Novel fused heterocycle-carbonohydrazonoyl dicyanide compounds and their uses

Abstract

The present invention relates to a novel fused heterocycle-carbonohydrazonoyl dicyanide compound and its use.

Description

[Technical field]

[0001] The present invention relates to a novel fused heterocycle-carbonohydrazonoyl dicyanide compound and its use. [Background technology]

[0002] Tau (τ) protein is a microtubule-associated protein (MAP) with a molecular weight of 50,000 to 70,000 that is mainly expressed in the axons of nerve cells. It stabilizes microtubules and shows molecular diversity through phosphorylation. In humans, six isoforms of tau are generated by the insertion of 29 or 58 amino acid residues at the N-terminus and alternative splicing of mRNA with three or four repeat structures (called microtubule-binding sites) at the C-terminus.

[0003] In healthy neurons, tau stabilizes microtubules by promoting growth from axons and neuronal polarization. Pathologically, when hyperphosphorylated, tau dissociates from microtubules and induces insoluble aggregation. A structural scaffold that induces tau aggregation has also been proposed, and evidence has been presented that insoluble filaments are formed from 10 soluble monomers and that the filaments bind to higher-order structures called neurofibrillary tangles (NFTs). Human full-length tau contains a microtubule-binding domain composed of four conserved sequence repeats. Among these repeats, the positively charged residues have an important function in binding to highly negatively charged microtubules (20-30 electrons per αβ-tubulin dimer). The binding affinity of tau to microtubules is also actively controlled by tau phosphorylation, which causes dynamic rearrangements of the microtubule network. When tau is abnormally hyperphosphorylated, its dynamic rearrangement is unbalanced and its affinity for microtubules is rapidly reduced.

[0004] The hyperphosphorylation and / or aggregation of tau protein induces abnormal accumulation of these tau proteins in nerve cells, which is thought to be the cause of degenerative neurological diseases. Tau protein aggregates are mainly observed in the cell body and dendrites of nerve cells, and are called neurofibrillary tangles (NFTs) and neuropil threads. Looking at the fine structure of neurofibrillary tangles, they are composed of paired helical filaments (PHFs) in which tau proteins are entangled like thin threads, and unlike normal tau proteins, they are aggregated and hyperphosphorylated. Abnormal tau protein aggregation phenomenon also occurs in tauopathy, but it has not been clearly shown what role the aggregation of tau proteins plays in the disease progression stage of tauopathy, and it appears in the same way as the aggregation phenomenon that commonly occurs in general degenerative brain diseases.

[0005] Thus, it is known that hyperphosphorylation and / or aggregation of tau protein induces various degenerative brain diseases including Alzheimer's disease and tauopathy. However, the specific mechanisms by which these tau protein-mediated diseases transmit signals and exhibit toxicity have not yet been elucidated, and there are no clear therapies or therapeutic agents that can treat these diseases. Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted extensive research to find novel small molecule compounds that inhibit the aggregation and / or hyperphosphorylation of tau protein, and as a result have confirmed that a series of novel fused heterocycle-carbonohydrazonoyl dicyanide compounds efficiently inhibit tau protein aggregation and do not exhibit cytotoxicity at active concentrations, thereby completing the present invention. [Means for solving the problem]

[0007] An object of the present invention is to provide a compound represented by chemical formula (1) or a pharma- ceutically acceptable salt thereof.

[0008] [ka]

[0009] In chemical formula (1), X 1 ~X 3 are each independently N or C(H), and Y 1 and Y 2 are each independently N(R 4 ), C(H), O or S, n is 0 or 1;

[0010] [ka]

[0011] R 1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl, R 2 and R 3 are independently hydrogen, C 1-6 Alkyl, halogen, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminocarbonyl or di(C 1-6 alkyl)aminocarbonyl, R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 0-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl, 5- or 6-membered heterocycle-C 0-6 Alkyl, C 6-10aryl or 5- to 10-membered heteroaryl, 6-10 Aryl and 5- to 10-membered heteroaryl are unsubstituted or C 1-6 Alkoxy or C 1-6 It is substituted with alkoxycarbonyl.

[0012] Another object of the present invention is to provide a method for producing the compound.

[0013] A further object of the present invention is to provide a composition for inhibiting tau protein aggregation, which comprises the compound as an active ingredient.

[0014] A further object of the present invention is to provide a composition for inhibiting hyperphosphorylation of tau protein, which contains the compound as an active ingredient.

[0015] A further object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease induced by the aggregation or hyperphosphorylation of tau protein, comprising the compound as an active ingredient.

[0016] Furthermore, the present invention aims to provide a method for preventing or treating a disease induced by aggregation or hyperphosphorylation of tau protein, comprising the step of administering the pharmaceutical composition to an individual in need thereof. Effect of the Invention

[0017] The novel fused heterocycle-carbonohydrazonoyl dicyanide compounds of the present invention efficiently inhibit the aggregation and / or hyperphosphorylation of tau protein, and are therefore useful for the prevention or treatment of diseases induced thereby, such as Alzheimer's disease and tauopathy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] A first aspect of the present invention provides a compound represented by chemical formula (1) or a pharma- ceutically acceptable salt thereof.

[0019] [ka]

[0020] In chemical formula (1), X 1 ~X 3 are each independently N or C(H), and Y 1 and Y 2 are each independently N(R 4 ), C(H), O or S, and n is 0 or 1;

[0021] [ka]

[0022] R 1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl, R 2 and R 3 are independently hydrogen, C 1-6 Alkyl, halogen, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminocarbonyl or di(C 1-6 alkyl)aminocarbonyl, R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 0-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl, 5- or 6-membered heterocycle-C 0-6 Alkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, 6-10 Aryl and 5- to 10-membered heteroaryl are unsubstituted or C 1-6Alkoxy or C 1-6 It is substituted with alkoxycarbonyl.

[0023] For example, in the compounds of the invention, R 1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl, R 2 are hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, R 3 is hydrogen or C 1-6 is alkyl, R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl or C 6-10 Examples include, but are not limited to, aryl.

[0024] Specifically, in the compounds of the present invention, R 1 is hydrogen, methyl or acetyl; R 2 is hydrogen, chloro, fluoro, methyl or methoxy; R 3 is hydrogen or methyl, R 4 is, but is not limited to, hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, or phenyl.

[0025] For example, the compound of the present invention may be a compound represented by chemical formula (2).

[0026] [ka]

[0027] In the chemical formula (2), Y 1 and Y 2 One of them is CH and the other is NR 4 and bonds to CH

[0028] [ka]

[0029] and NR 4 Join to

[0030] [ka]

[0031] and R 3 is hydrogen or methyl, R 4 is hydrogen, methyl or isopropyl.

[0032] Alternatively, the compound of the present invention may be a compound represented by chemical formula (3).

[0033] [ka]

[0034] In chemical formula (3), X 3 is C(H) or N, R 1 is hydrogen, methyl or acetyl; R 2 is hydrogen, chloro, fluoro, methyl or methoxy; R 4’ and R 4’’ are each independently hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, or phenyl.

[0035] Furthermore, the compound of the present invention may be a compound represented by chemical formula (4).

[0036] [ka]

[0037] In the chemical formula (4), Y 1 is S or O, R 4 is hydrogen, methyl, isopropyl or difluoromethyl.

[0038] More specifically, the compounds represented by chemical formula (1) are: 1. (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide; 2. (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide; 3. (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide; dicyanide), 4. (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide), 5. (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide), 6. (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide dicyanide), 7.(2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide), 8.8. (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 9. (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 10.(6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 11.(7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 12.(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 13.(2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide), 14.15. (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 16. (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide dicyanide), 17.(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 18.(3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide dicyanide), 19.(3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide), 20.(3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide), 21.21. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 22. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 23.(1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 24.(1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 25.(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide), 26.(4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide), 27.27. (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 28. (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide, 29. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 30. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide), 31. (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 32.(6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 33.33. (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 34. (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 35. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 36. (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 37.(3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 38.39. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 39. (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 40. (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 41. (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide dicyanide), 42.(1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide), 43.43. (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 44. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 45. (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 46. (1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 47.(3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonyl dicyanide. onoyl dicyanide), 48. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 49. (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 50. (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 51. (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 52.(3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 53.53. (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 54. (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 55.(1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide), 56.(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonohydrazonoyl dicyanide dicyanide, or 57. acetyl(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide.

[0039] Furthermore, these compounds may be compounds represented by the chemical formulas in Table 1.

[0040] [Table 1]

[0041] JPEG0007641994000011.jpg198169

[0042] JPEG0007641994000012.jpg219169

[0043] JPEG0007641994000013.jpg199169

[0044] JPEG0007641994000014.jpg198169

[0045] JPEG0007641994000015.jpg81169

[0046] The compound of the present invention may be in the form of a pharma- ceutically acceptable salt. As the salt, an acid addition salt formed with a pharma- ceutically acceptable free acid is useful. In the present invention, the term "pharma- ceutically acceptable salt" refers to any organic or inorganic addition salt of the compound represented by the chemical formulas (1) to (4) whose side effects do not reduce the beneficial efficacy of the compound at a concentration that is relatively non-toxic and harmless to the patient.

[0047] Acid addition salts are prepared in the usual manner, for example by dissolving the compound in an excess amount of aqueous acid and precipitating the salt with a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and the acid in water or an alcohol (for example glycol monomethyl ether) may be heated and then the mixture evaporated to dryness or the precipitated salt may be filtered off with suction.

[0048] Here, the free acid may be an organic acid or an inorganic acid. The inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, stannic acid, etc., and the organic acid may be 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, carboxylic acid, vanillic acid, hydroiodic acid, etc., but is not limited thereto.

[0049] Also, a base can be used to form a pharma- ceutically acceptable metal salt. An alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. Here, it is pharma- ceutical preferred to use sodium, potassium or calcium salts as the metal salt, but the metal salt is not limited to these. Also, the corresponding silver salt can be obtained by reacting an alkali metal salt or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0050] Unless otherwise specified, the pharma- ceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups present in the compounds of formulas (1) to (4). For example, pharma- ceutically acceptable salts include sodium, calcium, and potassium salts of hydroxyl groups, and other pharma- ceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate), which can be prepared by a method for preparing a salt known in the art.

[0051] As the salt of the compound of the present invention represented by chemical formulas (1) to (4), any salt may be used as long as it is a pharma- ceutically acceptable salt and exhibits pharmacological activity equivalent to that of the compound of the chemical formulas (1) to (4), for example, a salt of the compound of the chemical formulas (1) to (4) that inhibits aggregation and / or hyperphosphorylation of tau protein.

[0052] Furthermore, the compounds represented by chemical formulas (1) to (4) according to the present invention include not only pharma- ceutically acceptable salts thereof, but also all solvates such as hydrates and stereoisomers that can be prepared therefrom. The solvates and stereoisomers of the compounds represented by chemical formulas (1) to (4) can be prepared from the compounds represented by chemical formulas (1) to (4) using methods known in the art.

[0053] Furthermore, the compounds represented by the chemical formulas (1) to (4) according to the present invention can be prepared in a crystalline or non-crystalline form, and when prepared in a crystalline form, can be optionally hydrated or solvated. In the present invention, not only stoichiometric hydrates of the compounds represented by the chemical formulas (1) to (4) but also compounds containing various amounts of water are included. The solvates of the compounds represented by the chemical formulas (1) to (4) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0054] A second aspect of the present invention provides a method for producing a compound represented by chemical formula (1).

[0055] For example, the compound of the present invention can be prepared by reacting a compound represented by formula (5), which contains a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid to form an imine bond in a first step, and optionally reacting R 1 If is a non-hydrogen substituent, the product obtained in the previous step is treated with R 1 and a second step of introducing a substituent.

[0056] [ka]

[0057] In chemical formula (5), X 1 ~X 3 , Y 1 , Y 2 ,n,

[0058] [ka]

[0059] R 2 and R 3 is as defined above, and Y 1 and Y 2 If is N(H), it may be protected with tert-butoxycarbonyl.

[0060] Here, Y 1 and Y 2 If N(H) is protected with tert-butoxycarbonyl, the reaction may further include a deprotection step after the reaction.

[0061] Specifically, the first step of the process is 1-4The reaction can be carried out through a series of steps including, but not limited to, a 1-1 step of dissolving the compound of formula (5) and sodium nitrite in a lower alcohol solvent and adding an acidic aqueous solution at -5 to 5°C to form a diazonium salt, a 1-2 step of adding malononitrile to the reaction solution containing the diazonium salt obtained in the 1-1 step and reacting it at 15 to 40°C, and a 1-3 step of adding an aqueous base solution to the reaction solution of the 1-2 step to neutralize it.

[0062] For example, the first step uses a 1M hydrochloric acid solution, and the reaction in step 1-1 is carried out at a low temperature of around 0°C for 2 minutes to 1 hour, and then the reaction in step 1-2 is carried out at room temperature for 2 minutes to 1 hour, but is not limited to this.

[0063] For example, the second step is performed by using the R 1 The unsubstituted carbonohydrazonoyl dicyanide compound is dissolved in an organic solvent. 1 Specifically, the reaction is carried out by reacting with a halogenated derivative of R 1 C 1-6 If it is alkyl, the R obtained in the previous step 1 The unsubstituted carbonohydrazonoyl dicyanide compound is dissolved in an organic solvent such as DMF, and R 1 The reaction is carried out by adding a haloalkane, such as an iodinated alkane, corresponding to the above formula to the reaction solution and reacting at 50 to 70° C., and the reaction solution further contains potassium tert-butoxide, but is not limited thereto. 1 C 1-6 If it is an alkylcarbonyl, the R 1 The unsubstituted carbonohydrazonoyl dicyanide compound is dissolved in a lower alcohol such as methanol and reacted with a base, e.g., potassium hydroxide, and then solidified. The resulting product is reacted with C in an organic solvent such as acetonitrile in the presence of triethylamine. 1-6 This can be achieved by reacting the alkylcarbonyl with the corresponding alkylcarbonyl halide, such as, but not limited to, acetyl chloride.

[0064] For example, the compound of formula (5) used in the production of the compound of the present invention is prepared from a compound represented by any one of formulas (5-a) to (5-c).

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] In the chemical formula (5-b), two R 4 may be the same or different substituents selected from the set of substituents defined above.

[0069] Specifically, the production method of the present invention may further include, prior to the first step, a step of reducing the nitro group of the compound represented by any one of chemical formulas (5-a) to (5-c) to an amino group.

[0070] For example, the reduction may be carried out in an organic solvent such as 1,4-dioxane or methanol under Pd / C catalysis, or with AcOH in the presence of Fe, or with ammonium chloride in the presence of Fe, but is not limited thereto.

[0071] Specifically, the compound represented by the chemical formula (5-a) is 1 and Y 2 In the solution phase, a precursor in which one of the two is CH and the other is O is dissolved in an organic solvent, and the amine compound NH 2 R 4 React with to convert O-position to NR 4For example, but not limited to, the above reaction can be carried out by displacing ammonia or R in an organic solvent such as THF or methanol. 4 The method is, but is not limited to, stirring the amine substituted with 1-(2-methylphenyl)-2-propanediol at 70 to 130° C. for 30 minutes to 5 hours. Here, microwaves are used for stirring, but the method is not limited to this.

[0072] Furthermore, optionally, Y of the compound represented by the chemical formula (5-a) 1 and Y 2 The precursor, in which one of the two is CH and the other is O, is a nitrobenzoic acid derivative and N,N-dimethylformamide dimethyl acetal or Acetylacetone For example, the cyclization reaction can be carried out by reacting with N,N-dimethylformamide dimethyl acetal in a DMF solvent, or by reacting with Cu in a tert-butyl alcohol solvent. Acetylacetone The reaction is carried out by reacting with the above-mentioned. The reaction is carried out by stirring at 100 to 130° C. for 2 to 24 hours, but is not limited thereto. Here, microwaves are used for stirring, but are not limited thereto.

[0073] Specifically, in the production method of the present invention, the compound represented by the chemical formula (5-b) or (5-c) may be optionally 4 and reacting with reactive halide-containing precursor compounds to form R 4 The reaction can be carried out by further carrying out a step of introducing a substituent. For example, the reaction can be carried out by reacting DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and R 4 -Halide or sodium R 4 -haloacetate and stirring at room temperature for 6 to 24 hours, but is not limited thereto.

[0074] In the production method of the present invention, the compound represented by the chemical formula (5-b) is unsubstituted or 2The compound is prepared by cyclization of 1,2-diamine nitrophenyl substituted with carbonyldiimidazole (CDI). For example, the reaction is carried out at room temperature for 6 to 24 hours using DMF as a solvent, but is not limited thereto.

[0075] For example, in the preparation method of the present invention, the reactants and / or precursors used in each step may be purchased as commercially available compounds, or the reactants or intermediates of each step may be purchased and synthesized by a single reaction or a combination of several reactions known in the art, but are not limited thereto.

[0076] Each reaction may further include a step of separating and / or purifying the product, if necessary, which can be carried out by various methods known in the art.

[0077] A third aspect of the present invention provides a composition for inhibiting tau protein aggregation, comprising the compound of the present invention as an active ingredient.

[0078] A fourth aspect of the present invention provides a composition for inhibiting tau protein hyperphosphorylation, comprising the compound of the present invention as an active ingredient.

[0079] A fifth aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease induced by aggregation or hyperphosphorylation of tau protein, comprising a compound of the present invention as an active ingredient.

[0080] A sixth aspect of the present invention provides a method for preventing or treating a disease induced by aggregation or hyperphosphorylation of tau protein, comprising the step of administering a compound of the present invention to an individual in need thereof.

[0081] In a specific embodiment of the present invention, a total of 57 compounds, compounds 1 to 57 represented by chemical formula (1), were newly synthesized, and their inhibitory effects on tau protein aggregation and hyperphosphorylation were confirmed. Furthermore, in order to verify the possibility of using them as pharmaceutical compositions, it was confirmed that they were not toxic to cells.

[0082] In the present invention, "prevention" means any action of suppressing or delaying the onset, spread, and recurrence of a disease induced by the aggregation or hyperphosphorylation of tau protein by administering the pharmaceutical composition of the present invention, and "treatment" means any action of improving or favorably changing the symptoms of the disease by administering the pharmaceutical composition of the present invention.

[0083] As described above, the compound of the present invention not only inhibits the aggregation or hyperphosphorylation of tau protein, but also does not show toxicity to cells, so that a pharmaceutical composition containing the compound as an active ingredient can be used for the prevention or treatment of diseases induced by the aggregation or hyperphosphorylation of tau protein. The diseases induced by the aggregation or hyperphosphorylation of tau protein to which the pharmaceutical composition of the present invention can be applied may be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma, or tauopathies.Examples of the tauopathy include chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinsonism linked to chromosome 17, Lytico-Bodig disease, Parkinson-dementia complex of Guam, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, and cerebrovascular disease. These conditions include, but are not limited to, acute myelopathy ...

[0084] For example, the compositions of the present invention may further contain a pharma- ceutically acceptable carrier, diluent or excipient, and may be formulated in various forms, such as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and injections of sterile injection solutions, in a conventional manner, depending on the intended purpose of use, and may be administered orally or by various routes, such as intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Examples of carriers, excipients, or diluents suitable for inclusion in these compositions include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition of the present invention may further comprise fillers, anti-agglomerating agents, lubricants, wetting agents, flavorings, emulsifiers, preservatives, and the like.

[0085] Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations are formulated by mixing the composition with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to the usual excipients, lubricants such as magnesium stearate and talc are also used.

[0086] Oral liquid preparations include suspensions, liquid preparations for internal use, emulsions, syrups, etc., and in addition to the commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. are used.

[0087] Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerol gelatin. Injections may contain conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0088] The dosage form can be produced by a conventional mixing, granulating or coating method and contains the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of the active ingredient.

[0089] Here, the composition of the present invention is administered in a pharma- tically effective amount. In the present invention, the term "pharma- tically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects, and the effective dose level is determined by factors including the patient's health condition, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the method of administration, the administration time, the administration route and excretion rate, the treatment period, drugs used in combination or simultaneously, and other factors known in the medical field. The composition of the present invention may be administered alone or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to administer an amount that provides maximum effect at a minimum amount without side effects, taking into account all of the above factors, and this can be easily determined by a person skilled in the art.

[0090] For example, the dosage may increase or decrease depending on the route of administration, severity of the disease, sex, body weight, age, etc., and thus the dosage is not intended to limit the invention in any way.

[0091] The preferred dosage of the compound of the present invention varies depending on the condition and body weight of the patient, the degree of the disease, the form of the drug, the administration route and period, but can be appropriately selected by those skilled in the art. However, in order to obtain the desired effect, the compound of the present invention may be administered at 0.0001 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg (body weight). It may be administered once a day or in divided doses via oral or parenteral routes.

[0092] A seventh aspect of the present invention provides a method for preventing or treating a disease induced by aggregation or hyperphosphorylation of tau protein, comprising the step of administering the pharmaceutical composition of the present invention to an individual in need thereof.

[0093] In the present invention, the term "individual" refers to any animal, including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, and guinea pigs, that has developed or is at risk of developing a disease induced by the aggregation or hyperphosphorylation of tau protein, and the above-mentioned disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. In addition, since the pharmaceutical composition of the present invention exerts a therapeutic effect by inhibiting the aggregation or hyperphosphorylation of tau protein, it exerts a synergistic effect by administering it in parallel with a conventional therapeutic agent.

[0094] In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention may be any common route that can deliver the substance to the target tissue. This includes, but is not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, pulmonary administration, and rectal administration. In addition, the pharmaceutical composition of the present invention can be administered by any device that can deliver the active substance to the target cell. Preferred administration methods and formulations include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, and drip injections. Injections can be prepared using aqueous solvents such as physiological saline and Ringer's solution, or non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.), and may contain pharmaceutical carriers such as stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers to adjust pH, and preservatives to prevent the growth of microorganisms (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.). EXAMPLES

[0095] The present invention will be described in more detail below with reference to examples. These examples are provided to more specifically explain the present invention, and the present invention is not limited to these examples.

[0096] [Example 1] Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (Compound 1) Step 1-1: Preparation of 7-nitroisoquinolin-1(2H)-one 7-Nitro-1H-isochromen-1-one (130 mg, 0.68 mmol) was added with 2.0 M ammonia solution (3.4 mL, 6.80 mmol), and the reaction mixture was stirred for 2 hours in a microwave at 80° C. After completion of the reaction, the mixture was solidified with distilled water and then filtered to obtain 73 mg (yield 56%) of the title compound.

[0097] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 8.8, 2.5 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 6.73 (d, J = 7.1 Hz, 1H). Step 1-2: Preparation of 7-aminoisoquinolin-1(2H)-one 7-Nitroisoquinolin-1(2H)-one (70 mg, 0.37 mmol) obtained in step 1-1 was dissolved in 10% Pd / C (78 mg, 0.07 mmol) and 1,4-dioxane, and the reaction mixture was stirred at room temperature under hydrogen for 4 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 27 mg (yield 46%) of the title compound.

[0098] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 7.40 - 7.20 (m, 2H), 6.97 (dd, J = 8.4, 2.5 Hz, 1H), 6.80 (dd, J = 7.0, 5.5 Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 5.47 (s, 2H). Step 1-3: Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dicyanide Under nitrogen, 7-aminoisoquinolin-1(2H)-one (20 mg, 0.12 mmol) obtained in step 1-2 and sodium nitrite (13 mg, 0.19 mmol) were dissolved in ethanol, and then 1.0 M aqueous hydrochloric acid (0.4 mL, 0.37 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes to form a diazonium salt. Malononitrile (16 mg, 0.25 mmol) was added to the reaction mixture containing the diazonium salt and stirred at room temperature for 10 minutes. Then, the pH of the reaction mixture was adjusted to 6.0 using an aqueous sodium hydroxide solution, and then stirred at room temperature for another hour. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 20 mg of the title compound (yield 67%).

[0099] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.22 (s, 1H), 11.33 (d, J = 5.7 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.16 (dd, J = 7.1, 5.8 Hz, 1H), 6.56 (d, J = 7.0 Hz, 1H). [Example 2] Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (Compound 2) Step 2-1: Preparation of 7-nitro-1H-isochromen-1-one 2-Methyl-5-nitrobenzoic acid (500 mg, 2.76 mmol) was dissolved in dimethylformamide (DMF, 10 mL), and then N,N-dimethylformamide dimethyl acetal (1.10 mL, 8.23 ​​mmol) was added, and the reaction mixture was stirred at 115° C. for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 65 mg of the title compound (yield 12%).

[0100] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (d, J = 2.5 Hz, 1H), 8.61 (dd, J = 8.6, 2.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 5.6 Hz, 1H), 7.01 (d, J = 5.6 Hz, 1H). Step 2-2: Preparation of 2-methyl-7-nitroisoquinolin-1(2H)-one 1.0M methylamine (10.5mL, 20.93mmol) was added to 7-nitro-1H-isochromen-1-one (200mg, 1.05mmol) obtained in step 2-1, and the reaction mixture was stirred at 120°C for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 126mg (yield 59%) of the title compound.

[0101] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (d, J = 2.5 Hz, 1H), 8.43 (dd, J = 8.8, 2.5 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 3.57 (s, 3H). Step 2-3: Preparation of 7-amino-2-methylisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 2-methyl-7-nitroisoquinolin-1(2H)-one (100 mg, 0.49 mmol) obtained in step 2-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 49 mg of the title compound (yield 57%).

[0102] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.36 - 7.29 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.97 (dd, J = 8.4, 2.5 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.51 (s, 2H), 3.44 (s, 3H). Step 2-4: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 7-amino-2-methylisoquinolin-1(2H)-one (40 mg, 0.23 mmol) obtained in step 2-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 49 mg of the title compound (yield 85%).

[0103] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.25 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 3.52 (s, 3H). [Example 3] Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (compound 3) Step 3-1: Preparation of 2-isopropyl-7-nitroisoquinolin-1(2H)-one Isopropylamine (0.27 mL, 3.14 mmol) and methanol (3 mL) were added to 7-nitro-1H-isochromen-1-one (30 mg, 0.16 mmol) obtained in step 2-1 of Example 2, and the reaction mixture was stirred at 80° C. for 12 hours in a microwave. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, solidified with ether and hexane, and filtered to obtain 20 mg (yield 54%) of the title compound.

[0104] 1 H NMR (400 MHz, Chloroform-d) δ 9.31 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.7, 2.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 5.38 (p, J = 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 6H). Step 3-2: Preparation of 7-amino-2-isopropylisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 2-isopropyl-7-nitroisoquinolin-1(2H)-one (70 mg, 0.30 mmol) obtained in step 3-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 54 mg of the title compound (yield 89%).

[0105] 1 H NMR (400 MHz, DMSO-d 6) δ 9.31 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.7, 2.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 5.38 (p, J = 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 6H). Step 3-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 7-amino-2-isopropylisoquinolin-1(2H)-one (30 mg, 0.15 mmol) obtained in step 3-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 30 mg of the title compound (72% yield).

[0106] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.25 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.7, 2.3 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.19 (p, J = 6.8 Hz, 1H), 1.33 (d, J = 6.8 Hz, 6H). [Example 4] Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (compound 4) Step 4-1: Preparation of 5-nitro-1H-isochromen-1-one The reaction was carried out in the same manner as in Step 2-1 of Example 2, except that 2-methyl-3-nitrobenzoic acid (200 mg, 1.10 mmol) was used instead of 2-methyl-5-nitrobenzoic acid, to obtain 88 mg of the title compound (yield 42%).

[0107] 1H NMR (400 MHz, Chloroform-d) δ 8.69 - 8.61 (m, 1H), 8.49 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 6.1 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H). Step 4-2: Preparation of 5-nitroisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-1 of Example 1, except that 5-nitro-1H-isochromen-1-one (100 mg, 0.52 mmol) obtained in step 4-1 was used instead of 7-nitro-1H-isochromen-1-one, to obtain 45 mg of the title compound (yield 45%).

[0108] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.46 (dd, J = 7.9, 1.4 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H). Step 4-3: Preparation of 5-amino-2-isoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 5-nitroisoquinolin-1(2H)-one (50 mg, 0.26 mmol) obtained in step 4-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 18 mg of the title compound (yield 42%).

[0109] 1 H NMR (400 MHz, DMSO-d 6) δ 11.05 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.4, 4.8 Hz, 1H), 6.86 (dd, J = 7.7, 1.2 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.61 (s, 2H). Step 4-4: Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-2-isoquinolin-1(2H)-one (30 mg, 0.15 mmol) obtained in step 4-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 6 mg of the title compound (yield 38%).

[0110] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 7.8, 1.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.3, 5.8 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H). [Example 5] Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (compound 5) Step 5-1: Preparation of 2-methyl-5-nitroisoquinolin-1(2H)-one The reaction was carried out in the same manner as in Step 2-2 of Example 2, except that 5-nitro-1H-isochromen-1-one (74 mg, 0.39 mmol) was used instead of 7-nitro-1H-isochromen-1-one, to give 37 mg of the title compound (yield 47%).

[0111] 1 H NMR (400 MHz, DMSO-d 6) δ 8.61 (d, J = 7.9 Hz, 1H), 8.47 (dd, J = 7.9, 1.3 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 7.7, 0.8 Hz, 1H), 3.55 (s, 3H). Step 5-2: Preparation of 5-amino-2-methylisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 2-methyl-5-nitroisoquinolin-1(2H)-one (50 mg, 0.24 mmol) obtained in step 5-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 30 mg of the title compound (yield 69%).

[0112] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.84 (dd, J = 7.8, 1.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.64 (s, 2H), 3.46 (s, 3H). Step 5-3: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-2-methylisoquinolin-1(2H)-one (25 mg, 0.14 mmol) obtained in step 5-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 31 mg of the title compound (yield 86%).

[0113] 1H NMR (400 MHz, Chloroform-d) δ 9.87 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 3.64 (s, 3H). [Example 6] Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 6) Step 6-1: Preparation of 2-isopropyl-5-nitroisoquinolin-1(2H)-one The reaction was carried out in the same manner as in Step 3-1 of Example 3, except that 5-nitro-1H-isochromen-1-one (30 mg, 0.16 mmol) was used instead of 7-nitro-1H-isochromen-1-one, to give 11 mg of the title compound (yield 30%).

[0114] 1 H NMR (400 MHz, Chloroform-d) δ 8.80 (dd, J = 8.0, 1.4 Hz, 1H), 8.40 (dd, J = 8.0, 1.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.35 (s, 2H), 5.35 (p, J = 6.6 Hz, 1H), 1.42 (d, J = 6.8 Hz, 6H). Step 6-2: Preparation of 5-amino-2-isopropylisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 2-isopropyl-5-nitroisoquinolin-1(2H)-one (40 mg, 0.17 mmol) obtained in step 6-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 34 mg of the title compound (yield 99%).

[0115] 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 7.6, 1.2 Hz, 1H), 6.55 - 6.42 (m, 1H), 5.40 (p, J = 6.9 Hz, 1H), 3.95 (s, 2H), 1.38 (d, J = 6.9 Hz, 6H). Step 6-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-2-isopropylisoquinolin-1(2H)-one (20 mg, 0.10 mmol) obtained in step 6-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain the title compound (22 mg, 79% yield).

[0116] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d, J = 8.0 Hz, 1H), 7.72 - 7.58 (m, 2H), 7.51 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.18 (p, J = 6.8 Hz, 1H), 1.34 (d, J = 6.8 Hz, 6H). [Example 7] Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 7) Step 7-1: Preparation of 3-methyl-5-nitro-1H-isochromen-1-one To 2-bromo-3-nitrobenzoic acid (500 mg, 2.03 mmol), acetylacetone (1.04 mL, 10.16 mmol), copper (13 mg, 0.20 mmol), potassium tert-butoxide (456 mg, 4.06 mmol) and tert-butyl alcohol (10 mL) were added, and the reaction mixture was stirred at 110° C. for 5 hours in a microwave. After the reaction was completed, the reaction mixture was acidified by adding an aqueous hydrochloric acid solution, and then extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 68 mg (yield 16%) of the title compound.

[0117] 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (dt, J = 7.8, 1.1 Hz, 1H), 8.44 (dd, J = 8.2, 1.4 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 1.0 Hz, 1H), 2.38 (d, J = 1.0 Hz, 3H). Step 7-2: Preparation of 2,3-dimethyl-5-nitroisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 2-2 of Example 2, except that 3-methyl-5-nitro-1H-isochromen-1-one (60 mg, 0.29 mmol) obtained in step 7-1 was used instead of 7-nitro-1H-isochromen-1-one, to obtain 56 mg of the title compound (yield 88%).

[0118] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 6.23 (d, J = 1.0 Hz, 1H), 3.02 (s, 3H), 1.46 (s, 3H). Step 7-3: Preparation of 5-amino-2,3-dimethylisoquinolin-1(2H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 2,3-dimethyl-5-nitroisoquinolin-1(2H)-one (50 mg, 0.23 mmol) obtained in step 7-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 13 mg of the title compound (yield 29%).

[0119] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.38 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.81 (dd, J = 7.7, 1.2 Hz, 1H), 6.64 (s, 1H), 5.51 (s, 2H), 3.48 (s, 3H), 2.39 (d, J = 1.0 Hz, 3H). Step 7-4: Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-2,3-dimethylisoquinolin-1(2H)-one (10 mg, 0.05 mmol) obtained in step 7-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain the title compound (13 mg, 92% yield).

[0120] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.8, 1.3 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 6.78 (s, 1H), 3.54 (s, 3H), 2.47 (s, 3H). [Example 8] Preparation of (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (compound 8) Step 8-1: Preparation of 6-aminoisoquinolin-2(1H)-one The reaction was carried out in the same manner as in Step 1-2 of Example 1, except that 6-nitroisoquinolin-2(1H)-one (300 mg, 1.58 mmol) was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 34 mg of the title compound (yield 13%).

[0121] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.36 (s, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.02 (s, 1H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 4.98 (s, 2H). Step 8-2: Preparation of (2-oxo-1,2-dihydroisoquinolin-6-yl)carbohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-aminoisoquinolin-2(1H)-one (20 mg, 0.12 mmol) obtained in step 8-1 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain the title compound (17 mg, 59% yield).

[0122] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 11.87 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H). [Example 9] Preparation of (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 9) Step 9-1: Preparation of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one Under nitrogen, 4-fluoro-5-nitrobenzene-1,2-diamine (500 mg, 2.92 mmol) and carbonyldiimidazole (CDI, 1.44 g, 8.77 mmol) were dissolved in DMF, and the reaction mixture was then stirred at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 512 mg (yield 89%) of the title compound.

[0123] 1 H NMR (400 MHz, Acetone-d 6 ) δ 10.38 (s, 1H), 10.08 (s, 1H), 7.75 (d, J = 6.4 Hz, 1H), 7.09 (d, J = 11.2 Hz, 1H). Step 9-2: Preparation of 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one Under nitrogen, 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (450 mg, 2.28 mmol) obtained in step 9-1 was dissolved in DMF, then DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 1.02 mL, 6.84 mmol) and methyl iodide (0.42 mL, 6.84 mmol) were added, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 328 mg (yield 64%) of the title compound.

[0124] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.85 (d, J = 6.4 Hz, 1H), 7.26 (d, J = 11.6 Hz, 1H), 3.49 (s, 3H), 3.46 (s, 3H). Step 9-3: Preparation of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one Under nitrogen, 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one (250 mg, 1.11 mmol) obtained in step 9-2 and iron (496 mg, 8.88 mmol) were dissolved in acetic acid, and the reaction mixture was then stirred at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 190 mg (yield 88%) of the title compound.

[0125] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.84 (d, J = 10.8 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.36 (s, 2H), 3.28 (s, 3H), 3.26 (s, 3H). Step 9-4: Preparation of (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide Under nitrogen, 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.51 mmol) obtained in step 9-3 and 35% aqueous hydrochloric acid (0.2 mL) were dissolved in distilled water, and then sodium nitrite (65 mg, 0.77 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes to form a diazonium salt. Malononitrile (51 mg, 0.77 mmol) was added to the reaction mixture containing the diazonium salt, and the mixture was stirred at room temperature for 11 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 28 mg of the title compound (yield 20%).

[0126] 1 H NMR (400 MHz, Acetone-d6 ) δ 7.36 (d, J = 6.8 Hz, 1H), 7.15 (d, J = 10.8 Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H). [Example 10] Preparation of (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 10) Step 10-1: Preparation of 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 4-chloro-5-nitrobenzene-1,2-diamine (1 g, 5.33 mmol) was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 882 mg of the title compound (77% yield).

[0127] 1 H NMR (400 MHz, Acetone-d 6 ) δ 10.30 (s, 1H), 10.19 (s, 1H), 7.71 (s, 1H), 7.26 (s, 1H). Step 10-2: Preparation of 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (500 mg, 2.34 mmol) obtained in step 10-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 410 mg of the title compound (73% yield).

[0128] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.83 (s, 1H), 7.41 (s, 1H), 3.48 (s, 3H), 3.47 (s, 3H). Step 10-3: Preparation of 5-amino-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-3 of Example 9, except that 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one (250 mg, 1.03 mmol) obtained in step 10-2 was used instead of 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 190 mg of the title compound (yield 88%).

[0129] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.84 (d, J = 10.8 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.36 (s, 2H), 3.28 (s, 3H), 3.26 (s, 3H). Step 10-4: Preparation of (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.51 mmol) obtained in step 10-3 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, to obtain 28 mg of the title compound (yield 20%).

[0130] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.39 (s, 1H), 7.30 (s, 1H), 3.34 (s, 3H), 3.33 (s, 3H). [Example 11] Preparation of (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 11) Step 11-1: Preparation of 4-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 3-chloro-5-nitrobenzene-1,2-diamine (2.63 g, 15.99 mmol) was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 720 mg of the title compound (yield 63%).

[0131] 1 H NMR (400 MHz, Acetone-d 6 ) δ 10.77 (s, 1H), 10.40 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H). Step 11-2: Preparation of 4-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 4-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (500 mg, 2.34 mmol) obtained in step 11-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 412 mg of the title compound (73% yield).

[0132] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.99 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 3.53 (s, 3H). Step 11-3: Preparation of 6-amino-4-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-3 of Example 9, except that 4-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one (250 mg, 1.03 mmol) obtained in step 11-2 was used instead of 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 154 mg of the title compound (71% yield).

[0133] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.39 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 4.64 (s, 2H), 3.55 (s, 3H), 3.26 (s, 3H). Step 11-4: Preparation of (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-4-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.47 mmol) obtained in step 11-3 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, to obtain 42 mg of the title compound (41% yield).

[0134] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.20 (s, 2H), 3.58 (s, 3H). [Example 12] Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (Compound 12) Step 12-1: Preparation of 6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one Under nitrogen, 5-nitropyridine-2,3-diamine (600 mg, 3.89 mmol) and N,N'-disuccinimidyl carbonate (15 g, 5.84 mmol) were dissolved in acetonitrile, and the reaction mixture was then stirred for 8 hours at 80° C. After completion of the reaction, the mixture was filtered using acetonitrile to obtain 570 mg (yield 81%) of the title compound.

[0135] 1 H NMR (400 MHz, Acetone-d 6 ) δ 11.00 (s, 1H), 10.29 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H). Step 12-2: Preparation of 1,3-dimethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one (400 mg, 2.22 mmol) obtained in step 12-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 351 mg of the title compound (76% yield).

[0136] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.94 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 3.54 (s, 3H), 3.48 (s, 3H). Step 12-3: Preparation of 6-amino-1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one 1,3-Dimethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one (300 mg, 1.44 mmol) obtained in step 12-2 and 10% Pd / C (307 mg, 0.29 mmol) were dissolved in methanol, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered using methanol, and the filtrate was concentrated to obtain 241 mg (yield 94%) of the title compound.

[0137] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.49 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 4.49 (s, 2H), 3.30 (s, 3H), 3.29 (s, 3H). Step 12-4: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (150 mg, 0.84 mmol) obtained in step 12-3 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, to obtain 100 mg of the title compound (47% yield).

[0138] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.18 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 3.47 (s, 3H), 3.41 (s, 3H). [Example 13] Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (compound 13) Step 13-1: Preparation of 6-aminobenzo[d]thiazol-2(3H)-one Under nitrogen, 6-nitrobenzo[d]thiazol-2(3H)-one (200 mg, 1.02 mmol) was dissolved in ethanol / water, then Fe (228 mg, 4.08 mmol) and ammonium chloride (545 mg, 10.19 mmol) were added, and the reaction mixture was stirred at 80° C. for 1 h. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 83 mg (49% yield) of the title compound.

[0139] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.34 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 6.51 (dd, J = 8.5, 2.3 Hz, 1H), 4.95 (s, 2H). Step 13-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-aminobenzo[d]thiazol-2(3H)-one (50 mg, 0.30 mmol) obtained in step 13-1 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 34 mg of the title compound (yield 47%).

[0140] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.96 (s, 1H), 7.68 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H). [Example 14] Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 14) Step 14-1: Preparation of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitrobenzo[d]thiazol-2(3H)-one (100 mg, 0.48 mmol) was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain the title compound 68 mg (yield 64%).

[0141] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.61 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.9, 2.4 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 3.58 (s, 3H). Step 14-2: Preparation of 6-amino-3-methylbenzo[d]thiazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one (100 mg, 0.48 mmol) obtained in step 14-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 79 mg of the title compound (yield 91%).

[0142] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.95 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.5, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H). Step 14-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-methylbenzo[d]thiazol-2(3H)-one obtained in step 14-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 94 mg of the title compound (yield 83%).

[0143] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.81 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.8, 2.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.41 (s, 3H). [Example 15] Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (compound 15) Step 15-1: Preparation of 6-aminobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 14-2 of Example 14, except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, to obtain 131 mg (78% yield) of the title compound.

[0144] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.83 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3, 2.1 Hz, 1H), 4.60 (s, 2H). Step 15-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-aminobenzo[d]oxazol-2(3H)-one obtained in step 15-1 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 115 mg of the title compound (yield 76%).

[0145] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H). [Example 16] Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (Compound 16) Step 16-1: Preparation of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 282 mg (yield 87%) of the title compound.

[0146] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.87 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 8.3, 2.1 Hz, 1H), 4.64 (s, 2H), 3.32 (s, 3H). Step 16-2: Preparation of 6-amino-3-methylbenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 14-2 of example 14, except that 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one obtained in step 16-1 was used instead of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one, to obtain 111 mg of the title compound (yield 88%).

[0147] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.95 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.5, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H). Step 16-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-methylbenzo[d]oxazol-2(3H)-one obtained in step 16-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 107 mg (yield 73%).

[0148] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 3.34 (s, 3H). [Example 17] Preparation of (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 17) Step 17-1: Preparation of N-methyl-2,4-dinitroaniline Under nitrogen, 1-chloro-2,4-dinitrobenzene (3 g, 14.81 mmol) was dissolved in THF, then 2.0 M methylamine (37.03 mL, 74.06 mmol) dissolved in THF was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ether and filtered to obtain 2.81 g (yield 96%) of the title compound.

[0149] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.99 (d, J = 2.8 Hz, 1H), 8.82 (s, 1H), 8.35 - 8.32 (m, 1H), 7.23 (d, J = 9.6 Hz, 1H), 3.24 (d, J = 5.2 Hz, 3H). Step 17-2:N 1 Preparation of -methyl-4-nitrobenzene-1,2-diamine N-methyl-2,4-dinitroaniline (300 mg, 1.52 mmol) obtained in step 17-1 was dissolved in methanol solvent, and then sodium sulfide (356 mg, 4.57 mmol) and sodium bicarbonate (384 mg, 4.57 mmol) dissolved in distilled water were added, and the reaction mixture was stirred at 80° C. for 8 hours under nitrogen. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ether and filtered to obtain 193 mg (yield 76%) of the title compound.

[0150] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.68 (dd, J = 8.8, 2.8 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 5.42 (s, 1H), 4.54 (s, 2H), 2.96 (s, 3H). Step 17-3: Preparation of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one N obtained in step 17-2 1 1,2-Methyl-4-nitrobenzene-1,2-diamine (900 mg, 5.38 mmol) was dissolved in DMF solvent, then CDI (2.56 g, 16.15 mmol) was added, and the reaction mixture was stirred at room temperature under nitrogen for 15 hours. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ether and filtered to obtain 568 mg (yield 55%) of the title compound.

[0151] 1 H NMR (400 MHz, Acetone-d 6 ) δ 10.27 (s, 1H), 8.10 (dd, J = 8.6, 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 3.47 (s, 3H). Step 17-4: Preparation of 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 2.07 mmol) obtained in step 17-3 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 306 mg of the title compound (yield 91%).

[0152] 1 H NMR (400 MHz, Acetone-d 6 ) δ 9.37 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 6.39 (dd, J = 8.4, 2.0 Hz, 1H), 4.31 (s, 2H), 3.23 (s, 3H). Step 17-5: Preparation of (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (250 mg, 1.53 mmol) obtained in step 17-4 and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 62 mg of the title compound (yield 17%).

[0153] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 10.99 (s, 1H), 7.19 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.12-7.10 (m, 2H), 3.27 (s, 3H). [Example 18] Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 18) Step 18-1: Preparation of 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitrobenzo[d]thiazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane was used instead of methyl iodide, to obtain 162 mg (yield 44%) of the title compound.

[0154] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.59 (d, J = 2.4 Hz), 8.26 (dd, J = 9.2, 2.4 Hz), 7.67 (d, J = 9.2Hz), 4.97 - 4.90 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H). Step 18-2: Preparation of 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one The reaction was carried out in the same manner as in step 14-2 of example 14, except that 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one obtained in step 18-1 was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, to obtain 112 mg of the title compound (yield 85%).

[0155] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.13 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 4.76 - 4.69 (m, 1H), 4.64 (s, 2H), 1.53 (d, J = 6.8Hz, 6H). Step 18-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one obtained in step 18-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 109 mg of the title compound (yield 80%).

[0156] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.79 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 4.81 - 4.74 (m, 1H), 1.50 (d, J = 7.2 Hz, 6H). [Example 19] Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 19) Step 19-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one Under nitrogen, 6-nitrobenzo[d]thiazol-2(3H)-one (300 mg, 1.53 mmol) was dissolved in DMF, then sodium 2-chloro-2,2-difluoroacetate (467 mg, 3.06 mmol) and DBU (0.46 mL, 3.06 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol and filtered to obtain 176 mg (47% yield) of the title compound.

[0157] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.76 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = 9.2, 2.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 57.2 Hz, 1H). Step 19-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one obtained in step 19-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 125 mg (yield 95%) of the title compound.

[0158] 1 H NMR (400 MHz, Acetone-d 6) δ 7.55 (t, J = 58.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.2 Hz, 1H), 4.89 (s, 2H). Step 19-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one obtained in step 19-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 85 mg of the title compound (yield 63%).

[0159] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.90 (s, 1H), 7.82 (t, J = 56.8 Hz, 1H), 7.53 (s, 2H). [Example 20] Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (compound 20) Step 20-1: Preparation of 3-isopropyl-6-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane was used instead of methyl iodide, to obtain 201 mg of the title compound (yield 54%).

[0160] 1 H NMR (400 MHz, Acetone-d 6) δ 8.23 ​​(dd, J = 8.8, 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 4.72 - 4.65 (m, 1H), 1.61 (d, J = 6.8 Hz, 6H). Step 20-2: Preparation of 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one obtained in step 20-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 124 mg of the title compound (yield 85%).

[0161] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.00 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 8.4, 2.0 Hz, 1H), 4.62 (s, 2H), 4.48 - 4.41 (m, 1H), 1.48 (d, J = 6.8Hz, 6H). Step 20-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one obtained in step 20-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 99 mg of the title compound (yield 59%).

[0162] 1 H NMR (400 MHz, DMSO-d 6) δ 7.47 - 7.43 (m, 2H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 4.51 - 4.44 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H). [Example 21] Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (Compound 21) Step 21-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 19-1 of Example 19, except that 6-nitrobenzo[d]oxazol-2(3H)-one (300 mg, 1.67 mmol) was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, to obtain 144 mg of the title compound (yield 38%).

[0163] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.34 - 8.30 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.65 (t, J = 57.6 Hz, 1H). Step 21-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one obtained in step 21-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 110 mg (yield 98%) of the title compound.

[0164] 1 H NMR (400 MHz, Acetone-d 6) δ 7.68 (t, J = 58.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.0 Hz, 1H) 4.91 (s, 2H). Step 21-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one obtained in step 21-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 85 mg of the title compound (yield 63%).

[0165] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.73 (t, J = 57.2 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.45 - 7.40 (m, 2H). [Example 22] Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 22) Step 22-1: Preparation of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-nitro-1H-benzo[d]imidazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 207 mg (yield 64%) of the title compound.

[0166] 1 H NMR (400 MHz, Acetone-d 6) δ 8.09(dd, J = 8.6, 2.2 Hz), 7.98(d, J = 2.0Hz), 7.30(d, J = 8.4Hz), 3.51(s, 3H), 3.48(s, 3H). Step 22-2: Preparation of 5-amino-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 22-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 105 mg of the title compound (yield 82%).

[0167] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.76 (d, J = 8.0 Hz, 1H), 6.43 - 6.40 (m, 2H), 4.38 (s, 2H), 3.27 (s, 3H), 3.26 (s, 3H). Step 22-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 22-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 11 mg of the title compound (yield 8%).

[0168] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.18 - 7.14 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 3.37 (s, 3H), 3.35 (s, 3H). [Example 23] Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 23) Step 23-1: Preparation of 1,3-diisopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-nitro-1H-benzo[d]imidazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane was used instead of methyl iodide, to obtain 204 mg (yield 46%) of the title compound.

[0169] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.05 - 8.02 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 4.80 - 4.72 (m, 2H), 1.58 - 1.54 (m, 12H). Step 23-2: Preparation of 5-amino-1,3-diisopropyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1,3-diisopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 23-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 118 mg of the title compound (yield 89%).

[0170] 1 H NMR (400 MHz, Acetone-d 6 ) δ 6.92 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.37 (dd, J = 8.4, 2.4 Hz, 1H), 4.62 - 4.54 (m, 2H), 4.33 (s, 2H), 1.46 - 1.43 (m, 12H). Step 23-3: Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 23-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 12 mg of the title compound (yield 10%).

[0171] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.22 - 7.20 (m, 2H), 7.04 (dd, J = 8.8, 1.6 Hz, 1H), 4.61 - 4.55 (m, 2H), 1.44 - 1.42 (m, 12H). [Example 24] Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 24) Step 24-1: Preparation of 1,3-bis(difluoromethyl)-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 19-1 of Example 19, except that 5-nitro-1H-benzo[d]imidazol-2(3H)-one was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, to obtain 179 mg of the title compound (yield 38%).

[0172] 1 H NMR (400 MHz, Acetone-d 6 ) δ 8.33 (dd, J = 8.8, 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.83 - 7.53 (m, 2H). Step 24-2: Preparation of 5-amino-1,3-bis(difluoromethyl)-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1,3-bis(difluoromethyl)-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 24-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of 1,4-dioxane as a solvent, to obtain 69 mg of the title compound (yield 96%).

[0173] 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.62 - 7.32 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 6.63 (dd, J = 8.6, 2.2 Hz, 1H), 4.90 (s, 2H). Step 24-3: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 9-4 of Example 9, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 24-2 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a 1:3 mixture of ethanol and water was used as the solvent, to obtain 45 mg of the title compound (yield 58%).

[0174] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 - 7.61 (m, 2H), 7.56 (s,1H), 7.49 - 7.42 (m, 2H). [Example 25] Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 25) Step 25-1: Preparation of 1-methyl-6-nitroquinolin-2(1H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitroquinolin-2(1H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 123 mg (yield 38%) of the title compound.

[0175] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.74 (d, J = 2.7 Hz, 1H), 8.40 (dd, J = 9.4, 2.7 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 6.80 (d, J = 9.5 Hz, 1H), 3.67 (s, 3H). Step 25-2: Preparation of 6-amino-1-methylquinolin-2(1H)-one The reaction was carried out in the same manner as in step 13-2 of example 13, except that 1-methyl-6-nitroquinolin-2(1H)-one obtained in step 25-1 was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, and THF and water were used as the solvent, to obtain 56 mg (yield 59%) of the title compound.

[0176] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 (d, J = 9.4 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.7 Hz, 1H), 6.78 (d, J = 2.6 Hz, 1H), 6.48 (d, J = 9.4 Hz, 1H), 5.09 (s, 2H), 3.53 (s, 3H). Step 25-3: Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-1-methylquinolin-2(1H)-one obtained in step 25-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 55 mg of the title compound (yield 77%).

[0177] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.16 (s, 1H), 7.98 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 9.1, 2.6 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 6.66 (d, J = 9.5 Hz, 1H), 3.61 (s, 3H). [Example 26] Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (compound 26) Step 26-1: Preparation of 4-methyl-6-nitroquinolin-2(1H)-one 4-Methylquinolin-2(1H)-one (1g, 6.28mmol) was dissolved in sulfuric acid (4mL), and then a mixed solution of 65% nitric acid (0.5mL) and sulfuric acid (0.5mL) was added and stirred for 2 hours at 0°C. After the reaction was completed, distilled water (30mL) was added and stirred at 0°C, and then filtered to obtain 1.08g (yield 84%) of the title compound.

[0178] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.18 (s, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.35 (dd, J = 9.0, 2.5 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.58 (s, 1H). Step 26-2: Preparation of 6-amino-4-methylquinolin-2(1H)-one The reaction was carried out in the same manner as in step 13-2 of Example 13, except that 4-methyl-6-nitroquinolin-2(1H)-one obtained in step 26-1 was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, and THF and water were used as the solvent, to obtain 47 mg of the title compound (yield 37%).

[0179] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.22 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.87 - 6.78 (m, 2H), 6.28 (s, 1H), 5.00 (s, 2H), 2.31 (s, 3H). Step 26-3: Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-4-methylquinolin-2(1H)-one obtained in step 26-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain the title compound 48 mg (yield 83%).

[0180] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 11.73 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.47 (s, 1H), 2.41 (s, 3H). [Example 27] Preparation of (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 27) Step 27-1: Preparation of 1,4-dimethyl-6-nitroquinolin-2(1H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 4-methyl-6-nitroquinolin-2(1H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 206 mg (yield 38%) of the title compound.

[0181] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (d, J = 2.6 Hz, 1H), 8.42 (ddd, J = 9.3, 2.6, 1.1 Hz, 1H), 7.73 (dd, J = 9.4, 1.1 Hz, 1H), 6.72 (s, 1H), 3.65 (s, 3H), 2.53 (s, 3H). Step 27-2: Preparation of 6-amino-1,4-dimethylquinolin-2(1H)-one The reaction was carried out in the same manner as in step 13-2 of Example 13, except that 1,4-dimethyl-6-nitroquinolin-2(1H)-one obtained in step 27-1 was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, and THF and water were used as the solvent, to obtain 33 mg of the title compound (yield 19%).

[0182] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.25 (d, J = 8.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.42 (s, 1H), 5.10 (s, 2H), 3.52 (s, 3H), 2.32 (s, 3H). Step 27-3: Preparation of (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-1,4-dimethylquinolin-2(1H)-one obtained in step 27-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 55 mg of the title compound (yield 77%).

[0183] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.14 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 9.2, 2.5 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 6.59 (s, 1H), 3.59 (s, 3H), 2.42 (s, 3H). [Example 28] Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide (compound 28) Step 28-1: Preparation of 3-methyl-5-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-nitrobenzo[d]dioxol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 226 mg of the title compound (70% yield).

[0184] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 3.43 (s, 3H). Step 28-2: Preparation of 5-amino-3-methylbenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-methyl-5-nitrobenzo[d]oxazol-2(3H)-one obtained in step 28-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 150 mg of the title compound (yield 88%).

[0185] 1 H NMR (400 MHz, DMSO-d 6) δ 6.95 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.28 (dd, J = 8.5, 2.2 Hz, 1H), 5.07 (s, 2H), 3.23 (s, 3H). Step 28-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 5-amino-3-methylbenzo[d]oxazol-2(3H)-one obtained in step 28-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 73 mg of the title compound (yield 38%).

[0186] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.11 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 8.6, 2.2 Hz, 1H). [Example 29] Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide (compound 29) Step 29-1: Preparation of 3-isopropyl-5-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in Step 28-1 of Example 28, except that 2-iodopropane was used instead of methyl iodide, to give 94 mg of the title compound (yield 25%).

[0187] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.8, 2.3 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 4.62 (hept, J = 6.9 Hz, 1H), 1.48 (d, J = 6.9 Hz, 6H). Step 29-2: Preparation of 5-amino-3-isopropylbenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-isopropyl-5-nitrobenzo[d]oxazol-2(3H)-one obtained in step 29-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 48 mg of the title compound (yield 61%).

[0188] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.96 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 6.28 (dd, J = 8.4, 2.2 Hz, 1H), 5.01 (s, 2H), 4.37 (hept, J = 6.9 Hz, 1H), 1.42 (d, J = 7.1 Hz, 6H). Step 29-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 5-amino-3-isopropylbenzo[d]oxazol-2(3H)-one obtained in step 29-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 9 mg of the title compound (yield 15%).

[0189] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.7, 2.2 Hz, 1H), 4.51 (hept, J = 6.9 Hz, 1H), 1.46 (d, J = 6.9 Hz, 6H). [Example 30] Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide (compound 30) Step 30-1: Preparation of 3-(difluoromethyl)-5-nitrobenzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in Step 28-1 of Example 28, except that sodium 2-chloro-2,2-difluoroacetate was used instead of methyl iodide, to give 104 mg of the title compound (yield 27%).

[0190] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.71 (s, 1H), 8.38 (dd, J = 9.0, 2.3 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H). Step 30-2: Preparation of 5-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-(difluoromethyl)-5-nitrobenzo[d]oxazol-2(3H)-one obtained in step 30-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain the title compound, which was used in the next step without further purification.

[0191] Step 30-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one obtained in step 30-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 30 mg of the title compound (yield 22%).

[0192] 1 H NMR (400 MHz, DMSO-d 6) δ 13.13 (s, 1H), 8.80 (s, 1H), 7.85 - 7.81 (m, 2H), 7.59 (dd, J = 9.0, 2.1 Hz, 1H). [Example 31] Preparation of (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 31) Step 31-1: Preparation of 5-methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 4-methyl-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 67 mg of the title compound (yield 29%).

[0193] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.25 (s, 1H), 11.00 (s, 1H), 7.59 (s, 1H), 6.96 (s, 1H), 2.55 (s, 3H). Step 31-2: Preparation of 1,3,5-trimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 31-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 268 mg of the title compound (78% yield).

[0194] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (s, 1H), 7.26 (s, 1H), 3.37 (d, J = 5.5 Hz, 6H), 2.60 (s, 3H). Step 31-3: Preparation of 5-amino-1,3,6-trimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1,3,5-trimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 31-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 169 mg of the title compound (yield 78%).

[0195] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.73 (s, 1H), 6.41 (s, 1H), 4.55 (s, 2H), 3.20 (d, J = 5.0 Hz, 6H), 2.09 (s, 3H). Step 31-4: Preparation of (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-1,3,6-trimethyl-6-nitro-1H-benzo[d]imidazol-one obtained in step 31-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 20 mg of the title compound (yield 10%).

[0196] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.26 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 3.31 (d, J = 2.7 Hz, 6H), 2.38 (s, 3H). [Example 32] Preparation of (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 32) Step 32-1: Preparation of 5-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 4-methoxy-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 336 mg of the title compound (yield 98%).

[0197] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 10.86 (s, 1H), 7.48 (s, 1H), 6.81 (s, 1H), 3.90 (s, 3H). Step 32-2: Preparation of 5-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 5-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 32-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 224 mg of the title compound (yield 66%).

[0198] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.81 (s, 1H), 7.19 (s, 1H), 3.95 (s, 3H), 3.39 (s, 3H), 3.34 (s, 3H). Step 32-3: Preparation of 5-amino-6-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 5-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 32-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 78 mg of the title compound (yield 44%).

[0199] 1 H NMR (400 MHz, DMSO-d 6) δ 6.78 (s, 1H), 6.47 (s, 1H), 4.45 (s, 2H), 3.78 (s, 3H), 3.25 (s, 3H), 3.20 (s, 3H). Step 32-4: Preparation of (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-6-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-one obtained in step 32-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 37 mg of the title compound (yield 54%).

[0200] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H), 3.34 (s, 3H), 3.31 (s, 3H). [Example 33] Preparation of (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 33) Step 33-1: Preparation of 4-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 3-methoxy-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 509 mg of the title compound (yield 89%).

[0201] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 11.15 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 3.96 (s, 3H). Step 33-2: Preparation of 4-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 4-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 33-1 was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 119 mg of the title compound (70% yield).

[0202] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H). Step 33-3: Preparation of 6-amino-4-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 33-2 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 15 mg of the title compound (yield 16%).

[0203] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.04 (d, J = 1.7 Hz, 1H), 5.97 (d, J = 1.7 Hz, 1H), 4.85 (s, 2H), 3.76 (s, 3H), 3.38 (s, 3H), 3.17 (s, 2H). Step 33-4: Preparation of (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-4-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-one obtained in step 33-3 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 20 mg of the title compound (yield 30%).

[0204] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H), 3.48 (s, 3H), 3.30 (s, 3H). [Example 34] Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 34) Step 34-1: Preparation of 1,3-diisopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane was used instead of methyl iodide, to obtain 387 mg of the title compound (yield 30%).

[0205] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 4.72 (dhept, J = 16.6, 6.9 Hz, 2H), 1.50 (dd, J = 16.1, 6.9 Hz, 12H). Step 34-2: Preparation of 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 28-2 of example 28, except that 1,3-diisopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 34-1 was used instead of 1-methyl-6-nitroquinolin-2(1H)-one, to obtain 162 mg of the title compound (yield 42%).

[0206] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 4.84 (s, 2H), 4.61 - 4.48 (m, J = 7.0 Hz, 2H), 1.41 (dd, J = 19.6, 6.9 Hz, 12H). Step 34-3: Preparation of 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 34-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 43 mg of the title compound (yield 27%).

[0207] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 4.64 (dp, J = 11.5, 6.9 Hz, 2H), 1.46 (dd, J = 19.8, 6.9 Hz, 12H). [Example 35] Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 35) Step 35-1: Preparation of 3-ethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one 1-Methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (150 mg, 0.78 mmol) was dissolved in DMF (3 mL) and potassium carbonate (214.7 mg, 1.55 mmol) was added, and then the reaction mixture was cooled to 0°C. Ethyl iodide (0.156 mL, 1.94 mmol) was gradually added, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 17 hours. After the reaction was completed, it was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ether and filtered to obtain 133.5 mg (77% yield) of the title compound.

[0208] 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (dd, J = 8.7, 2.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 3.49 (s, 3H). Step 35-2: Preparation of 5-amino-3-ethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-ethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 35-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 74.7 mg (yield 68%) of the title compound.

[0209] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.79 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 6.31 (dd, J = 8.2, 2.1 Hz, 1H), 4.76 (s, 2H), 3.74 (q, J = 7.2 Hz, 2H), 3.21 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). Step 35-3: Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-3-ethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 35-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 60.9 mg (yield 58%) of the title compound.

[0210] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.88 (q, J = 7.2 Hz, 2H), 3.32 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). [Example 36] Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 36) Step 36-1: Preparation of 3-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-2 of Example 9, except that 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and isopropyl iodide was used instead of methyl iodide, to obtain 135.9 mg (yield 55%) of the title compound.

[0211] 1H NMR (400 MHz, Chloroform-d) δ 8.10 (dd, J = 8.7, 2.1 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 4.75 (hept, J = 7.0 Hz, 1H), 3.47 (s, 3H), 1.58 (d, J = 7.1 Hz, 7H). Step 35-2: Preparation of 5-amino-3-isopropyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 36-1 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 114.2 mg of the title compound (yield 100%).

[0212] 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.78 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.30 (dd, J = 8.3, 2.0 Hz, 1H), 4.73 (s, 2H), 4.49 (hept, J = 7.0 Hz, 1H), 3.19 (s, 3H), 1.39 (d, J = 7.0 Hz, 6H). Step 36-3: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-3-isopropyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 36-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 15.2 mg (yield 9%) of the title compound.

[0213] 1 H NMR (400 MHz, DMSO-d 6) δ 12.96 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.5, 1.9 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 4.61 (hept, J = 7.0 Hz, 1H), 3.30 (s, 3H), 1.44 (d, J = 6.9 Hz, 6H). [Example 37] Preparation of (3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 37) Step 37-1: Preparation of 3-difluoromethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one Under nitrogen, 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.52 mmol) was dissolved in DMF, followed by the addition of sodium 2-chloro-2,2-difluoroacetate (157.9 mg, 1.04 mmol) and potassium carbonate (143.1 mg, 1.04 mmol), and the reaction mixture was heated to 80° C. and stirred for 5 hours. After completion of the reaction, water was added and the resulting precipitate was filtered and purified by column chromatography to give 58.5 mg (46% yield) of the title compound.

[0214] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(dd, J = 8.8, 2.2 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.81 (t, J = 57.5 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 3.41 (s, 3H). Step 37-2: Preparation of 5-amino-3-difluoromethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-difluoromethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 37-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and the title compound was obtained in an amount of 56.1 mg (yield 72%).

[0215] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.56 (t, J = 58.3 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.45 (dd, J = 8.4, 2.1 Hz, 1H), 5.03 (s, 2H), 3.24 (s, 3H). Step 37-3: Preparation of (3-difluoromethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 5-amino-3-difluoromethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 37-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 53.2 mg (yield 71%) of the title compound.

[0216] 1 H NMR (400 MHz, Acetone-d 6 ) δ 11.86 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.52 (t, J = 58.4 Hz, 1H), 7.45 (dd, J = 8.6, 2.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 3.42 (s, 3H). [Example 38] Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 38) Step 38-1: Preparation of N-ethyl-2,4-dinitroaniline The reaction was carried out in the same manner as in Step 17-1 of Example 17, except that ethylamine was used instead of methylamine, to give 1.95 g of the title compound (yield 93%).

[0217] 1 H NMR (400 MHz, Chloroform-d) δ 9.13 (d, J = 2.7 Hz, 1H), 8.49 (s, 1H), 8.27 (ddd, J = 9.5, 2.7, 0.8 Hz, 1H), 6.92 (d, J = 9.5 Hz, 1H), 3.48 (qd, J = 7.2, 5.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). Step 38-2:N 1 Preparation of -ethyl-4-nitrobenzene-1,2-diamine The reaction was carried out in the same manner as in Step 17-2 of Example 17, except that N-ethyl-2,4-dinitroaniline obtained in Step 38-1 was used instead of N-methyl-2,4-dinitroaniline, to obtain 1.46 g of the title compound (yield 88%).

[0218] 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (dd, J = 8.9, 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.18 (s, 1H), 3.35 (s, 2H), 3.31 - 3.17 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H). Step 38-3: Preparation of 1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that N-ethyl-4-nitrobenzene-1,2-diamine obtained in step 38-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 1.57 g of the title compound (yield 95%).

[0219] 1H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.01 (dd, J = 8.7, 2.3 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). Step 38-4: Preparation of 1-ethyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that 1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 38-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and methyl iodide was used instead of ethyl iodide, to obtain 172.0 mg (yield 80%) of the title compound.

[0220] 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (dd, J = 8.7, 2.2 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.00 (q, J = 7.3 Hz, 2H), 3.49 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Step 38-5: Preparation of 5-amino-1-ethyl-3-methyl-H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-ethyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 38-4 was used instead of 7-nitroisoquinolin-1(2H)-one, to obtain 117.6 mg of the title compound (yield 80%).

[0221] 1 H NMR (400 MHz, DMSO-d 6) δ 6.82 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.30 (dd, J = 8.2, 2.1 Hz, 1H), 4.78 (s, 2H), 3.75 (q, J = 7.1 Hz, 2H), 3.20 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). Step 38-6: Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-1-ethyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 38-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 10.8 mg (yield 6%) of the title compound.

[0222] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.07 (s, 1H), 7.26-7.22 (m, 3H), 3.86 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). [Example 39] Preparation of (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 39) Step 39-1: Preparation of 3-difluoromethyl-1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 37-1 of example 37, except that 1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 38-3 of example 38 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 133.0 mg (yield 42%) of the title compound.

[0223] 1H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (dd, J = 8.8, 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.81 (t, J = 57.5 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). Step 39-2: Preparation of 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-difluoromethyl-1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 39-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and the title compound was obtained in an amount of 88.2 mg (yield 75%).

[0224] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.56 (t, J = 58.3 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 8.4, 2.1 Hz, 1H), 5.03 (s, 2H), 3.77 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H). Step 39-3: Preparation of (3-difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 39-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 64.7 mg (yield 56%) of the title compound.

[0225] 1H NMR (400 MHz, Acetone-d 6 ) δ 11.85 (s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.52 (t, J = 58.4 Hz, 1H), 7.44 (dd, J = 8.6, 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.97 (q, J = 7.3 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). [Example 40] Preparation of (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 40) Step 40-1: Preparation of N-cyclopropyl-2,4-dinitroaniline The reaction was carried out in the same manner as in Step 17-1 of Example 17, except that cyclopropylamine was used instead of methylamine, to give the title compound (179.9 mg, 81% yield).

[0226] 1 H NMR (400 MHz, Chloroform-d) δ 9.13 (d, J = 2.6 Hz, 1H), 8.56 (s, 1H), 8.31 (ddd, J = 9.5, 2.6, 0.7 Hz, 1H), 7.40 (d, J = 9.5 Hz, 1H), 2.70 (tdt, J = 6.8, 3.8, 1.8 Hz, 1H), 1.12 - 0.98 (m, 2H), 0.82 - 0.67 (m, 2H). Step 40-2:N 1 Preparation of -cyclopropyl-4-nitrobenzene-1,2-diamine The reaction was carried out in the same manner as in Step 17-2 of Example 17, except that N-cyclopropyl-2,4-dinitroaniline obtained in Step 40-1 was used instead of N-methyl-2,4-dinitroaniline, to give 1.69 g of the title compound (yield 89%).

[0227] 1H NMR (400 MHz, Chloroform-d) δ 7.85 (ddd, J = 8.9, 2.5, 0.6 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 4.66 (s, 1H), 3.29 (s, 2H), 2.53 (ttd, J = 6.7, 3.6, 1.3 Hz, 1H), 0.93 - 0.82 (m, 2H), 0.63 - 0.55 (m, 2H). Step 40-3: Preparation of 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that N-cyclopropyl-4-nitrobenzene-1,2-diamine obtained in step 40-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 1.83 g of the title compound (yield 96%).

[0228] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.30 (s, 1H), 8.01 (dd, J = 8.7, 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 2.93 (tt, J = 7.0, 3.7 Hz, 1H), 1.09 - 1.01 (m, 2H), 0.93 - 0.85 (m, 2H). Step 40-4: Preparation of 1-cyclopropyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 40-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and methyl iodide was used instead of ethyl iodide, to obtain 186.6 mg of the title compound (yield 87%).

[0229] 1H NMR (400 MHz, Chloroform-d) δ 8.10 (ddd, J = 8.6, 2.3, 1.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 3.45 (d, J = 1.0 Hz, 3H), 2.93 (tdd, J = 7.1, 4.1, 3.1 Hz, 1H), 1.22 - 1.11 (m, 2H), 1.07 - 0.98 (m, 2H). Step 40-5: Preparation of 5-amino-1-cyclopropyl-3-methyl-H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-cyclopropyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 40-4 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 41.6 mg (yield 75%) of the title compound.

[0230] 1 H NMR (400 MHz, Chloroform-d) δ 6.96 (d, J = 8.2 Hz, 1H), 6.44 (dd, J = 8.2, 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 3.58 (s, 2H), 3.31 (s, 3H), 2.90 - 2.69 (m, 1H), 1.08 - 1.01 (m, 2H), 1.01 - 0.94 (m, 2H). Step 40-6: Preparation of (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-1-cyclopropyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 40-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 29.9 mg (yield 52%) of the title compound.

[0231] 1 H NMR (400 MHz, Chloroform-d) δ 9.86 (s, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.4, 2.1 Hz, 1H), 3.41 (s, 3H), 2.89 (tt, J = 7.0, 3.7 Hz, 1H), 1.17 - 1.09 (m, 2H), 1.01 (tt, J = 5.3, 3.7 Hz, 2H). [Example 41] Preparation of (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 41) Step 41-1: Preparation of 1-cyclopropyl-3-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of example 35, except that 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 40-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 159.9 mg (yield 70%) of the title compound.

[0232] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 8.6, 2.3 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 2.98 (tt, J = 7.1, 3.7 Hz, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.12 - 1.03 (m, 2H), 0.95 - 0.86 (m, 2H). Step 41-2: Preparation of 5-amino-1-cyclopropyl-3-ethyl-H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-cyclopropyl-3-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 41-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 83.2 mg (yield 61%) of the title compound.

[0233] 1 H NMR (400 MHz, Chloroform-d) δ 6.96 (d, J = 8.2 Hz, 1H), 6.43 (dd, J = 8.2, 2.2 Hz, 1H), 6.37 (d, J = 2.1 Hz, 1H), 3.83 (q, J = 7.2 Hz, 2H), 3.58 (br s, 2H), 2.90 - 2.72 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.08 - 0.94 (m, 4H). Step 41-3: Preparation of (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-1-cyclopropyl-3-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 41-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 53.6 mg (yield 49%) of the title compound.

[0234] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 7.52 - 7.06 (m, 3H), 3.83 (q, J = 7.2 Hz, 2H), 2.89 (tt, J = 7.0, 3.7 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H), 1.02 (td, J = 7.3, 5.0 Hz, 2H), 0.92 - 0.82 (m, 2H). [Example 42] Preparation of (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 42) Step 42-1: Preparation of 1-cyclopropyl-3-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 40-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and isopropyl iodide was used instead of ethyl iodide, to obtain 207.5 mg (yield 69%) of the title compound.

[0235] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 8.8, 2.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 5.27 (hept, J = 6.2 Hz, 1H), 3.18 (tt, J = 7.1, 3.7 Hz, 1H), 1.43 (d, J = 6.2 Hz, 6H), 1.13 (td, J = 7.4, 5.2 Hz, 2H), 0.98 - 0.90 (m, 2H). Step 42-2: Preparation of 5-amino-1-cyclopropyl-3-isopropyl-H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-cyclopropyl-3-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 42-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 114.5 mg (yield 62%) of the title compound.

[0236] 1H NMR (400 MHz, Chloroform-d) δ 6.97 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 6.43 (dd, J = 8.2, 2.1 Hz, 1H), 4.65 (hept, J = 7.0 Hz, 1H), 3.56 (s, 2H), 2.84 - 2.71 (m, 1H), 1.48 (d, J = 7.0 Hz, 6H), 1.07 - 0.94 (m, 4H). Step 42-3: Preparation of (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 5-amino-1-cyclopropyl-3-isopropyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 42-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 39.8 mg (yield 26%) of the title compound.

[0237] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.96 (s, 1H), 7.39 (d, J = 1.3 Hz, 1H), 7.22 (d, J = 1.2 Hz, 2H), 4.58 (hept, J = 6.9 Hz, 1H), 2.87 (tt, J = 7.0, 3.6 Hz, 1H), 1.42 (d, J = 6.9 Hz, 6H), 1.01 (td, J = 7.2, 5.0 Hz, 2H), 0.90 - 0.82 (m, 2H). [Example 43] Preparation of (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 43) Step 43-1: Preparation of N-isopropyl-2,4-dinitroaniline The reaction was carried out in the same manner as in Step 17-1 of Example 17, except that isopropylamine was used instead of methylamine, to give 2.02 g of the title compound (yield 90%).

[0238] 1 H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J = 2.7 Hz, 1H), 8.50 (s, 1H), 8.26 (ddd, J = 9.6, 2.7, 0.8 Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 4.00 - 3.89 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H). Step 43-2:N 1 Preparation of -isopropyl-4-nitrobenzene-1,2-diamine The reaction was carried out in the same manner as in step 17-2 of Example 17, except that N-isopropyl-2,4-dinitroaniline obtained in step 43-1 was used instead of N-methyl-2,4-dinitroaniline, and a mixed solvent of water and methanol (1:1) was used as the solvent, to obtain 1.08 g of the title compound (yield 62%).

[0239] 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.63 (d, J = 2.6 Hz, 1H), 6.55 (d, J = 9.0 Hz, 1H), 4.20 (s, 1H), 3.82 - 3.63 (m, J = 6.3 Hz, 1H), 3.29 (s, 2H), 1.29 (d, J = 6.3 Hz, 6H). Step 43-3: Preparation of 1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that N-isopropyl-4-nitrobenzene-1,2-diamine obtained in step 43-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 1.15 g of the title compound (yield 94%).

[0240] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 4.63 (hept, J = 6.9 Hz, 1H), 1.46 (d, J = 7.0 Hz, 6H). Step 43-4: Preparation of 3-difluoromethyl-1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 37-1 of example 37, except that 1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 43-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and the title compound was obtained in an amount of 89.3 mg (yield 29%).

[0241] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (dd, J = 8.9, 2.3 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.79 (t, J = 57.6 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 4.68 (hept, J = 6.9 Hz, 1H), 1.49 (d, J = 6.9 Hz, 6H). Step 43-5: Preparation of 5-amino-3-difluoromethyl-1-ethyl-H-benzo[d]imidazol-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-difluoromethyl-1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 43-4 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 67.2 mg (yield 84%) of the title compound.

[0242] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.53 (t, J = 58.4 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 6.42 (dd, J = 8.5, 2.1 Hz, 1H), 5.03 (s, 2H), 4.49 (hept, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H). Step 43-6: Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 43-5 was used instead of 7-aminoisoquinolin-1(2H)-one, and water was used as the solvent, to obtain 53.6 mg (yield 60%) of the title compound.

[0243] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 7.69 (t, J = 57.8 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.35 (dd, J = 8.8, 2.1 Hz, 1H), 4.59 (p, J = 6.9 Hz, 1H), 1.46 (d, J = 7.0 Hz, 6H). [Example 44] Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 44) Step 44-1: Preparation of N-methyl-3,5-dinitropyridin-2-amine The reaction was carried out in the same manner as in Step 17-1 of Example 17, except that 2-chloro-3,5-dinitropyridine was used instead of 1-chloro-2,4-dinitrobenzene, to obtain 1.62 g of the title compound (yield 83%).

[0244] 1 H NMR (400 MHz, Acetone-d 6 ) δ 9.27 (d, J = 2.6 Hz, 1H), 9.13 (s, 1H), 9.10 (d, J = 2.6 Hz, 1H), 3.30 (d, J = 1.2 Hz, 3H). Step 44-2:N 1 Preparation of -methyl-5-nitropyridine-2.3-diamine The reaction was carried out in the same manner as in Step 17-2 of Example 17, except that N-methyl-3,5-dinitropyridin-2-amine obtained in Step 44-1 was used instead of N-methyl-2,4-dinitroaniline, to obtain 1.14 g of the title compound (yield 83%).

[0245] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.12 (s, 1H), 5.32 (s, 2H), 2.97 (d, J = 4.6 Hz, 3H). Step 44-3: Preparation of 3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that N-methyl-5-nitropyridine-2,3-diamine obtained in step 44-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 669.7 mg of the title compound (yield 53%).

[0246] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 3.36 (s, 3H). Step 44-4: Preparation of 1-ethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 44-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 148.8 mg (yield 65%) of the title compound.

[0247] 1 H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 4.01 (q, J = 7.3 Hz, 2H), 3.56 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H). Step 44-5: Preparation of 6-amino-1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-ethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 44-4 was used instead of 7-nitroisoquinolin-1(2H)-one, methanol was used instead of dioxane as a solvent, and the reaction was carried out at 40°C, to obtain 92.8 mg (yield 74%) of the title compound.

[0248] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 3.88 (q, J = 7.3 Hz, 2H), 3.52 (s, 2H), 3.43 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). Step 44-6: Preparation of (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 44-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 45.8 mg (yield 31%) of the title compound.

[0249] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 3.92 (q, J = 7.1 Hz, 2H), 3.33 (s, 4H), 1.20 (t, J = 7.1 Hz, 3H). [Example 45] Preparation of (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 45) Step 45-1: Preparation of 1-isopropyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of example 35, except that 3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 44-3 of example 44 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 98.5 mg (yield 40%) of the title compound.

[0250] 1 H NMR (400 MHz, Chloroform-d) δ 9.01 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 4.76 (hept, J = 7.0 Hz, 1H), 3.54 (s, 3H), 1.57 (d, J = 7.0 Hz, 6H). Step 45-2: Preparation of 6-amino-1-isopropyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-isopropyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 45-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and ethyl acetate was used instead of dioxane as a solvent, to obtain 64.1 mg (yield 81%) of the title compound.

[0251] 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4.71 (hept, J = 7.0 Hz, 1H), 3.51 (s, 2H), 3.41 (s, 3H), 1.48 (d, J = 7.0 Hz, 6H). Step 45-3: Preparation of (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 5-amino-1-cyclopropyl-3-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 45-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 8.6 mg (yield 9%) of the title compound.

[0252] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 4.64 (hept, J = 6.9 Hz, 1H), 3.32 (s, 3H), 1.44 (d, J = 6.9 Hz, 6H). [Example 46] Preparation of (1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 46) Step 46-1: Preparation of 1-difluoromethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 37-1 of example 37, except that 3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 44-3 of example 44 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 58.5 mg (yield 46%) of the title compound.

[0253] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.87 (t, J = 57.4 Hz, 1H), 3.40 (s, 3H). Step 46-2: Preparation of 6-amino-1-difluoromethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-difluoromethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 46-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 121.1 mg (yield 88%) of the title compound.

[0254] 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 2.4 Hz, 1H), 7.31 (t, J = 58.9 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 3.62 (s, 2H), 3.42 (s, 3H). Step 46-3: Preparation of (1-difluoromethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-1-difluoromethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 46-2 was used instead of 7-aminoisoquinolin-1(2H)-one, and the title compound was obtained in an amount of 57.3 mg (yield 81%).

[0255] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J = 2.1 Hz, 1H), 7.79 (t, J = 57.6 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 3.33 (s, 3H). [Example 47] Preparation of (3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 47) Step 47-1: Preparation of 3-methyl-6-nitro-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one 3-Methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one (50 mg, 0.26 mmol) obtained in step 44-3 of Example 44, potassium carbonate (71.2 mg, 0.52 mmol), copper iodide (9.8 mg, 0.052 mmol), and trans-4-hydroxy-L-proline (13.5 mg, 0.10 mmol) were dissolved in DMSO, and then iodine benzene (28.7 mg, 0.26 mmol) was dissolved in DMSO and slowly added. The reaction mixture was heated to 130° C. and stirred for 14 hours. After the reaction was completed, the mixture was extracted with a saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 36.6 mg (yield 52%) of the title compound.

[0256] 1 H NMR (400 MHz, DMSO-d 6) δ 9.05 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 5.7 Hz, 4H), 7.58 - 7.47 (m, 1H), 3.50 (s, 3H). Step 47-2: Preparation of 6-amino-3-methyl-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-methyl-6-nitro-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 47-1 was used instead of 7-nitroisoquinolin-1(2H)-one, DMF was used instead of dioxane as a solvent, and the reaction was carried out at 60°C, to obtain 18.2 mg (yield 34%) of the title compound.

[0257] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.61 - 7.49 (m, 4H), 7.46 (d, J = 2.3 Hz, 1H), 7.45 - 7.41 (m, 1H), 6.73 (d, J = 2.2 Hz, 1H), 4.96 (s, 2H), 3.32 (s, 3H). Step 47-3: Preparation of (1-difluoromethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-3-methyl-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 47-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 14.0 mg (yield 58%) of the title compound.

[0258] 1 H NMR (400 MHz, Acetone-d 6) δ 11.91 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.67 - 7.56 (m, 4H), 7.53 (d, J = 2.2 Hz, 1H), 7.48 (tt, J = 6.1, 2.2 Hz, 1H), 3.48 (s, 3H). [Example 48] Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 48) Step 48-1: Preparation of N-ethyl-3,5-dinitropyridin-2-amine The reaction was carried out in the same manner as in step 17-1 of Example 17, except that 2-chloro-3,5-dinitropyridine was used instead of 1-chloro-2,4-dinitrobenzene and ethylamine was used instead of methylamine, to obtain 1.66 g of the title compound (yield 79%).

[0259] 1 H NMR (400 MHz, Chloroform-d) δ 9.26 (d, J = 2.6 Hz, 1H), 9.22 (d, J = 2.6 Hz, 1H), 8.73 (s, 1H), 3.80 (qd, J = 7.2, 5.6 Hz, 2H), 1.37 (t, J = 7.3Hz, 3H). Step 48-2:N 1 Preparation of -ethyl-5-nitropyridine-2.3-diamine The reaction was carried out in the same manner as in step 17-2 of Example 17, except that N-ethyl-3,5-dinitropyridin-2-amine obtained in step 48-1 was used instead of N-methyl-2,4-dinitroaniline, and a mixed solvent of methanol and water (1:1) was used as the solvent, to obtain 1.15 g of the title compound (yield 80%).

[0260] 1H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 5.02 (s, 1H), 3.61 (qd, J = 7.2, 5.4 Hz, 2H), 3.30 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H). Step 48-3: Preparation of 3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 9-1 of Example 9, except that N-ethyl-5-nitropyridine-2,3-diamine obtained in step 48-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine, to obtain 891.8 mg of the title compound (yield 68%).

[0261] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 3.92 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). Step 48-4: Preparation of 3-ethyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 48-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and methyl iodide was used instead of ethyl iodide, to obtain 127.8 mg (yield 80%) of the title compound.

[0262] 1H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.50 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). Step 48-5: Preparation of 6-amino-3-ethyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-ethyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 48-4 was used instead of 7-nitroisoquinolin-1(2H)-one, and ethyl acetate was used instead of dioxane as a solvent, to obtain 94.8 mg (yield 87%) of the title compound.

[0263] 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.53 (s, 2H), 3.35 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). Step 48-6: Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-3-ethyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 48-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 61.6 mg (yield 46%) of the title compound.

[0264] 1 H NMR (400 MHz, Acetone-d 6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.45 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). [Example 49] Preparation of (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 49) Step 49-1: Preparation of 3-ethyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in Step 48-4 of Example 48, except that isopropyl iodide was used instead of methyl iodide, to give the title compound (108.3 mg, 45% yield).

[0265] 1 H NMR (400 MHz, Chloroform-d) δ 9.01 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 4.77 (hept, J = 7.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 1.57 (d, J = 7.1 Hz, 6H), 1.41 (t, J = 7.2 Hz, 3H). Step 49-2: Preparation of 6-amino-3-ethyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-ethyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 49-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and ethyl acetate was used instead of dioxane as a solvent, to obtain 75.2 mg (yield 82%) of the title compound.

[0266] 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 4.71 (hept, J = 7.0 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 1.48 (d, J = 7.0 Hz, 6H), 1.34 (t, J = 7.2 Hz, 3H). Step 49-3: Preparation of (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-3-ethyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 49-2 was used instead of 7-aminoisoquinolin-1(2H)-one, and water was used as the solvent, to obtain 43.5 mg (yield 42%) of the title compound.

[0267] 1 H NMR (400 MHz, Acetone-d 6 ) δ 11.89 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 4.72 (hept, J = 6.9 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 1.52 (d, J = 7.0 Hz, 6H), 1.30 (t, J = 7.2 Hz, 3H). [Example 50] Preparation of (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 50) Step 50-1: Preparation of 1-difluoromethyl-3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 37-1 of example 37, except that 3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 48-3 of example 48 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 129.6 mg (yield 70%) of the title compound.

[0268] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.12 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.87 (t, J = 57.4 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). Step 50-2: Preparation of 6-amino-1-difluoromethyl-3-ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 1-difluoromethyl-3-ethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in step 50-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and the title compound was obtained in an amount of 103.7 mg (yield 90%).

[0269] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.67 (t, J = 58.2 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 5.18 (s, 2H), 3.81 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2Hz, 3H). Step 50-3: Preparation of (3-difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-1-difluoromethyl-3-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 50-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 69.3 mg (yield 80%) of the title compound.

[0270] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (d, J = 2.1 Hz, 1H), 7.79 (t, J = 57.6 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). [Example 51] Preparation of (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 51) Step 51-1: Preparation of N-cyclopropyl-3,5-dinitropyridin-2-amine The reaction was carried out in the same manner as in step 17-1 of Example 17, except that 2-chloro-3,5-dinitropyridine was used instead of 1-chloro-2,4-dinitrobenzene and cyclopropylamine was used instead of methylamine, to obtain 1.99 g of the title compound (yield 90%).

[0271] 1 H NMR (400 MHz, Chloroform-d) δ 9.32 (d, J = 2.5 Hz, 1H), 9.21 (d, J = 2.5 Hz, 1H), 8.69 (s, 1H), 3.21 (ddt, J = 11.1, 7.1, 3.9 Hz, 1H), 1.11 - 0.97 (m, 2H), 0.80 - 0.64 (m, 2H). Step 51-2:N 2 Preparation of -cyclopropyl-5-nitropyridine-2.3-diamine The reaction was carried out in the same manner as in step 17-2 of Example 17, except that N-cyclopropyl-3,5-dinitropyridin-2-amine obtained in step 51-1 was used instead of N-methyl-2,4-dinitroaniline, and a mixed solvent of methanol and water (1:1) was used as the solvent, to obtain 1.33 g of the title compound (yield 78%).

[0272] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 5.35 (s, 2H), 2.93 (tq, J = 7.3, 3.8 Hz, 1H), 0.84 - 0.71 (m, 2H), 0.57 - 0.45 (m, 2H). Step 51-3: Preparation of 3-cyclopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one Instead of 4-fluoro-5-nitrobenzene-1,2-diamine, use N obtained in step 51-2. 2 The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that -cyclopropyl-5-nitropyridine-2,3-diamine was used, to obtain 1.16 g of the title compound (yield 77%).

[0273] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 8.91 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 3.07 - 2.92 (m, 1H), 1.17 - 0.78 (m, 4H). Step 51-4: Preparation of 3-cyclopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-cyclopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 51-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and methyl iodide was used instead of ethyl iodide, to obtain 172.0 mg (yield 80%) of the title compound.

[0274] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H), 3.40 (s, 3H), 3.08 - 2.97 (m, 1H), 1.11 - 0.99 (m, 4H). Step 51-5: Preparation of 6-amino-3-cyclopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-cyclopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 51-4 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 89.3 mg (yield 78%) of the title compound.

[0275] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, J = 2.3 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 4.92 (s, 2H), 3.20 (s, 3H), 2.86 (tt, J = 7.2, 3.5 Hz, 1H), 1.04 - 0.85 (m, 4H). Step 51-6: Preparation of (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-3-cyclopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 51-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain the title compound 25.6 mg (yield 20%).

[0276] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 3.32 (s, 3H), 2.94 (td, J = 6.8, 3.6 Hz, 1H), 0.99 (d, J = 7.5 Hz, 4H). [Example 52] Preparation of (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 52) Step 52-1: Preparation of 3-cyclopropyl-1-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of example 35, except that 3-cyclopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 51-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 179.5 mg (yield 79%) of the title compound.

[0277] 1 H NMR (400 MHz, DMSO-d 6 ) δ Chloroform-d) δ 9.03 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 3.98 (q, J = 7.3 Hz, 2H), 3.07 (tt, J = 6.6, 4.1 Hz, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.29 - 1.09 (m, 4H). Step 52-2: Preparation of 6-amino-3-cyclopropyl-1-ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-cyclopropyl-1-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 52-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 112.0 mg (yield 71%) of the title compound.

[0278] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 2.3 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 3.84 (q, J = 7.3 Hz, 2H), 3.52 (s, 2H), 2.93 (tt, J = 6.4, 4.1 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.10 (dddt, J = 7.0, 4.5, 2.8, 1.2 Hz, 4H). Step 52-3: Preparation of (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-3-cyclopropyl-1-ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 52-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 66.2 mg (yield 44%) of the title compound.

[0279] 1 H NMR (400 MHz, DMSO-d 6) δ 13.11 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 3.88 (q, J = 7.1 Hz, 2H), 2.95 (td, J = 7.0, 3.6 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.00 (ddt, J = 9.9, 5.2, 2.7 Hz, 4H). [Example 53] Preparation of (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 53) Step 53-1: Preparation of 3-cyclopropyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-cyclopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 51-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and isopropyl iodide was used instead of ethyl iodide, to obtain 187.7 mg (yield 76%) of the title compound.

[0280] 1 H NMR (400 MHz, DMSO-d 6 ) δ Chloroform-d) δ 9.02 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 4.74 (hept, J = 7.0 Hz, 1H), 3.06 (tt, J = 6.7, 4.1 Hz, 1H), 1.56 (d, J = 7.1 Hz, 6H), 1.24 - 1.12 (m, 4H). Step 53-2: Preparation of 6-amino-3-cyclopropyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-cyclopropyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 53-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 130.9 mg (yield 79%) of the title compound.

[0281] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 2.3 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 4.69 (hept, J = 7.0 Hz, 1H), 3.50 (s, 2H), 2.92 (tt, J = 6.5, 4.1 Hz, 1H), 1.47 (d, J = 7.0 Hz, 6H), 1.10 (dddd, J = 9.7, 4.2, 2.6, 1.2 Hz, 4H). Step 53-3: Preparation of (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-3-cyclopropyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 53-2 was used instead of 7-aminoisoquinolin-1(2H)-one, and water was used as the solvent, to obtain 22.9 mg (yield 34%) of the title compound.

[0282] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 4.61 (hept, J = 6.9 Hz, 1H), 3.03 - 2.79 (m, 1H), 1.42 (d, J = 6.9 Hz, 6H), 1.08 - 0.91 (m, 4H). [Example 54] Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 54) Step 54-1: Preparation of N-isopropyl-3,5-dinitropyridin-2-amine The reaction was carried out in the same manner as in step 17-1 of Example 17, except that 2-chloro-3,5-dinitropyridine was used instead of 1-chloro-2,4-dinitrobenzene and isopropylamine was used instead of methylamine, to obtain 2.07 g of the title compound (yield 93%).

[0283] 1 H NMR (400 MHz, Chloroform-d) δ 9.25 (d, J = 2.6 Hz, 1H), 9.22 (d, J = 2.5 Hz, 1H), 8.60 (s, 1H), 4.62 (dh, J = 7.6, 6.6 Hz, 1H), 1.37 (d, J = 6.5 Hz, 6H). Step 54-2:N 2 Preparation of -isopropyl-5-nitropyridine-2,3-diamine The reaction was carried out in the same manner as in step 17-2 of Example 17, except that N-isopropyl-3,5-dinitropyridin-2-amine obtained in step 54-1 was used instead of N-methyl-2,4-dinitroaniline, and a mixed solvent of methanol and water (1:1) was used as the solvent, to obtain 1.07 g of the title compound (yield 59%).

[0284] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 5.41 (s, 2H), 4.39 - 4.26 (m, J = 6.6 Hz, 1H), 1.21 (d, J = 6.5 Hz, 6H). Step 54-3: Preparation of 3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one Instead of 4-fluoro-5-nitrobenzene-1,2-diamine, use N 2 The reaction was carried out in the same manner as in Step 9-1 of Example 9, except that 5-isopropyl-5-nitropyridine-2,3-diamine was used, to obtain 1.08 g of the title compound (yield 91%).

[0285] 1 H NMR (400 MHz, DMSO-d 6 ) 8.91 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 4.69 (hept, J = 6.9 Hz, 1H), 1.51 (d, J = 6.9 Hz, 6H). Step 54-4: Preparation of 3-isopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 54-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, and methyl iodide was used instead of ethyl iodide, to obtain 143.5 mg (yield 67%) of the title compound.

[0286] 1 H NMR (400 MHz, Chloroform-d) δ 9.01 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 4.88 (hept, J = 6.9 Hz, 1H), 3.48 (s, 3H), 1.61 (d, J = 6.9 Hz, 6H). Step 54-5: Preparation of 6-amino-3-isopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of Example 1, except that 3-isopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 54-4 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 97.2 mg (yield 78%) of the title compound.

[0287] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, J = 2.3 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 4.90 (s, 2H), 4.55 (hept, J = 6.9 Hz, 1H), 3.22 (s, 3H), 1.44 (d, J = 6.9 Hz, 6H). Step 54-6: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of example 1, except that 6-amino-3-isopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 54-5 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 103.5 mg (yield 77%) of the title compound.

[0288] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.18 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 4.66 (hept, J = 6.9 Hz, 1H), 3.35 (s, 3H), 1.49 (d, J = 6.9 Hz, 6H). [Example 55] Preparation of (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (compound 55) Step 55-1: Preparation of 1-ethyl-3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 35-1 of Example 35, except that 3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 54-3 was used instead of 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one, to obtain 194.1 mg (yield 86%) of the title compound.

[0289] 1 H NMR (400 MHz, Chloroform-d) δ 9.00 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 4.87 (hept, J = 6.9 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 1.61 (d, J = 6.9 Hz, 6H), 1.39 (t, J = 7.3 Hz, 3H). Step 55-2: Preparation of 6-amino-1-ethyl-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-ethyl-3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 55-1 was used instead of 7-nitroisoquinolin-1(2H)-one, and methanol was used instead of dioxane as a solvent, to obtain 27.4 mg (yield 16%) of the title compound.

[0290] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 4.88 (s, 2H), 4.55 (hept, J = 6.9 Hz, 1H), 3.75 (q, J = 7.2 Hz, 2H), 1.44 (d, J = 6.9 Hz, 6H), 1.17 (t, J = 7.2 Hz, 3H). Step 55-3: Preparation of (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide The reaction was carried out in the same manner as in step 1-3 of Example 1, except that 6-amino-1-ethyl-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 55-2 was used instead of 7-aminoisoquinolin-1(2H)-one, to obtain 5.7 mg (yield 15%) of the title compound.

[0291] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 4.65 (h, J = 7.0 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.49 (d, J = 6.9 Hz, 6H), 1.21 (t, J = 7.0 Hz, 3H). [Example 56] Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonohydrazonoyl dicyanide (compound 56) Under nitrogen, (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (100 mg, 0.39 mmol) prepared in Example 22 was dissolved in dimethylformamide, and potassium tert-butoxide (66 mg, 0.59 mmol) was added at room temperature, followed by iodomethane (122 μL, 1.97 mmol). The reaction mixture was stirred at 60° C. for 4 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 41 mg of the title compound (yield 38%).

[0292] 1 H NMR (400 MHz, DMSO-d 6) δ 7.48 - 7.15 (m, 3H), 4.10 - 3.84 (m, 3H), 3.35 (s, 6H). [Example 57] Preparation of acetyl (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (compound 57) (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (150 mg, 0.59 mmol) and KOH (36 mg, 0.65 mmol) prepared in Example 22 were dissolved in methanol, and then stirred at room temperature for 3 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and solidified using ether. The resulting solid (170 mg, 0.58 mmol) and triethylamine (40 μL, 0.29 mmol) were dissolved in acetonitrile, and then acetyl chloride (103 μL, 1.45 mmol) was added and stirred at room temperature for 4 hours. After the reaction was completed, extraction was performed using distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, then solidified with ether and then filtered. The filtrate was concentrated again under reduced pressure and then solidified with hexane to give 43 mg (yield 25%) of the title compound.

[0293] 1 H NMR (400 MHz, Chloroform-d) δ 7.07 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 8.2, 1.7 Hz, 1H), 6.77 (s, 1H), 3.46 (s, 3H), 3.42 (s, 3H), 2.61 (s, 3H). [Formulation example] Meanwhile, the novel compound represented by the chemical formula (1) according to the present invention can be formulated into various forms according to the purpose. Below, several methods of formulation containing the compound represented by the chemical formula (1) according to the present invention as an active ingredient are exemplified, but the present invention is not limited to these.

[0294] Formulation Example 1: Production of tablets by direct compression 5.0 mg of the active ingredient prepared in Examples 1 to 57 was sieved, then mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate, and compressed to produce a tablet.

[0295] Formulation Example 2: Preparation of tablets by wet granulation 5.0 mg of the active ingredient prepared in Examples 1 to 57 was sieved, then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, and then an appropriate amount of this solution was added to the mixture to form fine particles. After drying, the fine particles were sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and compressed to produce tablets.

[0296] Formulation Example 3: Preparation of powder and capsules 5.0 mg of the active ingredient prepared in Examples 1 to 57 was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled into No. 5 hard gelatin capsules using an appropriate device to prepare capsules.

[0297] Formulation Example 4: Manufacture of injections Contains 100 mg of the active ingredient prepared in Examples 1 to 57, as well as 180 mg of mannitol, Na 2 HPO 4 12H 2 The injection was further prepared containing 26 mg of O and 2,974 mg of distilled water.

[0298] Experimental Example 1: Selection of tau aggregation inhibitors using a cell model In order to select a new tau aggregation inhibitor, a tau-BiFC cell model was used, which allows easy observation of tau oligomer formation in living cells. The tau-BiFC cells were dispensed into a 384-well plate, and the following day, treated with the compounds prepared in Examples 1 to 57 at concentrations of 1, 3, and 10 μM, respectively, together with Forskolin (treatment concentration 30 μM), a compound that activates tau kinase PKA to induce tau aggregation. After 48 hours, the nuclei in the cells were stained with Hoechst (treatment concentration 2 μg / mL), and the BiFC fluorescence intensity was automatically quantified using Operetta (PerkinElmer), and the stained nuclei in each well in all plates were counted. The group treated only with Forskolin, which induces tau aggregation, was set as the standard for 100% tau aggregation, and the effect was confirmed by the formula "BiFC fluorescence intensity by the compound synthesized in the examples of the present invention / (fluorescence intensity of the control group treated only with Forskolin, which induces tau aggregation-fluorescence intensity of the untreated control group) x 100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also calculated by the formula "(number of stained nuclei in the group treated with the compound / number of stained nuclei in the group treated with Forskolin) x 100", with the group treated only with Forskolin set as the standard for 100% viability. From the treatment results, a substance that inhibits intracellular tau aggregation was selected from a series of candidate groups, with 70% or more tau aggregation inhibition and 100% cell viability at a compound treatment concentration of 10 μM as the borderline.

[0299] Experimental Example 2: Confirmation of concentration-dependent tau aggregation inhibitory effect of new compounds To confirm the tau aggregation inhibitory effect at each concentration of the compound selected in Experimental Example 1, Tau-BiFC cells were treated with the selected compound at concentrations of 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM together with Forskolin (treatment concentration 30 μM), a tau aggregation inducer. After 48 hours, the cell images were checked to analyze the degree of tau aggregation reaction and cytotoxicity. The IC of the compound 50The toxicity was analyzed by nonlinear regression analysis using Prism software (GraphPad). The calculation results for representative compounds are shown in Table 2.

[0300] [Table 2]

[0301] JPEG0007641994000022.jpg219169

[0302] JPEG0007641994000023.jpg23169

[0303] Experimental Example 3: Inhibitory effect of new compounds on CYP enzyme activity The inhibitory effect of the compounds prepared in Examples 1 to 57 on the activity of CYP enzymes was confirmed. Specifically, human liver microsomes (0.25 mg / mL), 0.1 M phosphate buffer (pH 7.4), five drug-metabolizing enzyme substrate drug cocktails (phenacetin 50 μM, diclofenac 10 μM, S-mephenytoin 100 μM, dextromethorphan 5 μM, and midazolam 2.5 μM), and compounds were added at concentrations of 0 or 10 μM, and incubated at 37 ° C for 5 minutes in advance, after which an NADPH generation system solution was added and incubated at 37 ° C for another 15 minutes. Thereafter, an acetonitrile solution containing an internal standard (terfenadine) was added to terminate the reaction, and the mixture was centrifuged for 5 minutes (14,000 rpm, 4 ° C), and then the supernatant was injected into an LC-MS / MS system to simultaneously analyze the metabolites of the substrate drugs, thereby evaluating the drug-metabolizing enzyme inhibitory ability.

[0304] The metabolites of each CYP enzyme indicator drug produced by the reaction were analyzed using a Shimadzu Nexera XR system and a TSQ vantage (Thermo). The HPLC column used was Kinetex C18 (2.1 x 100 mm, 2.6 μm, particle size; Phenomenex, USA), and the mobile phase was (A) 0.1% formic acid-containing distilled water and (B) 0.1% formic acid-containing acetonitrile, with the gradient program shown in Table 3.

[0305] [Table 3]

[0306] The metabolites produced were quantified using the MRM (multiple reaction monitoring) quantitative mode, and data analysis was performed using Xcalibur (version 1.6.1). In order to confirm the CYP enzyme activity inhibitory effect of the novel compounds prepared in the examples of the present invention, the activity rate of CYP enzyme in the control group to which no compound was added is shown in Table 4.

[0307] [Table 4]

[0308] JPEG0007641994000026.jpg66169

[0309] Experimental Example 4: Confirmation of liver microsomal stability of new compounds The liver microsome stability of the compounds prepared in Examples 1 to 57 was confirmed. Specifically, four kinds of liver microsomes (human, dog, rat and mouse, 0.5 mg, mL each), 0.1 M phosphate buffer (pH 7.4), and the compound were added at a concentration of 1 μM, and incubated at 37° C. for 5 minutes in advance, after which an NADPH generation system solution was added and incubated at 37° C. for another 30 minutes. Then, an acetonitrile solution containing an internal standard substance (chloropropamide) was added to terminate the reaction, and the mixture was centrifuged (14,000 rpm, 4° C.) for 5 minutes, and the supernatant was then injected into an LC-MS / MS system to analyze the substrate drug, thereby evaluating the metabolic stability of the eight compounds.

[0310] The amount of substrate remaining in the reaction was analyzed using a Shimadzu Nexera XR system and a TSQ vantage (Thermo). The HPLC column used was a Kinetex XB-C18 (2.1×100 mm, 2.6 μm, particle size; Phenomenex, USA), and the mobile phase used was (A) 0.1% formic acid in distilled water, and (B) 0.1% formic acid in acetonitrile. Data analysis was performed using Analyst software (version 1.6.3) and Xcalibur (version 1.6.1). The calculation results are shown in Table 5.

[0311] [Table 5]

[0312] JPEG0007641994000028.jpg50169

[0313] From the above description, a person skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical ideas or essential features. It should be understood that the above examples are merely illustrative and not limiting. The present invention should be interpreted as including all modifications and alterations derived from the meaning and scope of the claims and their equivalent concepts, rather than the specification.

Claims

1. A compound represented by the following chemical formula (2) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 In the above chemical formula (2), Y １ and Y ２ One of them is CH and the other is NR ４ and Binds to CH 【Chemistry 2】 and NR ４ Bind to 【Chemistry 3】 and R ３ is hydrogen or C １－６ is alkyl, R ４ is hydrogen or C １－６ It is an alkyl.

2. A compound represented by the following chemical formula (3) or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 In the above chemical formula (3), X ３ is C(H) or N, R １ is hydrogen, C １－６ Alkyl or C １－６ is an alkylcarbonyl; R ２ is hydrogen, halogen, C １－６ Alkyl or C １－６ is an alkoxy; R ４’ and R ４’’ are each independently hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl-C ０－６ Alkyl or C ６－１０ It is aryl.

3. A compound represented by the following chemical formula (4) or a pharma- ceutically acceptable salt thereof: 【Chemistry 5】 In the chemical formula (4), Y １ is S or O, R ４ is hydrogen, C １－６ Alkyl or C １－６ It is haloalkyl.

4. 2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, In the above chemical formula (2), Y １ and Y ２ One of them is CH and the other is NR ４ and Binds to CH 【Chemistry 6】 and NR ４ Bind to 【Chemistry 7】 and R ３ is hydrogen or methyl; R ４ is hydrogen, methyl or isopropyl, or a pharma- ceutically acceptable salt thereof.

5. 3. A compound according to claim 2 or a pharma- ceutically acceptable salt thereof, In the above chemical formula (3), X ３ is C(H) or N, R １ is hydrogen, methyl or acetyl; R ２ is hydrogen, chloro, fluoro, methyl or methoxy; R ４’ and R ４’’ are each independently hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl, or phenyl, or a pharma- ceutically acceptable salt thereof.

6. 4. The compound of claim 3 or a pharma- ceutically acceptable salt thereof, In the chemical formula (4), Y １ is S or O, R ４ is hydrogen, methyl, isopropyl, or difluoromethyl, or a pharma- ceutically acceptable salt thereof.

7. The compound is 1. (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide 2. (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide 3. (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide 4. (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide 5. (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide 6. (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide 7. (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl) carbonohydrazonoyl dicyanide carbonohydrazonoyl dicyanide), 8. (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide 9. (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 10. (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 11. (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 12. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 13. (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide 14. (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide 15. (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide 16. (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide 17. (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 18. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide 19. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide 3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide), 20. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide 21. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide 22. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 23. (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 24. (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 25. (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide 26. (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide 27. (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide 28. (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide 29. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide 30. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide 31. (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 32. (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 33. (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 34. (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 35. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 36. (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 37. (3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 38. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 39. (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 40. (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 41. (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 42. (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 43. (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide 44. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 45. (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 46. ​​(1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 47. (3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 48. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 49. (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 50. (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 51. (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 52. (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 53. (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 54. (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide dicyanide), 55. (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide 56. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonohydrazonoyl dicyanide, or 57. The compound according to any one of claims 1 to 3, which is acetyl(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, or a pharma- ceutically acceptable salt thereof.

8. A method for producing the compound according to claim 1, comprising a first step of reacting a compound represented by the following chemical formula (5-a), which contains a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid to form an imine bond. 【Chemistry 8】 In the chemical formula (5-a), Y １ Y ２ 、 【Chemistry 9】 and R ３ is as defined in claim 1, Y １ Or Y ２ If is N(H), it is protected with tert-butoxycarbonyl.

9. A first step of forming an imine bond by reacting a compound represented by the following chemical formula (5-b), which contains a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid. Optionally, if R 1 is a substituent other than hydrogen, a second step of introducing the R 1 substituent into the product obtained in the previous step. 【Chemistry 10】 In the chemical formula (5-b), X3, 【Chemistry 11】 R 2 and R 4 are as defined in claim 2.

10. A method for producing the compound described in claim 3, comprising a first step of reacting a compound represented by the following chemical formula (5-c), which contains a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid to form an imine bond. 【Chemistry 12】 In the chemical formula (5-c), Y1, 【Chemistry 13】 and R 4 is as defined in claim 3.

11. Y １ Or Y ２ The method according to claim 8, further comprising the step of deprotecting N(H) of the formula (I) after the reaction if N(H) of the formula (I) is protected with tert-butoxycarbonyl.

12. The first step comprises: C １－４ A first step of dissolving the compound of formula (5-a) and sodium nitrite in a lower alcohol solvent, and adding an acid solution at −5 to 5° C. to form a diazonium salt; A first-2 step of adding malononitrile to the reaction solution containing the diazonium salt obtained in the first-1 step and reacting at 15 to 40° C.; The method according to claim 8, wherein the reaction solution of the first-2 step is neutralized by adding an aqueous base solution to the reaction solution of the first-2 step.

13. The first step comprises: A 1-1 step of dissolving the compound of formula (5-b) and sodium nitrite in a C 1-4 lower alcohol solvent, and adding an acid solution at −5 to 5° C. to form a diazonium salt; A first-2 step of adding malononitrile to the reaction solution containing the diazonium salt obtained in the first-1 step and reacting at 15 to 40° C.; The method according to claim 9, wherein the reaction solution of the first-2 step is neutralized by adding an aqueous base solution to the reaction solution of the first-2 step.

14. The first step comprises: A 1-1 step of dissolving the compound of formula (5-c) and sodium nitrite in a C 1-4 lower alcohol solvent, and adding an acid solution at −5 to 5° C. to form a diazonium salt; A first-2 step of adding malononitrile to the reaction solution containing the diazonium salt obtained in the first-1 step and reacting at 15 to 40° C.; The method according to claim 10, wherein the reaction solution of the first-2 step is neutralized by adding an aqueous base solution to the reaction solution of the first-2 step.

15. The method according to claim 8, further comprising a step of reducing the nitro group of the compound represented by the chemical formula (5-a) to an amino group prior to the first step.

16. The method according to claim 9, further comprising a step of reducing the nitro group of the compound represented by the chemical formula (5-b) to an amino group prior to the first step.

17. The method according to claim 10, further comprising a step of reducing the nitro group of the compound represented by the chemical formula (5-c) to an amino group before the first step.

18. The compound represented by the chemical formula (5-a) is Y １ and Y ２ In the solution phase, a precursor in which one of the two is CH and the other is O is dissolved in an organic solvent, and an amine compound NH ２ R ４ By reacting with O-position to NR ４ 16. The method of claim 15, wherein the compound is prepared by replacing

19. Alternatively, Y of the compound represented by the formula (5-a) may be １ and Y ２ The method according to claim 18, wherein the precursor, in which one of is CH and the other is O, is prepared by a cyclization reaction of a nitrobenzoic acid derivative with N,N-dimethylformamide dimethylacetal or acetylacetone.

20. Alternatively, the compound represented by the formula (5-b) may be R ４ and reacting with a precursor compound containing a reactive halide to form R ４ The method of claim 9 further comprising the step of introducing a substituent.

21. Alternatively, the compound represented by the formula (5-c) may be ４ and reacting with a precursor compound containing a reactive halide to form R ４ The method of claim 10, further comprising the step of introducing a substituent.

22. Alternatively, the compound represented by formula (5-b) may be unsubstituted or R ２ The method of claim 9, wherein the compound is prepared by cyclization of 1,2-diamine nitrophenyl substituted with carbonyldiimidazole (CDI).

23. A composition for inhibiting tau protein aggregation, comprising the compound according to claim 1 as an active ingredient.

24. A composition for inhibiting tau protein hyperphosphorylation, comprising the compound according to claim 1 as an active ingredient.

25. A pharmaceutical composition for preventing or treating a disease induced by aggregation or hyperphosphorylation of tau protein, comprising the compound according to claim 1 as an active ingredient.

26. 26. The pharmaceutical composition of claim 25, wherein the disease induced by aggregation or hyperphosphorylation of tau protein is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma, and tauopathies.

27. The tauopathy includes chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), parkinsonism linked to chromosome 17, and cerebrovascular disease (CED).

27. The pharmaceutical composition of claim 26, wherein the condition is selected from the group consisting of Parkinsonism linked to chromosome 17, Lytico-Bodig disease, Parkinson-dementia complex of Guam, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, posttraumatic stress disorder, and traumatic brain injury.

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