Dyrk1A inhibitors and use thereof

Abstract

The present invention relates to a compound represented by Formula 1, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing the same as an active ingredient. Since the compound represented by Formula 1 of the present invention exhibits high inhibitory activity against DYRK1A, it can be usefully used for the treatment of central nervous system diseases associated with DYRK1A. [Chemical Formula 1] In the above chemical formula 1, A and R1 to R4 are as described above in the specification.

Description

Technology Field

[0001] The present invention relates to an inhibitory compound that inhibits Dyrk1A enzyme, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing the same as an active ingredient. Background Technology

[0003] Protein kinases are known to be a major regulatory mechanism of cells that are frequently deregulated in human diseases and are a key component of intracellular signaling pathways that control many physiological processes. Most kinases act on both serine and threonine, others act on tyrosine, and many (bispecific kinases) act on all three.

[0005] Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) is known to play an important role in signaling pathway-regulating cell proliferation and is associated with brain development. The gene for Dyrk1A is located on human chromosome 21 in the Down syndrome critical region (DSCR), and increased activity of Dyrk1A has been reported to be associated with neurodegenerative diseases such as Down syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Pick's disease.

[0006] Hyperphosphorylation of the Thr-212 residue of Tau was observed in the brains of Alzheimer's disease patients, and the Thr-212 residue of Tau was also found to be hyperphosphorylated in mice transformed with human Dyrk1A. These results revealed that Dyrk1A may make a significant contribution to the pathology caused by the hyperphosphorylation of Tau in Alzheimer's disease and Down syndrome.

[0007] In particular, in Alzheimer's patients, in addition to the formation of intracellular neurofibrillary tangles composed of aggregates of neuropathologically hyperphosphorylated Tau, there is a cellular accumulation of insoluble precipitates of amyloid β peptide, and Dyrk1A is known to promote the formation of amyloid plaques, which are one of the important pathological causative agents of Alzheimer's disease, by directly phosphorylating related amyloid β precursor proteins, such as presenilin.

[0009] As a prior study on such Dyrk1A activity inhibitors, Souchet, B. et al. identified the compound Leucettine L41 as a DYRK1A activity inhibitor and confirmed through mouse experiments that the L41 compound inhibits STAT3 phosphorylation, reduces levels of pro-inflammatory cytokines (IL1-β, TNF-α, and IL-12) associated with increased microglial recruitment around amyloid plaques, reduces the amyloid-β plaque burden, improves synaptic plasticity, and can restore memory function.

[0011] Accordingly, while striving to develop a therapeutic agent for central nervous system diseases that inhibits Dyrk1A, the inventors discovered that a novel compound according to the present invention exhibits high inhibitory activity against Dyrk1A, thereby being useful for the prevention or treatment of central nervous system diseases, and thus completed the present invention. Prior art literature

[0013] SOUCHET, Beno t,et al. Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP / PS1 mice. Acta neuropathologica communications, 2019, 7: 1-15. The problem to be solved

[0014] One objective of the present invention is to provide a novel compound having the ability to inhibit Dyrk1A activity.

[0015] Another objective of the present invention is to provide a method for preparing a novel compound having the ability to inhibit Dyrk1A activity.

[0016] Another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing a novel compound having Dyrk1A activity inhibitory ability as an active ingredient.

[0017] Another objective of the present invention is to provide a health functional food for the prevention or improvement of central nervous system diseases containing a novel compound having Dyrk1A activity inhibitory ability as an active ingredient. means of solving the problem

[0019] In order to achieve the above objective,

[0020] According to one aspect of the present invention, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0021] [Chemical Formula 1]

[0022]

[0023] In the above chemical formula 1,

[0024] A is CH or N, and

[0025] R 1 and R 2 Each independently hydrogen, halogen, CF3, and C 1-10 alkyl or C 1-10 It is alkoxy, or

[0026] R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and

[0027] R 3 is C 1-10 It is alkyl, and

[0028] R 4 is C 1-10 It is an alkyl.

[0030] In addition, the present invention, as shown in the following reaction scheme 1,

[0031] A method for preparing a compound represented by Chemical Formula 1 is provided, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1:

[0032] [Reaction Equation 1]

[0033]

[0034] (A and R in the above reaction scheme 1 1 to R 4 is as defined in Chemical Formula 1 above.)

[0036] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases is provided, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] According to another aspect of the present invention, a health functional food for the prevention or improvement of neurodegenerative diseases is provided, containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] Furthermore, the present invention provides a method for preventing or treating a neurodegenerative disease, comprising the step of administering the above pharmaceutical composition in a therapeutically effective amount to a subject in need thereof.

[0039] In addition, the present invention provides a method for preventing or treating a neurodegenerative disease comprising the step of administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a subject in need thereof.

[0040] Furthermore, the present invention provides a use of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer. Effects of the invention

[0042] The novel compound according to the present invention exhibits high inhibitory activity against DYRK1A, so it can be usefully used in the treatment of central nervous system diseases associated with DYRK1A. Brief explanation of the drawing

[0044] Figure 1 is a diagram showing the DYRK1A activity according to the concentration of the compound according to the example. Figure 2 is a diagram showing the p-tau protein expression amount according to the concentration of the compound according to the example. Specific details for implementing the invention

[0045] The present invention will be described in detail below.

[0046] One aspect of the present invention is,

[0047] Provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0048] [Chemical Formula 1]

[0049]

[0050] In the above chemical formula 1,

[0051] A is CH or N, and

[0052] R 1 and R 2 Each independently hydrogen, halogen, CF3, and C 1-10 alkyl or C 1-10 It is alkoxy, or

[0053] R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and

[0054] R 3 is C 1-10 It is alkyl, and

[0055] R 4 is C 1-10 It is an alkyl.

[0056] In addition, in the above chemical formula 1,

[0057] R 1 and R 2 Each independently hydrogen, halogen, CF3, and C 1-6 alkyl or C 1-6 It is alkoxy, or

[0058] R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and

[0059] R 3 is C 1-6 It is alkyl, and

[0060] R 4 is C 1-6 It can be an alkyl.

[0061] In addition, in the above chemical formula 1,

[0062] R 1 and R 2 Each independently hydrogen, halogen, CF3, and C 1-3 alkyl or C 1-3 It is alkoxy, or

[0063] R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and

[0064] R 3 is C 1-3 It is alkyl, and

[0065] R 4 is C 1-3 It can be an alkyl.

[0067] Another embodiment of the present invention is, in each of the prior embodiments,

[0068] A can be CH.

[0070] Another embodiment of the present invention is, in each of the prior embodiments,

[0071] R 1 Silver is hydrogen, halogen, CF3, or C 1-10 It is an alkoxy, and R 2 is hydrogen, C 1-10 alkyl or C 1-10 It can be an alkoxy,

[0072] R 1 Silver is hydrogen, halogen, CF3, or C 1-6 It is an alkoxy, and R 2 is hydrogen, C 1-6 alkyl or C 1-6 It can be an alkoxy,

[0073] R 1 Silver is hydrogen, halogen, CF3, or C 1-3 It is an alkoxy, and R 2 is hydrogen, C 1-3 alkyl or C 1-3 It can be an alkoxy.

[0075] Another embodiment of the present invention is, in each of the prior embodiments,

[0076] R 1 and R 2 At least one of them may not be hydrogen.

[0078] In another embodiment of the present invention,

[0079] Examples of compounds represented by Chemical Formula 1 according to the present invention include the following compounds.

[0080] <1> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide;

[0081] <2> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide;

[0082] <3> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide;

[0083] <4> 5-chloro-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0084] <5> 5-chloro-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0085] <6> 5-chloro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0086] <7> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0087] <8> 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0088] <9> 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide;

[0089] <10> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide;

[0090] <11> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide;

[0091] <12> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide;

[0092] <13> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide;

[0093] <14> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide;

[0094] <15> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide;

[0095] <16> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide;

[0096] <17> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide;

[0097] <18> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide;

[0098] <19> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide;

[0099] <20> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide;

[0100] <21> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide;

[0101] <22> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide;

[0102] <23> 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide;

[0103] <24> 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide;

[0104] <25> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxynicotinamide;

[0105] <26> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-6-methylnicotinamide;

[0106] <27> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide;

[0107] <28> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide;

[0108] <29> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide.

[0110] The terms used in this specification are defined.

[0111] The term "alkyl" includes straight-chain or branched-chain saturated hydrocarbon residues unless otherwise specified. For example, "C 1-6 "Alkyl" refers to an alkyl group with a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc.

[0112] The term "alkoxy" refers to a group in which an alkyl group is connected to a parent through an oxygen atom and substituted.

[0113] The term "aryl" refers to an aromatic radical in which a single ring or two or three hydrocarbon aromatic rings are fused, and C 6-10 Aryl refers to an aromatic ring compound containing 6 to 10 carbons, including phenyl or naphthyl.

[0114] The term “halogen” refers to halogen atoms such as F, Cl, Br, and I, and when it is said to be “halogen” substituted, it means that it has been substituted with one or more halogen atoms. The halogen atoms being substituted can be selected from a range of 1 to 5.

[0115] Unless otherwise indicated in this specification as "substituted," it means not substituted.

[0117] In this specification, the term “pharmaceuticalally acceptable salt” means a salt that is pharmaceutically acceptable as a salt formed by ionic bonding with a compound when the compound contains a carboxylic acid or amine functional group.

[0118] The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., non-toxic organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These types of pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butyne-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and phthalates. Includes terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0119] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid to produce a precipitate, filtering and drying it, or by vacuum distilling the solvent and excess acid, drying it, and crystallizing it under an organic solvent.

[0120] In addition, pharmaceutically acceptable metal salts can be produced using a base. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts as the metal salts. In addition, the corresponding salts are obtained by reacting the alkali metal or alkaline earth metal salt with a suitable base salt (e.g., silver nitrate).

[0122] Another aspect of the present invention is, as shown in the following reaction scheme 1,

[0123] The present invention provides a method for preparing a compound represented by Chemical Formula 1 according to claim 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

[0124] [Reaction Equation 1]

[0125]

[0126] In the above reaction scheme 1, A and R 1 to R 4 It is as defined in Chemical Formula 1 above.

[0127] In the above reaction scheme, the reaction of Chemical Formula 2 and Chemical Formula 3 is an amide synthesis reaction, and the reaction conditions are carried out using a conventional activating reagent for forming amide bonds, and carbodiimide, acyl halide, acyl anhydride, phosphonic acid halide, phosphonic anhydride, etc. may be used, and the reaction temperature is not particularly limited but may be carried out in the range of 0 to 100°C, 10 to 50°C, and may be carried out at room temperature.

[0129] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of central nervous system diseases, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0130] At this time, the above central nervous system disease may be a neurodegenerative disease, and

[0131] The above neurodegenerative diseases include Down syndrome, Alzheimer's disease, hippocampal sclerosis, frontotemporal dementia (FTD), frontotemporal degeneration (FTLD), Huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, motor neuron disease, inclusion body myositis, Parkinson's disease, Lewy body dementia, Lewy body disease, multiple system atrophy, progressive supranuclear palsy, Pick's disease, prion disease, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia, hypoxia, and glutamate neurotoxicity, etc.

[0132] In addition, the above compound or its pharmaceutically acceptable salt can inhibit the activity of Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), and through such inhibition, may have preventive, improving, or therapeutic activity for central nervous system diseases. In this case, the central nervous system disease is the same as previously described.

[0133] The above compound or a pharmaceutically acceptable salt thereof is characterized by inhibiting the phosphorylation of tau protein through Dyrk1A inhibition.

[0135] In addition, a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual treatment or administered in combination with other treatments currently in use.

[0136] In addition, a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can enhance the therapeutic effect by administering it in combination with other therapeutic agents.

[0137] The compound represented by Chemical Formula 1 above or its pharmaceutically acceptable salt may be administered in various oral and parenteral formulations during clinical administration. When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid formulations for oral administration include tablets, pills, powders, granules, and capsules, and these solid formulations are prepared by mixing at least one excipient, e.g., starch, calcium carbonate, sucrose or lactose, gelatin, etc., with one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups; in addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspension agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleates.

[0138] A pharmaceutical composition having a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is by a method of injecting subcutaneously, intravenously, intramuscularly, or intrathoracically.

[0139] At this time, in order to formulate a parenteral administration formulation, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, and may be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation, or coating methods.

[0140] Oral dosage forms include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and these dosage forms contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salts and / or absorbents, coloring agents, flavoring agents, and sweeteners.

[0142] Another aspect of the present invention provides a health functional food for the prevention or improvement of central nervous system diseases, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In this case, the central nervous system disease is the same as that described above.

[0143] The compound represented by Formula 1 according to the present invention may be added directly to food or used together with other food or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient may be appropriately determined according to its purpose of use (for prevention or improvement). Generally, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term consumption for the purpose of health and hygiene or for health control, the amount may be less than the above range, and the active ingredient may be used in an amount greater than the above range as there is no problem in terms of safety.

[0144] Another aspect of the present invention provides a method for preventing, improving, or treating a central nervous system disease, comprising the step of administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need.

[0145] Preferably, a method for preventing, improving, or treating a neurodegenerative disease is provided, comprising the step of administering a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a necessary subject.

[0146] Another aspect of the present invention provides the use or application of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention, improvement, or treatment of central nervous system diseases.

[0147] Preferably, the use or application of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is provided in the prevention, improvement, or treatment of neurodegenerative diseases.

[0148] The compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a “pharmaceutically effective amount.” In the present invention, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level may be determined based on factors including individual type and severity, age, sex, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts include 0.001 mg / kg to 1000 mg / kg, 0.01 mg / kg to 100 mg / kg, 0.1 to 20 mg / kg, or 0.1 to 500 mg / kg. The amount of the pharmaceutical composition of the present invention may be selected and administered by a person skilled in the art within an appropriate range.

[0150] The present invention will be explained in detail below through manufacturing examples, examples, and experimental examples.

[0151] However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following manufacturing examples, examples, and experimental examples.

[0153] Materials and Methods

[0154] Unless otherwise specified, reactions were performed in flame-dried glass. Thin-layer chromatography (TLC) for analysis was performed on pre-coated silica gel 60 F254 plates, and TLC visualization was achieved with UV illumination (254 and 365 nm). Flash column chromatography was performed on CombiFlash® Rf+ systems with silica gel (400-630 mesh) or RediSep® Rf silica columns (230-400 mesh) using appropriate eluents. 1¹H NMR was recorded at Brucker Avance 400 MHz or 500 MHz. Chemical shifts were expressed in parts per million (ppm) relative to the appropriate solvent peak, or 0.0 ppm for tetramethylsilane.

[0155] The following abbreviations were used to describe peak splitting patterns where appropriate.

[0156] br = broad, s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, dd = doublet of a doublet, td = triplet of a doublet, ddd = doublet of a doublet of a doublet. The coupling constant J was reported in Hertz (Hz).

[0157] 13 13C NMR was recorded at Brucker Avance 100 MHz or 125 MHz and fully separated by broadband proton separation. Chemical shifts were reported in ppm relative to the centerline of the triplet at 77.6 ppm of CDCl3. LC / MS analysis was performed on a Waters Acquity UPLC system using electrospray ionization in either cation or anion mode. EI / MS data were obtained using a Varian 1200L. Commercial reagents and solvents were used without further purification, except as indicated below.

[0159] <Preparation of Compound of Example Preparation> Manufactured according to the scheme below.

[0160]

[0161] R in the above scheme 3 is as previously defined for Chemical Formula 1.

[0163] <Preparation Example 1> Preparation of (E)-N'-(6-(2-((E)-(dimethylamino)methylene)hydrazine-1-carbonyl)pyridine-2-yl)-N,N-dimethylformimidamide (Intermediate 1) (Step a)

[0164] N,N-dimethylformamide dimethyl acetal (57.8 mL) was heated at 110°C for 1 day in a stirred solution of 6-aminopicolinohydrazide (1.5 g, 9.86 mmol). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was washed with diethyl ether. The obtained solid was filtered and dried (2.39 g, 92.4%).

[0165] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.67 (s, 1H), 8.86 (s, 1H), 8.07 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.48 (dd, J = 7.4, 1.1 Hz, 1H), 6.95 - 6.88 (m, 1H), 3.14 (s, 3H), 3.01 (s, 3H), 2.87 (s, 6H) ); LCMS: calculated for C 12 H 18 N6O 262.2, found 263.1 [M + H + ].

[0167] <Preparation Example 2> Preparation of 6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-amine (Intermediate 2) (Step b)

[0168] A solution of intermediate 1 compound (829 mg, 3.16 mmol) and ethylamine hydrochloride (2.58 g, 15.3 mmol) stirred in acetonitrile / acetic acid (v / v=4 / 1, 7.5 mL) was heated at 90°C for 4 hours using a sealed tube. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (12 mL). Then, hydrochloride (2 mL) was added to the mixture and stirred at 65°C for 2 hours. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with sodium bicarbonate, and dried with MgSO4. The resulting product was purified using silica gel column chromatography with 10% methanol added to DCM as the eluent to obtain the desired intermediate 2 compound (241.4 mg, 40.4%).

[0169] 1¹H NMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0171] <Preparation Example 3> Preparation of 6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-amine (Intermediate 3) (Step b)

[0172] In Preparation Example 2, methylamine was used instead of ethylamine to obtain the desired intermediate compound 3 (390 mg, 67%).

[0173] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.74 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 3.99 (s, 4H).

[0175] <Preparation Example 4> Preparation of 6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-amine (Intermediate 4) (Step b)

[0176] As in Preparation Example 2, isopropylamine was used instead of ethylamine to obtain the desired intermediate compound 4 (250 mg, 42%).

[0177] 1 1H NMR (300 MHz, DMSO- d 6) δ 8.78 (s, 1H), 7.52 (dd, J = 8.3, 7.4 Hz, 1H), 7.17 (dd, J = 7.4, 0.8 Hz, 1H), 6.53 (dd, J = 8.4, 0.9 Hz, 1H), 6.18 (s, 2H), 5.53 (hept, J = 6.7 Hz, 1H), 1.43 (d, J = 6.7 Hz, 6H).

[0179] Specific examples of the preparation of the compounds in the following examples are presented, and they were prepared according to the scheme of Reaction Scheme 1.

[0180] [Reaction Equation 1]

[0181]

[0182] In the above reaction scheme 1, A and R 1 to R 4 It is as defined in Chemical Formula 1 above.

[0184] <Example 1> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide

[0185] 5-fluoro-2-methoxybenzoic acid (29 mg, 0.17 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.236 ml, 0.40 mmol) was added and stirred at room temperature for 10 minutes. DMAP (48 mg, 0.40 mmol) and intermediate 2 compound (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (22.6 mg, 50.1%).

[0186] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.71 (s, 1H), 8.71 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.64 (dd, J = 9.1, 3.3) Hz, 1H), 7.46 (td, J = 8.5, 3.3 Hz, 1H), 7.30 (dd, J = 9.1, 4.2 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0188] <Example 2> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide

[0189] In Example 1, intermediate 3 compound was used instead of intermediate 2 compound to prepare the product.

[0190] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.80 (s, 1H), 8.62 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.59 (dd, J = 8.9, 3.3) Hz, 1H), 7.44 (td, J = 8.5, 3.2 Hz, 1H), 7.27 (d, J = 4.2 Hz, 0H), 4.06 (s, 3H), 3.95 (s, 3H).

[0192] <Example 3> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide

[0193] In Example 1, intermediate 4 was used instead of intermediate 2 to prepare the product.

[0194] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.70 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 9.0, 3.3) Hz, 1H), 7.51 - 7.41 (m, 1H), 7.31 (dd, J = 9.2, 4.2 Hz, 1H), 5.54 (p, J = 6.7 Hz, 1H), 3.97 (s, 3H), 1.51 (d, J = 6.6 Hz, 6H).

[0196] <Example 4> Preparation of 5-chloro-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0197] 5-chloro-2-methoxybenzoic acid (29 mg, 0.17 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic acid anhydride (0.24 mL, 0.40 mmol) was added and stirred at room temperature for 10 minutes. DMAP (48 mg, 0.40 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (22.6 mg, 50.1%).

[0198] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.71 (s, 1H), 8.71 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.64 (dd, J = 9.1, 3.3) Hz, 1H), 7.46 (td, J = 8.5, 3.3 Hz, 1H), 7.30 (dd, J = 9.1, 4.2 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0200] <Example 5> Preparation of 5-chloro-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0201] In Example 4, intermediate 3 compound was used instead of intermediate 2 compound to prepare the product.

[0202] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.79 (s, 1H), 8.62 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.62 (dd, J = 9.0, 2.8 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 4.05 (s, 3H), 3.94 (s, 3H).

[0204] <Example 6> Preparation of 5-chloro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0205] In Example 4, intermediate 4 was used instead of intermediate 2.

[0206] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.68 (s, 1H), 8.90 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.9, 2.8 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 5.56 (p, J = 6.7 Hz, 1H), 3.96 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H); LCMS: calculated for C 18 H 18 ClN5O2371.1, found 372.2 [M + H + ].

[0208] <Example 7> Preparation of 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0209] 5-bromo-2-methoxybenzoic acid (48 mg, 0.21 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.28 mL, 0.48 mmol) was added and stirred at room temperature for 10 minutes. DMAP (58 mg, 0.48 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (29.9 mg, 46.8%).

[0210] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.68 (s, 1H), 8.70 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.93 - 7.89 (m, 1H), 7.75 (dd, J = 8.9, 2.6 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); LCMS: calculated for C 17 H 16 BrN5O2401.1, found 402.2 [M + H + ].

[0212] <Example 8> Preparation of 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0213] In Example 7, intermediate 3 was used instead of intermediate 2.

[0214] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.91 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.06 (t, J = 8.0 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.9, 2.6 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.09 (s, 3H), 3.93 (s, 3H).

[0216] <Example 9> Preparation of 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide

[0217] In Example 7, intermediate 4 was used instead of intermediate 2.

[0218] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.67 (s, 1H), 8.90 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.75 (dd, J = 8.9, 2.6 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 5.56 (p, J = 6.7 Hz, 1H), 3.95 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H); LCMS: calculated for C 18 H 18 BrN5O2415.1, found 416.3 [M + H + ].

[0220] <Example 10> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide

[0221] 2-methoxy-5-(trifluoromethyl)benzoic acid (38 mg, 0.17 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.24 mL, 0.40 mmol) was added and stirred at room temperature for 10 minutes. DMAP (48 mg, 0.40 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (34.6 mg, 66.9%).

[0222] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.73 (s, 1H), 8.70 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.94 (dd, J = 8.2, 4.2 Hz, 2H), 7.45 (d, J = 8.7 Hz, 1H), 4.60 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0224] <Example 11> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide

[0225] In Example 10, intermediate 3 compound was used instead of intermediate 2 compound to prepare the product.

[0226] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.61 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.93 (dd, J = 8.2, 4.2 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 4.05 (s, 3H), 4.01 (s, 3H).

[0228] <Example 12> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide

[0229] In Example 10, intermediate 4 was used instead of intermediate 2.

[0230] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.71 (s, 1H), 8.89 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.08 (q, J = 3.2 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.8, 2.4) Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.63 - 5.52 (m, 1H), 4.03 (s, 3H), 1.49 (d, J = 6.7 Hz, 6H).

[0232] <Example 13> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide

[0233] 2,5-dimethoxybenzoic acid (38 mg, 0.21 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.28 mL, 0.48 mmol) was added and stirred at room temperature for 10 minutes. DMAP (58 mg, 0.48 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was quenched with ice water, and the resulting solid was filtered and dried (28.9 mg, 45.2%).

[0234] 1 1H NMR (300 MHz, DMSO- d 6) δ 10.74 (s, 1H), 8.85 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.06 (t, J = 8.0 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 3.0 Hz, 1H), 7.29 - 7.14 (m, 2H), 4.60 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).

[0236] <Example 14> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide

[0237] In Example 13, intermediate 3 was used instead of intermediate 2 to prepare the product.

[0238] 1 1H NMR (300 MHz, DMSO- d 6) δ 10.80 (s, 1H), 8.63 (s, 1H), 8.34 - 8.26 (m, 1H), 8.04 (t, J = 7.9 Hz, 1H), 7.91 (dd, J = 7.7, 1.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.27 - 7.12 (m, 2H), 4.07 (s, 3H), 3.95 (s, 3H), 3.79 (s, 3H); LCMS: calculated for C 17 H 17N5O3339.1, found 340.3 [M + H + ].

[0240] <Example 15> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide

[0241] In Example 13, intermediate 4 was used instead of intermediate 2.

[0242] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.71 (s, 1H), 8.90 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.24 (d, J = 9.1 Hz, 1H), 7.19 (dd, J = 9.0, 3.1 Hz, 1H), 5.51 (h, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.53 (d, J = 6.7) Hz, 6H).

[0244] <Example 16> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide

[0245] 2,4-dimethoxybenzoic acid (38 mg, 0.21 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.28 mL, 0.48 mmol) was added and stirred at room temperature for 10 minutes. DMAP (58 mg, 0.48 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was quenched with ice water, and the resulting solid was filtered and dried (15.6 mg, 24.4%).

[0246] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.47 (s, 1H), 8.72 (s, 1H), 8.34 (dd, J = 8.4, 1.0 Hz, 1H), 8.06 - 7.96 (m, 2H), 7.91 (dd, J = 7.6, 0.9 Hz, 1H), 6.82 - 6.72 (m, 2H), 4.57 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 3.88 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H).

[0248] <Example 17> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide

[0249] In Example 16, intermediate 3 was used instead of intermediate 2.

[0250] 1 1H NMR (300 MHz, DMSO- d 6) δ 10.55 (s, 1H), 8.64 (s, 1H), 8.31 (dd, J = 8.3, 1.0 Hz, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 7.7, 1.0 Hz, 1H), 6.82 - 6.70 (m, 2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.88 (s, 3H); LCMS: calculated for C 17 H 17 N5O3339.1, found 340.3 [M + H + ].

[0252] <Example 18> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide

[0253] In Example 16, intermediate 4 was used instead of intermediate 2.

[0254] 1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.91 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.07 - 7.96 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 6.82 - 6.72 (m, 2H), 5.47 (hept, J = 6.8 Hz, 1H), 4.03 (s, 3H), 3.88 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H); LCMS: calculated for C 19 H 21 N5O3367.2, found 368.5 [M + H + ].

[0256] <Example 19> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide

[0257] 2,4,5-trimethoxybenzoic acid (44 mg, 0.21 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.28 mL, 0.48 mmol) was added and stirred at room temperature for 10 minutes. DMAP (58 mg, 0.48 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, extracted with ethyl acetate, washed with sodium bicarbonate, and dried with MgSO4. The resulting product was purified using silica gel column chromatography with 5% methanol added, using DCM as the eluent (20.1 mg, 25.5%).

[0258] 1 1H NMR (300 MHz, DMSO- d6) δ 10.59 (s, 1H), 8.73 (s, 1H), 8.35 (dd, J = 8.3, 1.0 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.91 (dd, J = 7.7, 1.0 Hz, 1H), 7.57 (s, 1H), 6.90 (s, 1H), 4.56 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 3.93 (s, 3H), 3.80 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); LCMS: calculated for C 19 H 21 N5O4383.2, found 384.4 [M + H + ].

[0260] <Example 20> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide

[0261] In Example 19, intermediate 3 was used instead of intermediate 2 to prepare the product.

[0262] 1 H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.65 (s, 1H), 8.32 (dd, J = 8.3, 0.9 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.90 (dd, J = 7.7, 1.0 Hz, 1H), 7.55 (s, 1H), 6.89 (s, 1H), 4.07 (d, J = 1.5 Hz, 6H), 3.92 (s, 3H), 3.79 (s, 3H); LCMS: calculated for C 18 H 19 N5O4369.1, 370.4 [M + H + ].

[0264] <Example 21> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide

[0265] In Example 19, intermediate 4 was used instead of intermediate 2.

[0266] 1 ¹H NMR (400 MHz, DMSO- d6) δ 10.58 (s, 1H), 8.91 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 6.89 (s, 1H), 5.44 (p, J = 6.6 Hz, 1H), 4.06 (s, 3H), 3.92 (s, 3H), 3.79 (d, J = 1.0 Hz, 3H), 1.56 (d, J = 7.0 Hz, 6H).

[0268] <Example 22> Preparation of 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide

[0269] 5-bromo-2-methoxy-4-methylbenzoic acid (29 mg, 0.12 mmol) was added to NMP (0.11 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.16 mL, 0.27 mmol) was added and stirred at room temperature for 10 minutes. DMAP (33 mg, 0.27 mmol) and intermediate compound 2 (17 mg, 0.09 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (18.3 mg, 48.9%).

[0270] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.58 (s, 1H), 8.72 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.34 (s, 1H), 4.57 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 2.44 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); LCMS: calculated for C 18 H 18 BrN5O2415.1, found 416.1 [M + H + ].

[0272] <Example 23> Preparation of 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide

[0273] In Example 22, intermediate compound 3 was used instead of intermediate compound 2 to prepare the product.

[0274] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.66 (s, 1H), 8.63 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.32 (s, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 2.43 (s, 3H); LCMS: calculated for C 17 H 16 BrN5O2401.1, found 402.3 [M + H + ].

[0276] <Example 24> Preparation of 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide

[0277] In Example 22, intermediate 4 was used instead of intermediate 2.

[0278] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.58 (s, 1H), 8.91 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 6.89 (s, 1H), 5.44 (p, J = 6.6 Hz, 1H), 4.06 (s, 3H), 3.92 (s, 3H), 3.79 (d, J = 1.0 Hz, 3H), 1.56 (d, J = 7.0 Hz, 6H).

[0280] <Example 25> Preparation of 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxynicotinamide

[0281] In Example 22, 5-bromo-2-methoxynicotinic acid was used instead of 5-bromo-2-methoxy-4-methylbenzoic acid.

[0282] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.77 (s, 1H), 8.94 (s, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.35 - 8.25 (m, 2H), 8.07 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 4.63 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); LCMS: calculated for C 16 H 15 BrN6O2402.0, found 403.2 [M + H + ].

[0284] <Example 26> Preparation of 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-6-methylnicotinamide

[0285] In Example 22, 5-bromo-2-methoxy-6-methylnicotinic acid was used instead of 5-bromo-2-methoxy-4-methylbenzoic acid.

[0286] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.58 (s, 1H), 8.71 (s, 1H), 8.31 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.04 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).

[0288] <Example 27> Preparation of N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide

[0289] 3-methoxy-2-naphthoic acid (35 mg, 0.17 mmol) was added to NMP (0.2 mL) and stirred. To the stirred solution, 50% propanephosphonic anhydride (0.24 mL, 0.40 mmol) was added and stirred at room temperature for 10 minutes. DMAP (48 mg, 0.40 mmol) and intermediate compound 2 (25 mg, 0.13 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was cooled in ice water, and the resulting solid was filtered and dried (26.8 mg, 54.3%).

[0290] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.84 (s, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.05 (q, J = 8.0 Hz, 2H), 7.93 (dd, J = 8.1, 6.2 Hz, 2H), 7.64 - 7.56 (m, 2H), 7.50 - 7.42 (m, 1H), 4.61 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0292] <Example 28> Preparation of N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide

[0293] In Example 27, intermediate 3 was used instead of intermediate 2.

[0294] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.93 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 12.0 Hz, 2H), 8.09 - 7.96 (m, 2H), 7.96 - 7.89 (m, 2H), 7.58 (d, J = 7.4 Hz, 2H), 7.49 - 7.41 (m, 1H), 4.05 (d, J = 11.6 Hz, 6H).

[0296] <Example 29> Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide

[0297] In Example 27, intermediate 4 was used instead of intermediate 2.

[0298] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.89 (s, 1H), 8.45 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.11 - 8.00 (m, 2H), 7.92 (t, J = 8.2 Hz, 2H), 7.62 - 7.58 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 5.60 (p, J = 6.7 Hz, 1H), 4.05 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H).

[0300] The structural formulas of the compounds of Examples 1 to 29 prepared according to the present invention are summarized in Table 1 below.

[0301] Examples structure Examples structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

[0303] <Experimental Example 1> Measurement of metabolic stability

[0304] The metabolic stability of the compound represented by Chemical Formula 1 was evaluated using mouse, rat, and human liver microsomes (mouse liver microsomes, Cat# 452701; rat liver microsomes, Cat# 452501; human liver microsomes, Cat# 452117; Corning). The compounds tested were prepared as 10 mM stock solutions in DMSO, and buspirone hydrochloride (Sigma-Aldrich, Cat# B7148) was used as a reference compound.

[0305] A reaction mixture containing 0.1 M potassium phosphate buffer (pH 7.4, Cat# 451201, Corning), 0.5 mg / mL liver microsomes, 1 mM NADPH, 3 mM MgCl₂, and 1 μM of the example compound or buspirone was incubated at 37°C for 30 minutes. Samples were collected at 0 minutes (baseline) and 30 minutes, and the reaction was stopped by adding an equal amount of ice-cooled acetonitrile. After centrifugation at 14,000 × g for 10 minutes, the supernatant was collected. The amount of the parent compound remaining after the reaction was quantified as a percentage relative to 0 minutes using LC-MS / MS analysis.

[0306] The results of measuring the metabolic stability of the example compounds and buspirone according to the present invention are shown in Table 2.

[0307] Mouse Rat Human Example 19 73% 87% 100% Example 22 34% 67% 88% Example 23 15% 34% 100% Buspiron 0.01% 0.35% 0.72%

[0308] As shown in Table 2, the compound of the example according to the present invention was confirmed to be very stable in metabolic reactions against microsomes in mice, rats, and human livers.

[0310] <Experimental Example 2> Measurement of Human DYRK1A Activity

[0311] DYRK1A(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM RRRFRPASPLRGPPK, 10 mM MgAcetate, and [gamma-33P]-ATP (45 nM). The reaction was initiated by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by adding phosphoric acid to the example compound. Then, a portion of the reaction was spotted onto a filter, washed four times in 0.425% phosphoric acid for 4 minutes each and once in methanol, followed by drying and scintillation counting.

[0312] The results of measuring DYRK1A activity when the compound of the example according to the present invention was treated at 0.3 μM are shown in Table 3, and the DYRK1A activity of the compound of Example 19 at different concentrations was measured and is shown in Figure 1.

[0313] Examples DYTK1A %activity remaining @ 0.3 μM Examples DYTK1A %activity remaining @ 0.3 μM 1 8% 16 6% 2 12% 17 9% 3 29% 18 12% 4 6% 19 4% 5 14% 20 6% 6 16% 21 15% 7 4% 22 1% 8 4% 23 2% 9 15% 24 8% 10 11% 25 17% 11 16% 26 2% 12 23% 27 2% 13 5% 28 4% 14 6% 29 7% 15 9%

[0314] As shown in FIG. 1 and Table 3, it was confirmed that the compounds of the examples according to the present invention exhibit an excellent DYRK1A activity inhibitory effect, and in particular, it was confirmed that the half-inhibitory concentration of the compound of Example 19 is 22 nM (Fig. 1).

[0316] <Experimental Example 3> Western blotting

[0317] SH-SY5Y cells (1 × 10⁶ / mL) were treated with Compound 19 at concentrations of 1, 3, and 10 μM for 1 hour, followed by treatment with MPP+ (Sigma-Aldrich, Cat# D048). Cells were lysed using RIPA buffer (Elpis Biotech, EBA-1149) supplemented with Pierce Protease Inhibitor, EDTA Free (Thermo Fisher, Cat# A32955), and Phosphatase Inhibitor (Thermo Fisher, Cat# A32857). The lysate was incubated on ice for 30 minutes, then centrifuged at 13,000 rpm for 10 minutes at 4°C, and the supernatant was collected. Protein concentration was measured using the Pierce BCA Protein Assay Kit (Thermo Fisher, Cat# 23228). An equal amount of protein was mixed with Protein 5X Sample Buffer (Cat# EBA-1052), boiled at 95°C for 5 minutes, and then separated by SDS-PAGE on a 10% polyacrylamide gel prepared with 10x Tris-Glycine SDS Buffer (Cat# CBT015). The protein was transferred to a PVDF membrane using Tris-Glycine Transfer Buffer. The membrane was blocked for 1 hour at room temperature with 5% BSA (Bovogen, Cat# BSAS0.1) added to 10x TBS (10x Tris-buffered saline, pH 7.4, CBT005) containing 0.1% Tween-20 (TBST), and then incubated overnight at 4°C with a Phospho-Tau (Ser202, Thr205) monoclonal antibody (Cell Signaling, Cat# MN1020) diluted in 5% BSA / TBST. After washing, the membrane was incubated with an HRP-conjugated secondary antibody for 1 hour at room temperature. Protein bands were visualized using an ECL detection kit and imaged using a chemiluminescence detection system.GAPDH (Cell Signaling, Cat# 5174S) was used as a loading control.

[0318] The activity of DYRK1A on the hyperphosphorylation of tau has been revealed in previous studies (J Biol Chem 2007 282(48) 34850, Aging Cell 2019 18 e13000). Therefore, we evaluated the potential DYRK1A inhibitory efficacy of the compound of Example 19 on tau phosphorylation in human neuroblastoma cells SH-SY5Y.

[0319] The results of measuring the p-tau protein expression amount at different concentrations of the compound of Example 19 according to the present invention are shown in Figure 2.

[0320] As a result, as shown in Figure 2, it was shown that p-tau expression was significantly reduced by treatment with the compound of Example 19 in a concentration-dependent manner.

[0322] From the results of the above experimental examples, it was confirmed that the compound represented by Formula 1 according to the present invention not only exhibits high inhibitory activity against DYRK1A, but is also very stable in metabolic reactions and inhibits tau phosphorylation by inhibiting DYRK1A. From this, the compound represented by Formula 1 according to the present invention can be usefully used in the treatment of central nervous system diseases related to DYRK1A.

Claims

Claim 1 Compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, A is CH or N, and R 1 and R 2 Each independently hydrogen, halogen, CF3, and C 1-10 alkyl or C 1-10 It is an alkoxy, or R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and R 3 is C 1-10 It is alkyl, and R 4 is C 1-10 It is an alkyl. Claim 2 In paragraph 1, A is a compound or a pharmaceutically acceptable salt thereof which is CH. Claim 3 In paragraph 1, R 1 Silver is hydrogen, halogen, CF3, or C 1-10 It is an alkoxy, and R 2 is hydrogen, C 1-10 alkyl or C 1-10 A compound or a pharmaceutically acceptable salt thereof, wherein R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted. Claim 4 In paragraph 1, R 1 and R 2 At least one of which is a compound or a pharmaceutically acceptable salt thereof that is not hydrogen. Claim 5 In paragraph 1, A is CH or N, and R 1 Silver is hydrogen, halogen, CF3, or C 1-6 It is an alkoxy, and R 2 is hydrogen, C 1-6 alkyl or C 1-6 It is an alkoxy, or R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and R 3 is C 1-6 It is alkyl, and R 4 is C 1-6 Alkyl, compound, or pharmaceutically acceptable salt thereof. Claim 6 In paragraph 1, A is CH, and R 1 Silver is hydrogen, halogen, CF3, or C 1-3 It is an alkoxy, and R 2 is hydrogen, C 1-3 alkyl or C 1-3 It is an alkoxy, or R1 and R2 form a benzene ring together with the carbon atoms to which they are substituted, and R 3 is C 1-3 It is alkyl, and R 4 is C 1-3 Alkyl, compound, or pharmaceutically acceptable salt thereof. Claim 7 A compound according to claim 1 selected from the following or a pharmaceutically acceptable salt thereof: <1> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide; <2> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide; <3> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-5-fluoro-2-methoxybenzamide; <4> 5-chloro-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <5> 5-chloro-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <6> 5-chloro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <7> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <8> 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <9> 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxybenzamide; <10> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide; <11> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide; <12> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-5-(trifluoromethyl)benzamide; <13> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide; <14> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide; <15> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,5-dimethoxybenzamide;<16> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide; <17> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide; <18> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4-dimethoxybenzamide; <19> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide; <20> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide; <21> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2,4,5-trimethoxybenzamide; <22> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide; <23> 5-Bromo-N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide; <24> 5-Bromo-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-4-methylbenzamide; <25> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxynicotinamide; <26> 5-Bromo-N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-2-methoxy-6-methylnicotinamide; <27> N-(6-(4-ethyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide; <28> N-(6-(4-methyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide; <29> N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-3-methoxy-2-naphtamide.; Claim 8 A method for preparing a compound represented by Formula 1 of claim 1, comprising the step of reacting a compound represented by Formula 2 with a compound represented by Formula 3 to prepare a compound represented by Formula 1, as shown in Reaction Scheme 1 below: [Reaction Scheme 1] In the above reaction scheme 1, A and R 1 to R 4 It is as defined in Chemical Formula 1 of Article 1. Claim 9 A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, comprising as an active ingredient a compound represented by Chemical Formula 1 of Claim 1 or a pharmaceutically acceptable salt thereof. Claim 10 A pharmaceutical composition for the prevention or treatment of diseases associated with Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), containing as an active ingredient a compound represented by Chemical Formula 1 of Claim 1 or a pharmaceutically acceptable salt thereof. Claim 11 A pharmaceutical composition for the prevention or treatment of a disease caused by the overexpression of tau protein, comprising as an active ingredient a compound represented by Chemical Formula 1 of Claim 1 or a pharmaceutically acceptable salt thereof. Claim 12 A pharmaceutical composition according to claim 9, characterized in that the neurodegenerative disease is one or more selected from the group consisting of Down syndrome, Alzheimer's disease, hippocampal sclerosis, frontotemporal dementia, frontotemporal degeneration, Huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, motor neuron disease, inclusion body myositis, Parkinson's disease, Lewy body dementia, Lewy body disease, multiple system atrophy, progressive supranuclear palsy, Pick's disease, prion disease, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia, hypoxia, and glutamate neurotoxicity. Claim 13 A health functional food composition for the prevention or improvement of neurodegenerative diseases, containing as an active ingredient a compound represented by Chemical Formula 1 of Claim 1 or a pharmaceutically acceptable salt thereof.

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