium carbonate, sucrose, lactose and gelatin with the composition. At the same time, in addition to simple excipients, lubricants such as magnesium stearate or talc can also be used.

[0109] As oral liquid preparations, suspensions, oral solutions, emulsions, syrups, etc. can be cited. In addition to water and liquid paraffin which are usually used as simple diluents, oral liquid preparations can include various excipients, such as wetting agents, sweetening agents, flavoring agents and preservatives.

[0110] Preparations for parenteral administration include sterile aqueous solvents, non-aqueous solvents, suspending agents, emulsifying agents, freeze-dried preparations and suppositories.

[0111] Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used as non-aqueous solvents or suspending agents. Witepsol, polyethylene glycol (macrogol), twin 61, cocoa butter, laurel oil, glycerol gelatin, etc. can be used as the matrix of suppositories. At the same time, injections may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0112] The preparation can be prepared by conventional mixing, granulating or coating methods, and can contain the active ingredient in an amount of about 0.1 wt% to 75 wt%, preferably about 0.1 wt% to 50 wt%. A unit preparation for a mammal weighing about 50 kg to 70 kg contains about 10 mg to 200 mg of the active ingredient.

[0113] In such a case, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects, and the level of the effective amount can be determined according to factors such as the patient's health condition, type of disease, severity, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, factors including drugs used in combination or simultaneously, and other factors well known in the medical field. The composition of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, can be administered successively or simultaneously with conventional therapeutic agents, and can be administered in a single dose or multiple doses. Considering all the above factors, it is important to administer the minimum amount that can achieve the maximum effect without side effects, which can be easily determined by those skilled in the art.

[0114] For example, since the dose can be increased or decreased according to the administration route, disease severity, gender, body weight, age, etc., the dose does not limit the scope of the present invention in any way.

[0115] The preferred dose of the compound of the present invention varies according to the condition and body weight of the patient, the severity of the disease, the form of the drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compound of the present invention can be administered in an amount of 0.0001 mg / kg to 100 mg / kg (body weight) per day, preferably 0.001 mg / kg to 100 mg / kg (body weight). The compound can be administered in divided doses once a day or several times a day by oral or parenteral routes.

[0116] The sixth aspect of the present invention is to provide a method for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, the method comprising administering the pharmaceutical composition of the present invention to a subject in need thereof.

[0117] As used herein, the term "subject" refers to any animal, including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rabbits, and guinea pigs in addition to humans, which have or may have a disease caused by tau protein aggregation or hyperphosphorylation. The disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject. In addition, since the pharmaceutical composition of the present invention exhibits a therapeutic effect by inhibiting tau protein aggregation or hyperphosphorylation, a synergistic effect can be exhibited by administering the composition in combination with a conventional therapeutic agent.

[0118] As used herein, the term "administer" refers to providing a predetermined substance to a patient by any suitable method, and the route of administration of the compositions of the present invention can be any conventional route as long as the substance can reach the target tissue. The composition can be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, pulmonary administration, or rectal administration, but the present invention is not limited thereto. In addition, the pharmaceutical compositions of the present invention can be administered by using any device capable of moving the active substance to the target cells. Preferred administrations and formulations include intravenous injection drugs, subcutaneous injection drugs, intradermal injection drugs, intramuscular injection drugs, and infusion drugs. Injection drugs can be prepared using aqueous solvents such as physiological saline solution or Ringer's solution, or non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate), or alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerol), and can include pharmaceutical carriers such as stabilizers for preventing denaturation (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, or EDTA), emulsifiers, buffers for pH control, or preservatives for inhibiting the growth of microorganisms (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, or benzyl alcohol).

[0119] Mode of Carrying Out the Invention

[0120] Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.

[0121] Example 1: Preparation of (4-(1-isopropyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 1)

[0122] Step 1-1: Preparation of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one

[0123] 6-(4-Aminophenyl)-4,5-dihydropyridazin-3(2H)-one (105 mg, 0.55 mmol) and 60% sodium hydride (24 mg, 0.61 mmol) were dissolved in dimethylformamide (DMF), and 2-iodopropane (58 μL, 0.58 mmol) was added thereto, followed by stirring at 0 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 121 mg (yield: 99%) of the title compound.

[0124] 11H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.51 (s, 2H), 4.84 (p, J = 6.6 Hz, 1H), 2.79 (dd, J = 8.9 Hz, 7.3 Hz, 2H), 2.39 (dd, J = 8.9 Hz, 7.2 Hz, 2H), 1.17 (d, J = 6.6 Hz, 6H).

[0125] Step 1-2: Preparation of (4-(1-isopropyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile Preparation

[0126] In the presence of nitrogen, 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one (110 mg, 0.47 mmol) obtained in the above step 1-1 and sodium nitrite (15 mg, 0.23 mmol) were dissolved in ethanol, and 1.0 M aqueous hydrochloric acid solution (0.3 mL, 0.30 mmol) was added thereto at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes to form a diazonium salt. Malononitrile (19 mg, 0.28 mmol) was added to the reaction mixture containing the diazonium salt, and the mixture was stirred at room temperature for 10 minutes. Thereafter, the pH of the reaction mixture was adjusted to 6.0 using an aqueous sodium hydroxide solution, and the reaction mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 140 mg (yield: 95%) of the title compound.

[0127] 1 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H), 4.88 (p, J = 6.6 Hz, 1H), 2.92 (dd, J = 8.9 Hz, 7.5 Hz, 2H), 2.49 (m, 2H), 1.20 (d, J = 6.7 Hz, 6H).

[0128] Example 2: Preparation of (4-(1-isopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 2)

[0129] Step 2-1: Preparation of 6-(4-aminophenyl)-2-isopropyl-5-methyl-4,5-dihydropyridazin-3(2H)-one

[0130] Except for using 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (200 mg, 0.98 mmol) instead of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one, the title compound (194 mg, yield: 75%) was obtained in the same manner as in Step 1-1 of Example 1.

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.53 (s, 2H), 4.88 (p, J = 6.7 Hz, 1H), 3.31–3.19 (m, 1H), 2.59 (dd, J = 16.5 Hz, 6.6 Hz, 1H), 2.23 (dd, J = 16.5 Hz, 1.6 Hz, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 7.3 Hz, 3H).

[0132] Step 2-2: Preparation of (4-(1-isopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl Dinitrile

[0133] Except for using 6-(4-aminophenyl)-2-isopropyl-5-methyl-4,5-dihydropyridazin-3(2H)-one (180 mg, 0.73 mmol) obtained in the above Step 2-1 instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, the title compound (229 mg, yield: 97%) was obtained in the same manner as in Step 1-2 of Example 1.

[0134] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 4.91 (p, J = 6.6 Hz, 1H), 2.71 (dd, J = 16.6 Hz, 6.8 Hz, 1H), 2.32 (dd, J = 16.6, 1.5 Hz, 1H), 1.25 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H).

[0135] Example 3: Preparation of (4-(1-ethyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 3)

[0136] Step 3-1: Preparation of 6-(4-aminophenyl)-2-ethyl-5-methyl-4,5-dihydropyridazin-3(2H)-one

[0137] Except for using 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.53 mmol) instead of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one, and using iodoethane (47 μL, 0.58 mmol) instead of iodopropane, the title compound (79 mg, yield: 65%) was obtained in the same manner as in Step 1-1 of Example 1.

[0138] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.53 (s, 2H), 3.73 (ddq, J = 51.9 Hz, 13.8 Hz, 7.1 Hz, 2H), 3.30–3.24 (m, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 2.61 (dd, J = 16.5 Hz, 6.6 Hz, 1H), 2.23 (d, J = 16.6 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H), 1.02 (d, J = 7.3 Hz, 3H).

[0139] Step 3-2: Preparation of (4-(1-ethyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile Preparation

[0140] Except for using 6-(4-aminophenyl)-2-ethyl-5-methyl-4,5-dihydropyridazin-3(2H)-one (70 mg, 0.30 mmol) obtained in the above Step 3-1 instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, the title compound (33 mg, yield: 35%) was obtained in the same manner as in Step 1-2 of Example 1.

[0141] 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 3.79 (ddt, J = 32.0 Hz, 13.5 Hz, 6.8 Hz, 2H), 2.73 (dd, J = 16.6 Hz, 6.7 Hz, 1H), 2.35–2.23 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.2 Hz, 3H).

[0142] Example 4: Preparation of (4-(4-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 4)

[0143] Step 4-1: Preparation of 6-(4-aminophenyl)-5-methyl-2-(2,2,2-trifluoroethyl)-4,5-dihydropyridazin-3(2H)-one

[0144] 4-(4-Aminophenyl)-3-methyl-4-oxobutanoic acid hydrochloride (100 mg, 0.41 mmol) and 65% (2,2,2-trifluoroethyl) hydrazine (83 μL, 0.61 mmol) were dissolved in propanol, and the reaction mixture was stirred in a microwave at 100 °C for 3 h. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure and purified by column chromatography to give 52 mg (yield: 45%) of the title compound.

[0145] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.61 (s, 2H), 4.81 (dq, J = 15.1 Hz, 9.3 Hz, 1H), 4.25 (dq, J = 15.1 Hz, 9.2 Hz, 1H), 3.41–3.35 (m, 1H), 2.75 (dd, J = 16.7 Hz, 6.4 Hz, 1H), 2.38 (dd, J = 16.7 Hz, 1.6 Hz, 1H), 1.04 (d, J = 7.2 Hz, 3H).

[0146] Step 4-2: Preparation of (4-(4-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyridazin-3-yl)benzene yl)carbamoyl dinitrile

[0147] Except for using 6-(4-aminophenyl)-5-methyl-2-(2,2,2-trifluoroethyl)-4,5-dihydropyridazin-3(2H)-one (50 mg, 0.17 mmol) obtained in Step 4-1 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as in Steps 1-2 of Example 1, 45 mg (yield: 70%) of the title compound was obtained.

[0148] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H), 4.86 (dq, J = 15.2 Hz, 9.3 Hz, 1H), 4.34 (dq, J = 15.1 Hz, 9.1 Hz, 1H), 3.49 (td, J = 7.1 Hz, 1.7 Hz, 1H), 2.86 (dd, J = 16.8 Hz, 6.6 Hz, 1H), 2.49–2.44 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H).

[0149] Preparation of Example 5: (4-(1-(2-Methoxyethyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 5)

[0150] Step 5-1: Preparation of 6-(4-aminophenyl)-2-(2-methoxyethyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one Preparation

[0151] Except for using 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.53 mmol) instead of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one, and using 1-bromo-2-methoxyethane (55 μL, 0.58 mmol) instead of iodopropane, in the same manner as in Step 1-1 of Example 1, 84 mg (yield: 61%) of the title compound was obtained.

[0152] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.56 (s, 2H), 4.11–4.05 (m, 1H), 3.74–3.63 (m, 1H), 3.58–3.49 (m, 2H), 3.29 (t, J = 7.0 Hz, 1H), 3.24 (s, 3H), 2.63 (dd, J = 16.5 Hz, 6.5 Hz, 1H), 2.25 (dd, J = 16.5 Hz, 1.5 Hz, 1H), 1.03 (d, J = 7.3 Hz, 3H).

[0153] Step 5-2: Preparation of (4-(1-(2-methoxyethyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzene yl)carbamoyl dinitrile

[0154] Except for using 6-(4-aminophenyl)-2-(2-methoxyethyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (80 mg, 0.31 mmol) obtained in the above Step 5-1 instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as in Step 1-2 of Example 1, 35 mg (yield: 34%) of the title compound was obtained.

[0155] 11H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 4.10 (dt, J = 12.8 Hz, 6.0 Hz, 1H), 3.75 (dt, J = 13.6 Hz, 5.6 Hz, 1H), 3.62–3.52 (m, 2H), 3.24 (s, 3H), 2.74 (dd, J = 16.6 Hz, 6.7 Hz, 1H), 2.33 (d, J = 16.6 Hz, 1H), 1.07 (d, J = 7.2 Hz, 3H).

[0156] Example 6: Preparation of (4-(1-cyclopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 6)

[0157] Step 6-1: Preparation of 6-(4-aminophenyl)-2-cyclopropyl-5-methyl-4,5-dihydropyridazin-3(2 H )-one

[0158] 6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.53 mmol) and 60% sodium hydride (25 mg, 0.63 mmol) were dissolved in N-methylpyrrolidone (NMP), and bromocyclopropane (46 μL, 0.58 mmol) was added thereto. Then, the reaction mixture was stirred in a microwave at 180 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with diethyl ether to obtain 41 mg (yield: 30%) of the title compound.

[0159] 1 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 5.54 (s, 2H), 3.50 (tt, J = 7.5 Hz, 4.2 Hz, 1H), 3.26 (dd, J = 7.9 Hz, 6.1 Hz, 1H), 2.63 (dd, J = 16.6 Hz, 6.6 Hz, 1H), 2.26 (d, J = 16.6 Hz, 1H), 0.98 (d, J = 7.3 Hz, 3H), 0.92–0.82 (m, 1H), 0.79–0.68 (m, 3H).

[0160] Step 6-2: Preparation of (4-(1-cyclopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl Dinitrile

[0161] Except for using 6-(4-aminophenyl)-2-cyclopropyl-5-methyl-4,5-dihydropyridazin-3(2H)-one (30 mg, 0.12 mmol) obtained in Step 6-1 above to replace 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as Steps 1-2 of Example 1, 36 mg (yield: 96%) of the title compound was obtained.

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 3.50 (p, J = 6.4 Hz, 1H), 3.39–3.35 (m, 1H), 2.74 (dd, J = 16.7 Hz, 6.8 Hz, 1H), 2.34 (d, J = 16.6 Hz, 1H), 1.03 (d, J = 7.2 Hz, 3H), 0.96–0.85 (m, 1H), 0.83–0.70 (m, 3H).

[0163] Example 7: Preparation of (4-(1-(4-methoxyphenyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 7)

[0164] Step 7-1: 6-(4-aminophenyl)-2-(4-methoxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2 H )-one Preparation

[0165] Except for using (4-methoxyphenyl)hydrazine hydrochloride (107 mg, 0.61 mmol) to replace (2,2,2-trifluoroethyl)hydrazine, in the same manner as Step 4-1 of Example 4, 34 mg (yield: 27%) of the title compound was obtained.

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.58 (s, 2H), 3.78 (s, 3H), 3.46–3.37 (m, 1H), 2.86 (dd, J = 16.5 Hz, 6.5 Hz, 1H), 2.40 (dd, J = 16.5 Hz, 1.6 Hz, 1H), 1.15 (d, J = 7.3 Hz, 3H).

[0167] Step 7-2: Preparation of (4-(1-(4-methoxyphenyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzene yl)carbamoyl dinitrile

[0168] Except for using 6-(4-aminophenyl)-2-(4-methoxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (30 mg, 0.29 mmol) obtained in Step 7-1 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as Steps 1-2 of Example 1, 29 mg (yield: 77%) of the title compound was obtained.

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.59–3.46 (m, 1H), 2.97 (dd, J = 16.6 Hz, 6.6 Hz, 1H), 2.45 (s, 1H), 1.20 (d, J = 7.3 Hz, 3H).

[0170] Example 8: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 8)

[0171] Step 8-1: Preparation of 6-chloropyridazin-3(2H)-one

[0172] 3,6-Dichloropyridazine (1 g, 6.71 mmol) was dissolved in acetic acid (26 mL), and the reaction mixture was stirred at 110 °C for 12 h. After completion of the reaction, the reaction mixture was concentrated, an aqueous solution of sodium bicarbonate was added thereto, and the mixture was stirred at room temperature to solidify the reactant. The product was concentrated under reduced pressure to obtain 420 mg (yield: 48%) of the title compound.

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 7.52 (d, J = 9.8 Hz, 1H), 6.98 (d, J = 9.9 Hz, 1H).

[0174] Step 8-2: Preparation of 6-chloro-2-methylpyridazin-3(2H)-one

[0175] The 6-chloropyridazin-3(2H)-one (100 mg, 0.77 mmol), iodomethane (95 μL, 1.53 mmol), and potassium carbonate (212 mg, 1.53 mmol) obtained in step 8-1 of Example 8 above were dissolved in DMF, and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 82 mg (yield: 74%) of the title compound.

[0176] 1 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 2.06 (d, J = 1.4 Hz, 3H).

[0177] Step 8-3: Preparation of 6-(4-aminophenyl)-2-methylpyridazin-3(2H)-one

[0178] The 6-chloro-2-methylpyridazin-3(2H)-one (65 mg, 0.45 mmol) and 4-aminophenylboronic acid pinacol ester (98 mg, 0.45 mmol) obtained in step 8-2 of Example 8 above were dissolved in a 1,4-dioxane solution, and Pd(PPh3)2 (52 mg, 0.04 mmol) and 2.0 M aqueous potassium phosphate solution (0.9 mL, 1.80 mmol) were added thereto. The reaction mixture was stirred in a microwave at 160 °C for 1.5 h. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 86 mg (yield: 95%) of the title compound.

[0179] 1 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 9.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 9.7 Hz, 1H), 6.62 (d, J = 8.6 Hz, 2H), 5.50 (s, 2H), 3.68 (s, 3H).

[0180] Step 8-4: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile

[0181] Except for using the 6-(4-aminophenyl)-2-methylpyridazin-3(2H)-one (50 mg, 0.25 mmol) obtained in step 8-3 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydro-pyridazin-3(2H)-one, in the same manner as in step 1-2 of Example 1, 41 mg (yield: 59%) of the title compound was obtained.

[0182] 1 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.06 (d, J = 9.8 Hz, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.7 Hz, 1H), 3.74 (s, 3H).

[0183] Example 9: Preparation of (4-(1-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 9)

[0184] Step 9-1: Preparation of 6-chloro-2-isopropylpyridazin-3(2 H )-one

[0185] Except for using 2-iodopropane (153 μL, 1.53 mmol) instead of iodomethane, in the same manner as Step 8-2 of Example 8 above, 107 mg (yield: 81%) of the title compound was obtained.

[0186] 1 1H NMR (400 MHz, chloroform-d) δ 7.14 (d, J = 9.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 5.23 (pd, J = 6.7 Hz, 0.8 Hz, 1H), 1.36 (dd, J = 6.6 Hz, 0.9 Hz, 6H).

[0187] Step 9-2: Preparation of 6-(4-aminophenyl)-2-isopropylpyridazin-3(2H)-one

[0188] Except for using 6-chloro-2-isopropylpyridazin-3(2H)-one (100 mg, 0.58 mmol) obtained in Step 9-1 above instead of 6-chloro-2-methylpyridazin-3(2H)-one, in the same manner as Step 8-3 of Example 8 above, 77 mg (yield: 58%) of the title compound was obtained.

[0189] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 10.0 Hz, 1H), 7.61 (d, J = 3.6 Hz, 2H), 6.90 (d, J = 10.2 Hz, 1H), 6.64 (d, J = 3.8 Hz, 2H), 5.49 (s, 2H), 5.18 (q, J = 6.4 Hz, 1H), 1.33 (s, 6H).

[0190] Step 9-3: Preparation of (4-(1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile

[0191] Except for using 6-(4-aminophenyl)-2-isopropylpyridazin-3(2H)-one (60 mg, 0.26 mmol) obtained in Step 9-2 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as Step 1-2 of Example 1 above, 74 mg (yield: 92%) of the title compound was obtained.

[0192] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.03 (d, J = 9.8 Hz, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 9.7 Hz, 1H), 5.21 (p, J = 6.6 Hz, 1H), 1.35 (d, J = 6.7 Hz, 6H).

[0193] Example 10: Preparation of (4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 10)

[0194] Step 10-1: Preparation of 6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one and 3-chloro-6-(difluoromethoxy)pyridazine Preparation

[0195] Except for using sodium 2-chloro-2,2-difluoroacetate (234 mg, 1.53 mmol) instead of methyl iodide, in the same manner as Step 8-2 of Example 8 above, a mixture of the title compound was obtained, and the solvent was removed therefrom for use in the next step without additional purification.

[0196] Step 10-2: Preparation of 6-(4-aminophenyl)-2-(difluoromethyl)pyridazin-3(2H)-one and 4-(6-(difluoromethoxy) pyridazin-3-yl)aniline

[0197] Except for using a mixture of 6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one and 3-chloro-6-(difluoromethoxy)pyridazine (100 mg, 0.55 mmol) obtained in Step 10-1 above instead of 6-chloro-2-methylpyridazin-3(2H)-one, in the same manner as Step 8-3 of Example 8, 35 mg (yield: 27%) of 6-(4-aminophenyl)-2-(difluoromethyl)pyridazin-3(2H)-one and 41 mg (yield: 31%) of 4-(6-(difluoromethoxy)pyridazin-3-yl)aniline (the title compound) were obtained.

[0198] 6-(4-aminophenyl)-2-(difluoromethyl)pyridazin-3(2H)-one

[0199] 11H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 10.2 Hz, 1H), 7.93 (t, J = 60.0 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 9.9 Hz, 1H), 6.65 (d, J = 8.7 Hz, 2H), 5.68 (s, 2H); and

[0200] 4-(6-(Difluoromethoxy)pyridazin-3-yl)aniline

[0201] 1 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 9.3 Hz, 1H), 7.89 (t, J = 72.1 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 9.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 5.61 (s, 2H).

[0202] Step 10-3: Preparation of (4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazimidoyl dinitrile Preparation

[0203] Except for using 6-(4-aminophenyl)-2-(difluoromethyl)pyridazin-3(2H)-one (26 mg, 0.11 mmol) obtained in Step 10-2 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as Steps 1-2 of Example 1 above, 20 mg (yield: 59%) of the title compound was obtained.

[0204] 1 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.19 (d, J = 10.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.98 (t, J = 58.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 10.0 Hz, 1H).

[0205] Example 11: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 11)

[0206] Step 11-1: Preparation of 6-chloro-2,5-dimethylpyridazin-3(2H)-one

[0207] Except for using 6-chloro-5-methylpyridazin-3(2H)-one (100 mg, 0.69 mmol) instead of 6-chloropyridazin-3(2H)-one, in the same manner as Step 8-2 of Example 8, 53 mg (yield: 49%) of the title compound was obtained.

[0208] 1 1H NMR (400 MHz, DMSO-d6) δ 6.79 (d, J = 1.3 Hz, 1H), 3.73 (s, 3H), 2.26 (d, J = 1.3 Hz, 3H).

[0209] Step 11-2: Preparation of 6-(4-aminophenyl)-2,5-dimethylpyridazin-3(2H)-one

[0210] Except for using 6-chloro-2,5-dimethylpyridazin-3(2H)-one (50 mg, 0.31 mmol) obtained in Step 11-1 above to replace 6-chloro-2-methylpyridazin-3(2H)-one, in the same manner as Step 8-3 of Example 8 above, 51 mg (yield: 76%) of the title compound was obtained.

[0211] 1 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 5.47 (s, 2H), 3.68 (s, 3H), 2.13 (d, J = 1.2 Hz, 3H).

[0212] Step 11-3: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazimidoyl dinitrile Preparation

[0213] Except for using 6-(4-aminophenyl)-2,5-dimethylpyridazin-3(2H)-one (35 mg, 0.16 mmol) obtained in Step 11-2 above to replace 6-(4-aminophenyl)-2-isopropyl-4,5-dihydro-pyridazin-3(2H)-one, in the same manner as Step 1-2 of Example 1 above, 37 mg (yield: 77%) of the title compound was obtained.

[0214] 1 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H), 3.74 (s, 3H), 2.16 (d, J = 1.2 Hz, 3H).

[0215] Example 12: Preparation of (4-(1-isopropyl-4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 12)

[0216] Step 12-1: Preparation of 6-chloro-2-isopropyl-5-methylpyridazin-3(2H)-one

[0217] Except using 6-chloro-5-methylpyridazin-3(2H)-one (200 mg, 1.38 mmol) instead of 6-chloropyridazin-3(2H)-one, and using 2-iodopropane (166 μL, 1.66 mmol) instead of iodomethane, the title compound (112 mg, yield: 43%) was obtained in the same manner as in Step 8-2 of Example 8.

[0218] 1 H NMR (400 MHz, chloroform-d) δ 7.03 (d, J = 1.2 Hz, 1H), 5.26 (p, J = 6.6 Hz, 1H), 2.21 (d, J = 1.3 Hz, 4H), 1.35 (d, J = 6.7 Hz, 6H).

[0219] Step 12-2: Preparation of 6-(4-aminophenyl)-2-isopropyl-5-methylpyridazin-3(2H)-one

[0220] Except using 6-chloro-2-isopropyl-5-methylpyridazin-3(2H)-one (100 mg, 0.53 mmol) obtained in Step 12-1 above instead of 6-chloro-2-methylpyridazin-3(2H)-one, the title compound (84 mg, yield: 64%) was obtained in the same manner as in Step 8-3 of Example 8.

[0221] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 8.6 Hz, 2H), 5.45 (s, 2H), 5.20 (p, J = 6.6 Hz, 1H), 2.13 (s, 2H), 1.32 (d, J = 6.6 Hz, 6H).

[0222] Step 12-3: Preparation of (4-(1-isopropyl-4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazimidoyl dinitrile Preparation

[0223] Except using 6-(4-aminophenyl)-2-isopropyl-5-methylpyridazin-3(2H)-one (70 mg, 0.29 mmol) obtained in Step 12-2 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, the title compound (88 mg, yield: 95%) was obtained in the same manner as in Step 1-2 of Example 1.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.03–7.93 (m, 3H), 7.57 (d, J = 8.9 Hz, 2H), 5.24 (p, J = 6.6 Hz, 1H), 2.16 (d, J = 1.2 Hz, 3H), 1.35 (d, J = 6.6 Hz, 6H).

[0225] Example 13: Preparation of (3-chloro-4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbamoyl dinitrile (Compound 13)

[0226] Step 13-1: Preparation of 6-(4-amino-2-chlorophenyl)-2,5-dimethylpyridazin-3(2H)-one

[0227] Except for using 4-amino-2-chlorophenylboronic acid pinacol ester (164 mg, 1.04 mmol) instead of 4-aminophenylboronic acid pinacol ester, and using 6-chloro-2,5-dimethylpyridazin-3(2H)-one (150 mg, 0.95 mmol) obtained in Step 11-1 of Example 11 above instead of 6-chloro-2-methylpyridazin-3(2H)-one, in the same manner as Step 8-3 of Example 8 above, 181 mg (yield: 77%) of the title compound was obtained.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 1.3 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 2.2 Hz, 1H), 6.57 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 3.68 (s, 3H), 2.11 (d, J = 1.2 Hz, 3H).

[0229] Step 13-2: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-chlorophenyl)carbazimidoyl dinitrile Preparation

[0230] Except for using 6-(4-amino-2-chlorophenyl)-2,5-dimethylpyridazin-3(2H)-one (150 mg, 0.60 mmol) obtained in Step 13-1 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydropyridazin-3(2H)-one, in the same manner as Step 1-2 of Example 1 above, 115 mg (yield: 59%) of the title compound was obtained.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 7.61–7.55 (m, 3H), 7.51 (dd, J = 8.5 Hz, 2.1 Hz, 1H), 3.72 (s, 3H), 2.14 (d, J = 1.2 Hz, 3H).

[0232] Example 14: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-fluorophenyl)carbamoyl dinitrile (Compound 14)

[0233] Step 14-1: Preparation of 6-(4-amino-2-fluorophenyl)-2,5-dimethylpyridazin-3(2H)-one

[0234] Except for using 4-amino-2-fluorophenylboronic acid pinacol ester (197 mg, 0.83 mmol) instead of 4-aminophenylboronic acid pinacol ester, and using 6-chloro-2,5-dimethylpyridazin-3(2H)-one (120 mg, 0.76 mmol) obtained in Step 11-1 of Example 11 above instead of 6-chloro-2-methylpyridazin-3(2H)-one, in the same manner as Step 8-3 of Example 8 above, 146 mg (yield: 83%) of the title compound was obtained.

[0235] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.34 (t, J = 8.9 Hz, 1H), 6.45 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.38 (dd, J = 14.3 Hz, 2.1 Hz, 1H), 5.77 (s, 2H), 3.69 (s, 3H), 2.12 (d, J = 1.2 Hz, 3H).

[0236] Step 14-2: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-fluorophenyl)carbazimidoyl dinitrile Preparation

[0237] Except for using 6-(4-amino-2-fluorophenyl)-2,5-dimethylpyridazin-3(2H)-one (100 mg, 0.43 mmol) obtained in Step 14-1 above instead of 6-(4-aminophenyl)-2-isopropyl-4,5-dihydro-3(2H)-pyridazinone, in the same manner as Step 1-2 of Example 1 above, 88 mg (yield: 66%) of the title compound was obtained.

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.42–7.33 (m, 3H), 3.74 (s, 3H), 2.15 (s, 3H).

[0239] Preparation Example

[0240] Meanwhile, the novel compound represented by Formula 1 according to the present invention can be formulated into various forms. The following examples exemplarily describe several methods for preparing a preparation comprising the compound represented by Formula 1 according to the present invention as an active ingredient, and the present invention is not limited thereto.

[0241] Preparation Example 1: Preparation of Tablets by Direct Compression

[0242] 5.0 mg of each active ingredient prepared in Examples 1-14 was sieved, mixed with 14.1 mg of lactose, 0.8 mg of cross-linked polyvinylpyrrolidone USNF, and 0.1 mg of magnesium stearate, and then compressed into tablets.

[0243] Preparation Example 2: Preparation of tablets by wet granulation

[0244] Sieve 5.0 mg of each active ingredient prepared in Examples 1-14, and mix it with 16.0 mg of lactose and 4.0 mg of starch. Dissolve 0.3 mg of polysorbate 80 in pure water, and add the solution to the mixture in an appropriate amount, and then atomize to obtain fine particles. After drying, sieve the fine particles, mix them with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and press them into tablets.

[0245] Preparation Example 3: Preparation of powder and capsules

[0246] Sieve 5.0 mg of each active ingredient prepared in Examples 1-14, and then mix it with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. Use appropriate equipment to fill the mixture into No. 5 hard gelatin capsules to prepare capsules.

[0247] Preparation Example 4: Preparation of injectable drug

[0248] Mix 100 mg of each active ingredient prepared in Examples 1-14 with 180 mg of mannitol, 26 mg of Na2HPO4·12H2O and 2974 mg of distilled water to prepare an injectable drug.

[0249] Experimental Example 1: Selection of tau protein aggregation inhibitory substances using a cell model

[0250] To select a new tau protein aggregation inhibitor, a tau-BiFC cell model was used, in which the formation of tau oligomers can be easily observed in living cells. The tau-BiFC cells were aliquoted into 384-well plates. The next day, the cells were treated with each of the compounds prepared according to Examples 1-14 at concentrations of 1 μM, 3 μM, and 10 μM, together with forskolin (treatment concentration: 30 μM), which is a compound that induces tau protein aggregation by activating the tau phosphorylase PKA. After 48 hours, the nuclei were stained with Hoechst (treatment concentration: 2 μg / mL), and the BiFC fluorescence intensity was automatically measured using an Operetta (PerkinElmer) to count the stained nuclei in each well of the entire plate. The group treated only with forskolin that induces tau protein aggregation was set as a reference point for 100% tau protein aggregation state, and the following formula was used to confirm the effect of the compound: "BiFC fluorescence intensity of the compound synthesized according to the embodiments of the present invention / (fluorescence intensity of the control group treated only with forskolin that induces tau protein aggregation - fluorescence intensity of the untreated control group) × 100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also measured, where 100% cell viability of the group treated only with forskolin was used as a reference, and the cytotoxicity value of each compound was calculated using the following formula: "(number of stained nuclei in the group treated with the compound / number of stained nuclei in the group treated with forskolin) × 100". Based on the treatment results, the substances that inhibit intracellular tau protein aggregation were selected from a series of candidate groups that showed a tau protein aggregation inhibition rate of 70% or higher and 100% cell viability at a compound treatment concentration of 10 μM or higher.

[0251] Experimental Example 2: Confirmation of the concentration-dependent inhibitory effect of the new compound on tau protein aggregation

[0252] To evaluate the dose-dependent tau protein aggregation inhibitory effect of the compound selected according to Experimental Example 1 on tau protein aggregation, the selected compound at concentrations of 0.03 μM, 0.01 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM, and forskolin (treatment concentration: 30 μM, which is a tau protein aggregation inducer) were used to treat tau-BiFC cells. After 48 hours, the tau protein aggregation reaction and the degree of cytotoxicity were analyzed by observing cell images. The IC of the compound was analyzed by non-linear regression analysis using Prism software (Graph Pad). 50 and toxicity. The calculation results of representative compounds are shown in Table 2 below. The structural formulas of the compounds in the comparative example for comparison are shown in Table 3 below.

[0253] Table 2

[0254]

[0255]

[0256] Table 3

[0257]

[0258] As shown in Table 2 and Table 3, compared with the known substance levosimendan, the compounds of the present invention show excellent inhibitory effects on tau protein aggregation. However, it has also been confirmed that the compounds of the comparative examples (which include a backbone similar to that of the compounds of the present invention, except for the presence or absence of substituents on the 2-position nitrogen atom of the pyridazinone or 4,5-dihydropyridazinone, and the binding position thereof to the phenyl group) have a lower inhibitory effect on tau protein aggregation than levosimendan as a reference substance.

[0259] Experimental Example 3: Inhibitory Effects of New Compounds on CYP Coenzyme Activity

[0260] The inhibitory effects of the compounds prepared according to Examples 1 to 14 on CYP coenzyme activity were identified. Specifically, human liver microsomes (0.25 mg / mL), 0.1 M phosphate buffer solution (pH 7.4), a substrate drug mixture of five drug-metabolizing enzymes (50 μM phenacetin, 10 μM diclofenac, 100 μM S-mephenytoin, 5 μM dextromethorphan, and 2.5 μM midazolam), and a compound at a concentration of 0 μM or 10 μM were mixed and pre-incubated at 37 °C for 5 minutes, and then a NADPH-generating system solution was added thereto and further incubated at 37 °C for 15 minutes. Thereafter, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (terfenadine) and centrifuged for 5 minutes (14,000 rpm, 4 °C), and then the supernatant was injected into an LC-MS / MS system for simultaneous analysis of the metabolites of the substrate drugs, thereby evaluating the inhibitory effect on drug metabolism.

[0261] The metabolites of each CYP coenzyme indicator drug generated by the reaction were analyzed using a Shimadzu Nexera XR system and a TSQ Vantage (Thermo). In the HPLC column, Kinetex C18 (2.1 mm × 100 mm, 2.6 μm, particle size; Phenomenex, USA) was used, and the mobile phases were (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid, and the gradient program shown in Table 4 was applied thereto.

[0262] Table 4

[0263] Time (min) Flow rate (mL / min) ％A ％B 0 0.3 100 0 1.0 0.3 60 40 4.0 0.3 50 50 4.1 0.3 100 0 7.0 0.3 100 0

[0264] The metabolites produced were quantified using the multiple reaction monitoring (MRM) quantification mode, and the data analysis was performed using Xcalibur (version 1.6.1). To represent the inhibitory effect of the new compounds prepared according to the embodiments of the present invention on the CYP coenzyme activity, the CYP coenzyme activity (%) relative to the control group not treated with any compound is shown in Table 5 below.

[0265] Table 5

[0266]

[0267]

[0268] Experimental Example 4: Identification of the hepatic microsomal stability caused by the new compounds

[0269] The stability of the compounds prepared according to Examples 1-14 in hepatic microsomes was confirmed. Specifically, four types of hepatic microsomes (human, dog, rat, and mouse, each at 0.25 mg / mL), 0.1 M phosphate buffer solution (pH 7.4), and each compound at a concentration of 1 μM were mixed, pre-incubated at 37 °C for 5 minutes, and then the NADPH generating system solution was added thereto, and further incubated at 37 °C for 30 minutes. Thereafter, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (chloropropamide), and centrifuged for 5 minutes (14,000 rpm, 4 °C), and then the supernatant was injected into the LC-MS / MS system for analyzing the substrate drug, thereby evaluating the metabolic stability of 8 compounds.

[0270] The amount of the remaining substrate after the reaction was analyzed using a Shimadzu Nexera XR system and a TSQ Vantage (Thermo). In the HPLC column, Kinetex XB-C18 (2.1 mm × 100 mm, particle size 2.6 μm; Phenomenex, USA) was used, and the mobile phase was (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. The data analysis was performed using the analytical software (version 1.6.3) and Xcalibur (version 1.6.1). The calculation results are shown in Table 6 below.

[0271] Table 6

[0272]

[0273]

[0274] The above description of the present invention is provided for illustrative purposes, and those skilled in the art will understand that various changes and modifications can be made without changing the technical concept and basic characteristics of the present invention. Therefore, it is obvious that the above embodiments are illustrative in all aspects and do not limit the present invention. The various embodiments disclosed herein are not restrictive, and the true scope and spirit are indicated by the appended claims. The present invention is limited only by the terms of the appended claims and the full scope of equivalents to which those claims are entitled.

Claims

1. A compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] Among them, In formula 1, is - or =; R1 is hydrogen or a halogen; R2 is hydrogen or C 1-6 alkyl; and R3 is C 1-6 alkyl, C 1-6 alkoxy-C 0-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or C 1-6 alkoxy-C 6-10 aryl; provided that the compounds (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile and (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile are excluded.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is hydrogen, chlorine or fluorine; R2 is hydrogen or methyl; and R3 is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, 2,2,2-trifluoroethyl, methoxyphenyl or methoxyethyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by the following formula 2 or formula 3: [Formula 2] [Formula 3] 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is: (1) (4-(1-isopropyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (2) (4-(1-isopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (3) (4-(1-ethyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (4) (4-(4-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (5) (4-(1-(2-methoxyethyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (6) (4-(1-cyclopropyl-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (7) (4-(1-(4-methoxyphenyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazonyldinitrile, (9) (4-(1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, (10) (4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, (12) (4-(1-isopropyl-4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, (13) (3-chloro-4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazonyldinitrile, or (14) (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-fluorophenyl)carbazonyldinitrile.

5. A method for preparing the compound according to claim 1, the method comprising: In the presence of an acid, a compound having a reactive amino group at one end represented by Formula 4 below is reacted with sodium nitrite and malononitrile to form an imine bond: [Formula 4] Wherein, in Formula 4 above, R1 to R3 are as defined in Claim 1.

6. The method according to Claim 5, wherein the method is carried out through a series of steps, including: First step, dissolve the compound of formula 4 and sodium nitrite in C 1-4 a lower alcohol solvent, and add an aqueous solution of an acid thereto at a temperature of -5°C to 5°C to form a diazonium salt, In the second step, malononitrile is added to the reaction solution containing the diazonium salt obtained in the first step, and the reaction is carried out at a temperature of 15°C to 40°C, and In the third step, an aqueous solution of a base is added to the reaction solution of the second step for neutralization.

7. The method according to Claim 5, wherein the compound of Formula 4 is a compound represented by Formula 4-a or 4-b below: [Formula 4-a] [Formula 4-b] 8. The method according to Claim 7, wherein the compound represented by Formula 4-a is prepared through a series of steps, including the following steps: Step a-1’) React 4-(4-aminophenyl)-4-oxo-3-(unsubstituted or R2-substituted)-butyric acid with unsubstituted or R3-substituted hydrazine.

9. The method according to Claim 7, wherein the compound represented by Formula 4-b above is prepared through a series of steps, including the following steps: b-1) React by dissolving 3,6-dihalo-4-(unsubstituted or R2-substituted) pyridazine in an acid, and solidify by adding a base thereto, b-2) Optionally, when R3 is a substituent other than hydrogen, under basic conditions, react the 6-halo-5-(unsubstituted or R2-substituted) pyridazin-3(2H)-one prepared in the previous step with R3X, where X is a halogen, b-3) In the presence of a Pd(PPh3)2 catalyst, react the 6-halo-2-(unsubstituted or R3-substituted)-5-(unsubstituted or R2-substituted) pyridazin-3(2H)-one obtained in the previous step with 4-amino or nitro-2-(unsubstituted or R1-substituted phenyl) boronic acid pinacol ester, and b-4) Optionally, when reacting with 4-nitro-2-(unsubstituted or R1-substituted phenyl) boronic acid pinacol ester in step b-3, in a hydrogen atmosphere, in the presence of a Pd / C catalyst, react the compound having a nitro substituent at one end obtained in the previous step to reduce the nitro group to an amino group.

10. A composition for inhibiting tau protein aggregation, which comprises the compound according to Claim 1 as an active ingredient.

11. A composition for inhibiting tau protein hyperphosphorylation, which comprises the compound according to Claim 1 as an active ingredient.

12. A pharmaceutical composition for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, which comprises the compound according to Claim 1 as an active ingredient.

13. The pharmaceutical composition according to Claim 12, wherein the disease caused by tau protein aggregation or hyperphosphorylation is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, trauma, cerebrovascular disease, peripheral neuropathy, retinopathy, and glaucoma.

14. The pharmaceutical composition according to claim 12, wherein the disease caused by tau protein aggregation or hyperphosphorylation is a tauopathy, and the tauopathy is selected from the group consisting of: primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, frontotemporal dementia, Parkinson's syndrome associated with chromosome 17, Lytico-bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic Parkinson's syndrome, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, and traumatic brain injury.

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